研究者詳細 - 北村　和雄

Age-Dependent Effects of Adrenomedullin on Muscle Fiber Composition, Angiogenesis, and Muscle Satellite Cells Maintenance 査読あり

Ryota Iyama, Eriko Kurogi, Takumi Yokokawa, Kazuo Kitamura, Tatsuya Hayashi, Tatsuro Egawa

Geriatrics & Gerontology International 26 ( 6 ) e70584 2026年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： https://doi.org/10.1111/ggi.70584

Age-Dependent Effects of Adrenomedullin on Muscle Fiber Composition, Angiogenesis, and Muscle Satellite Cells Maintenance. 査読あり

Iyama R, Kurogi E, Yokokawa T, Kitamura K, Hayashi T, Egawa T

Geriatrics & gerontology international 26 ( 6 ) e70584 2026年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1111/ggi.70584

In Vitro and In Vivo Characterization of 40 kDa PEGylated Adrenomedullin in a DSS-Induced Colitis Model 査読あり

Kitamura K., Akashi E., Nagata S., Kita T., Yamasaki M.

International Journal of Molecular Sciences 26 ( 19 ) 9373 2025年10月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Molecular Sciences

Adrenomedullin (AM), a biologically active peptide, induces complete remission with mucosal healing in patients with refractory ulcerative colitis. We have developed 40 kDa PEGylated AM (PEG-AM), a long-acting AM derivative, as a potential therapeutic agent for inflammatory bowel disease (IBD). Both PEG-AM and native AM stimulated cyclic adenosine monophosphate (cAMP) production in HEK-293 cells stably expressing the AM1 receptor (CLR/RAMP2 complex), in a dose-dependent manner. The pEC<inf>50</inf> values for PEG-AM and AM were 7.23 ± 0.05 and 8.42 ± 0.10, respectively. PEG-AM exhibited significantly greater stability in plasma and serum than native AM. We evaluated the in vivo anti-colitis effects of intravenously administered PEG-AM in a dextran sodium sulfate (DSS)-induced murine colitis model. A single intravenous dose of PEG-AM, as low as 25 nmol/kg, demonstrated therapeutic efficacy. Notably, AM receptor expression was not downregulated, despite sustained high plasma concentrations of PEG-AM. Additionally, PEG-AM exerted both therapeutic and preventive effects in a DSS colitis model. These findings suggest that PEG-AM is a promising therapeutic candidate for the treatment of patients with IBD.

DOI： 10.3390/ijms26199373

Adrenomedullin Therapy for Moderate-to-Severe COVID-19 Pneumonia: Double-Blind Placebo-Controlled Phase 2a Trial. 査読あり

Kita T, Ohmagari N, Saito S, Mukae H, Takazono T, Nakada TA, Shimada T, Hirai Y, Shindo Y, Komiya K, Saito A, Yamato M, Homma K, Okamoto M, Yamamoto Y, Mutoh Y, Hasegawa C, Mori N, Nakamura-Uchiyama F, Honda M, Tomii K, Ishii H, Takajo I, Watanabe K, Kitamura K

Viruses 17 ( 7 ) 2025年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.3390/v17070982

Mitral Regurgitation Due to Mitral Valve Prolapse Detected by Cardiac Auscultation during Routine Health Screening: A Case Report and Literature Review

Kawano Sayaka, Onitsuka Hisamitsu, Kitamura Kazuo, Kaikita Koichi

総合健診 advpub ( 0 ) 2025年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本総合健診医学会

Although most cardiovascular abnormalities detected in health screenings are asymptomatic, some of them may indicate clinically significant valvular heart disease. We present a case of mitral regurgitation due to mitral valve prolapse identified through routine cardiac auscultation. A 60-year-old asymptomatic man presented with a newly detected systolic murmur at the apex. Echocardiography confirmed severe mitral regurgitation, and exercise stress echocardiography revealed exercise-induced pulmonary hypertension. Given these clinical findings, surgical intervention was recommended. Based on literature-based considerations, this case highlights a viable role for auscultation in health checkups to identify valvular heart disease and guide treatment.

DOI： 10.7143/jhep.2025-35

Optogenetic stimulation of neurons in the anterior cingulate cortex induces changes in intravesical bladder pressure and the micturition reflex 査読あり

Mochizuki T., Manita S., Shimura H., Kira S., Sawada N., Bito H., Sakimura K., Augustine G.J., Mitsui T., Takeda M., Kitamura K.

Scientific Reports 14 ( 1 ) 2024年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Lower urinary tract (LUT) function is controlled by the central nervous system, including higher-order cognitive brain regions. The anterior cingulate cortex (ACC) is one of these regions, but the role of its activity in LUT function remains poorly understood. In the present study, we conducted optogenetic experiments to manipulate neural activity in mouse ACC while monitoring bladder pressure to elucidate how the activity of ACC regulates LUT function. Selective optogenetic stimulation of excitatory neurons in ACC induced a sharp increase in bladder pressure, whereas activation of inhibitory neurons in ACC prolonged the interval between bladder contractions. Pharmacological manipulation of ACC also altered bladder contractions, consistent with those observed in optogenetic experiments. Optogenetic mapping of the cortical area responsible for eliciting the increase in bladder pressure revealed that stimulation to ACC showed more potent effects than the neighboring motor cortical areas. These results suggest that ACC plays a crucial role in initiating the bladder pressure change and the micturition reflex. Thus, the balance between excitation and inhibition in ACC may regulate the reflex bidirectionally.

DOI： 10.1038/s41598-024-56806-8

Efficacy and safety of adrenomedullin for acute ischemic stroke (AMFIS): a phase 2, randomized, double-blinded, placebo-controlled, clinical trial 査読あり

Yoshimoto T., Saito S., Omae K., Tanaka K., Kita T., Kitamura K., Fukuma K., Washida K., Abe S., Ishiyama H., Yamaguchi E., Yamagami H., Nagatsuka K., Tsuji M., Minami M., Yamamoto H., Hattori Y., Tanaka T., Ihara M.

eClinicalMedicine 77 2024年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：eClinicalMedicine

Background: Adrenomedullin has angiogenic and vasoprotective effects in acute ischemic stroke (AIS). This investigator-initiated trial aimed to evaluate the safety, efficacy, and optimal administration of adrenomedullin in treating AIS. Methods: In this single-center, multi-cohort, double-blinded, randomized, placebo-controlled, Phase II trial, patients with AIS received pulsed adrenomedullin (9 ng/kg/min for 8 h daily over 7 days) or placebo in the first-half cohort, and continuous-pulsed adrenomedullin (9 ng/kg/min for 72 h during the first 3 days and 8 h daily between Day 4–7) or placebo in the second-half cohort. We included male and female patients aged 20–90 years with newly confirmed ischemic lesions on diffusion-weighted magnetic resonance imaging, and for whom protocol treatment could be initiated within 24 h of symptom onset. The primary safety endpoint was the occurrence of intervention-related severe adverse events. For the primary efficacy endpoint, the least square means and 95% confidence intervals of National Institutes of Health Stroke Scale (NIHSS) scores up to 7 days post-intervention initiation were calculated using generalized estimating equation models. This trial was registered at Japan Registry of Clinical Trials, jRCT2051190092. Findings: Between January 16, 2020, and November 14, 2021, 60 patients were enrolled (median [interquartile range] age, 75 [66–81] years; NIHSS score, 3 [2–4]; 21 [35.0%] females). Neither intervention-related serious adverse events nor severe adverse events were observed in patients receiving adrenomedullin. No life-threatening adverse events or deaths were reported. The least square means (95% confidence intervals) of the changes in NIHSS scores from pre-treatment to Day 7 were −0.76 (−1.43 to −0.09) in the adrenomedullin group (−1.08 [−2.17 to 0.00] in the pulsed adrenomedullin group and −0.42 [−1.12 to 0.29] in the continuous-pulsed adrenomedullin group) and −1.08 (−2.11 to −0.05) in the placebo group. Interpretation: Adrenomedullin was well tolerated in patients with non-severe, non-embolic AIS, although its beneficial effects were not demonstrated. It is necessary to show the efficacy of adrenomedullin in further clinical trials. Funding: Japan Agency for Medical Research and Development.

DOI： 10.1016/j.eclinm.2024.102901

Efficacy and safety of adrenomedullin for acute ischemic stroke (AMFIS): a phase 2, randomized, double-blinded, placebo-controlled, clinical trial 査読あり

Takeshi YoshimotoTakeshi Yoshimoto , Satoshi Saito , Katsuhiro Omae , Kenta Tanaka, Toshihiro Kita , Kazuo Kitamura Masafumi Ihara

EClinicalMedicine 13 ( 77 ) 102901 2024年10月

掲載種別：研究論文（学術雑誌）

DOI： 10.1016/j.eclinm.2024.102901

A multicolor suite for deciphering population coding of calcium and cAMP in vivo 査読あり

Yokoyama T., Manita S., Uwamori H., Tajiri M., Imayoshi I., Yagishita S., Murayama M., Kitamura K., Sakamoto M.

Nature Methods 21 ( 5 ) 897 - 907 2024年5月

掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Methods

cAMP is a universal second messenger regulated by various upstream pathways including Ca2+ and G-protein-coupled receptors (GPCRs). To decipher in vivo cAMP dynamics, we rationally designed cAMPinG1, a sensitive genetically encoded green cAMP indicator that outperformed its predecessors in both dynamic range and cAMP affinity. Two-photon cAMPinG1 imaging detected cAMP transients in the somata and dendritic spines of neurons in the mouse visual cortex on the order of tens of seconds. In addition, multicolor imaging with a sensitive red Ca2+ indicator RCaMP3 allowed simultaneous measurement of population patterns in Ca2+ and cAMP in hundreds of neurons. We found Ca2+-related cAMP responses that represented specific information, such as direction selectivity in vision and locomotion, as well as GPCR-related cAMP responses. Overall, our multicolor suite will facilitate analysis of the interaction between the Ca2+, GPCR and cAMP signaling at single-cell resolution both in vitro and in vivo.

DOI： 10.1038/s41592-024-02222-9

A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy 査読あり

Washida K., Saito S., Tanaka T., Nakaoku Y., Ishiyama H., Abe S., Kuroda T., Nakazawa S., Kakuta C., Omae K., Tanaka K., Minami M., Morita Y., Fukuda T., Shindo A., Maki T., Kitamura K., Tomimoto H., Aso T., Ihara M.

Cerebral Circulation - Cognition and Behavior 6 2024年1月

掲載種別：研究論文（学術雑誌）出版者・発行元：Cerebral Circulation - Cognition and Behavior

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit. Objective: The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL. Sample size: Overall, 60 patients will be recruited. Methods: The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180. Study outcomes: The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis. Conclusion: The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition. Clinical Trial Registration: jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117).

DOI： 10.1016/j.cccb.2024.100211

Acyl modifications in bovine, porcine, and equine ghrelins 査読あり

Ida T., Tominaga H., Iwamoto E., Kurogi A., Okura A., Shimada K., Kato J., Kuwano A., Ode H., Nagata S., Kitamura K., Yazawa T., Sato-Hashimoto M., Yasuda M., Miyazato M., Shiimura Y., Sato T., Kojima M.

Frontiers in Endocrinology 15 2024年

掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers in Endocrinology

Ghrelin is a peptide hormone with various important physiological functions. The unique feature of ghrelin is its serine 3 acyl-modification, which is essential for ghrelin activity. The major form of ghrelin is modified with n-octanoic acid (C8:0) by ghrelin O-acyltransferase. Various acyl modifications have been reported in different species. However, the underlying mechanism by which ghrelin is modified with various fatty acids remains to be elucidated. Herein, we report the purification of bovine, porcine, and equine ghrelins. The major active form of bovine ghrelin was a 27-amino acid peptide with an n-octanoyl (C8:0) modification at Ser3. The major active form of porcine and equine ghrelin was a 28-amino acid peptide. However, porcine ghrelin was modified with n-octanol (C8:0), whereas equine ghrelin was modified with n-butanol (C4:0) at Ser3. This study indicates the existence of structural divergence in ghrelin and suggests that it is necessary to measure the minor and major forms of ghrelin to fully understand its physiology.

DOI： 10.3389/fendo.2024.1411483

Adrenomedullin alleviates mucosal injury in experimental colitis and increases claudin-4 expression in the colonic epithelium

A Case of New Electrocardiographic Changes During a Routine Health Checkup Requiring Urgent Cardiologist Consultation 査読あり

KAWANO Sayaka, KITAMURA Kazuo

Health Evaluation and Promotion 51 ( 4 ) 409 - 411 2024年

掲載種別：研究論文（学術雑誌）

DOI： 10.7143/jhep.2024-26

Kawaguchi M., Kataoka H., Kiwaki T., Weiting L., Nagata S., Kitamura K., Fukushima T.

FEBS Open Bio 13 ( 4 ) 713 - 723 2023年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：FEBS Open Bio

Adrenomedullin (AM) is a peptide with pleiotropic physiological functions that attenuates intestinal mucosal inflammation. However, the mechanism underpinning mucosal protection by AM is not fully understood, and its effect on intestinal epithelial cells remains unclear. Here, we investigated the effects of AM on junctional molecules in primary-cultured murine intestinal epithelial cells and discovered that AM upregulates claudin-4 expression. In a mouse model of dextran sulfate sodium-induced colitis, AM administration also enhanced claudin-4 expression and accelerated mucosal regeneration. Furthermore, AM reversed TNFα-mediated downregulation of claudin-4 and loss of cell–cell adhesion of the HCT116 human intestinal epithelial cell line in vitro. These results indicate that AM may enhance intestinal epithelial integrity by upregulating claudin-4 expression.

DOI： 10.1002/2211-5463.13577

WS8-9. 生物学的製剤抵抗性クローン病を対象とした多施設共同二重盲検アドレノメデュリンPhase 2a医師主導治験査読あり

芦塚伸也、北俊弘、北村和雄

日本消化器 120 ( suppl-1 ) A192 - A192 2023年

掲載種別：研究論文（学術雑誌）

追悼　松尾壽之先生査読あり

北村和雄

宮崎大学医学科同窓会発行　篠懸 33 35 - 36 2022年12月

掲載種別：研究論文（学術雑誌）

【消化管から全身を診る!～消化管ホルモンや神経ペプチドは内科治療の中心になる?～】アドレノメデュリンの消化管運動や炎症への役割(解説) 査読あり

芦塚伸也、北村和雄

消化器病学サイエンス 6 ( 3 ) 167 - 172 2022年9月

掲載種別：研究論文（学術雑誌）

消化管ホルモンの最前線~消化管ホルモンから全身を診る~ 査読あり

猿田雅之、坂本昌也、鈴木秀和、北村和雄

消化器病学サイエンス 6 ( 3 ) 133 - 141 2022年9月

掲載種別：研究論文（学術雑誌）

In Vivo Wide-Field and Two-Photon Calcium Imaging from a Mouse using a Large Cranial Window 査読あり

Manita S., Shigetomi E., Bito H., Koizumi S., Kitamura K.

Journal of Visualized Experiments 2022 ( 186 ) 2022年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Visualized Experiments

Wide-field calcium imaging from the mouse's neocortex allows one to observe cortexwide neural activity related to various brain functions. On the other hand, twophoton imaging can resolve the activity of local neural circuits at the single-cell level. It is critical to make a large cranial window to perform multiple-scale analysis using both imaging techniques in the same mouse. To achieve this, one must remove a large section of the skull and cover the exposed cortical surface with transparent materials. Previously, glass skulls and polymer-based cranial windows have been developed for this purpose, but these materials are not easily fabricated. The present protocol describes a simple method for making a large cranial window consisting of commercially available polyvinylidene chloride (PVDC) wrapping film, a transparent silicone plug, and a cover glass. For imaging the dorsal surface of an entire hemisphere, the window size was approximately 6 x 3 mm2. Severe brain vibrations were not observed regardless of such a large window. Importantly, the condition of the brain surface did not deteriorate for more than one month. Wide-field imaging of a mouse expressing a genetically-encoded calcium indicator (GECI), GCaMP6f, specifically in astrocytes, revealed synchronized responses in a few millimeters. Twophoton imaging of the same mouse showed prominent calcium responses in individual astrocytes over several seconds. Furthermore, a thin layer of an adeno-associated virus was applied to the PVDC film and successfully expressed GECI in cortical neurons over the cranial window. This technique is reliable and cost-effective for making a large cranial window and facilitates the investigation of the neural and glial dynamics and their interactions during behavior at the macroscopic and microscopic levels.

DOI： 10.3791/64224

グルタミンは血管平滑筋細胞の凝固活性を抑制する査読あり

小山彰平、山下篤、松浦祐之介、齋藤祐介、前川和也、魏峻洸、北村和雄、海北幸一、浅田祐士郎

日本動脈硬化学会総会プログラム・抄録集 54 237 2022年7月

掲載種別：研究論文（学術雑誌）

A Novel Device of Reaching, Grasping, and Retrieving Task for Head-Fixed Mice 査読あり

Manita S., Ikezoe K., Kitamura K.

Frontiers in Neural Circuits 16 2022年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers in Neural Circuits

Reaching, grasping, and retrieving movements are essential to our daily lives and are common in many mammalian species. To understand the mechanism for controlling this movement at the neural circuit level, it is necessary to observe the activity of individual neurons involved in the movement. For stable electrophysiological or optical recordings of neural activity in a behaving animal, head fixation effectively minimizes motion artifacts. Here, we developed a new device that allows mice to perform reaching, grasping, and retrieving movements during head fixation. In this method, agar cubes were presented as target objects in front of water-restricted mice, and the mice were able to reach, grasp, and retrieve them with their forelimb. The agar cubes were supplied by a custom-made automatic dispenser, which uses a microcontroller to control the two motors to push out the agar cubes. This agar presentation system supplied approximately 20 agar cubes in consecutive trials. We confirmed that each agar cube could be presented to the mouse with an average weight of 55 ± 3 mg and positional accuracy of less than 1 mm. Using this system, we showed that head-fixed mice could perform reaching, grasping, and retrieving tasks after 1 week of training. When the agar cube was placed near the mice, they could grasp it with a high success rate without extensive training. On the other hand, when the agar cube was presented far from the mice, the success rate was initially low and increased with subsequent test sessions. Furthermore, we showed that activity in the primary motor cortex is required for reaching movements in this task. Therefore, our system can be used to study neural circuit mechanisms for the control and learning of reaching, grasping, and retrieving movements under head-fixed conditions.

DOI： 10.3389/fncir.2022.842748

The cytokine expression in patients with cardiac complication after immune checkpoint inhibitor therapy

トロンビン抵抗性アドレノメデュリン誘導体の開発(会議録) 査読あり

永田さやか、矢野弥生、北村和雄

日本内分泌学会雑誌 97 ( 5 ) 1488 - 1488 2022年3月

掲載種別：研究論文（学術雑誌）

血中ナトリウム利尿ペプチド濃度と高血圧発症(会議録) 査読あり

加藤丈司、川越由紀子、姜丹鳳、松﨑美南、井田隆徳、北村和雄

日本内分泌学会雑誌 97 ( 5 ) 1488 - 1488 2022年3月

掲載種別：研究論文（学術雑誌）

Beyond Discovery:日本で発見されたペプチドホルモンとその臨床応用　アドレノメデュリン　基礎研究から臨床研究・医師主導治験へ(会議録) 査読あり

北村和雄

日本内分泌学会雑誌 97 ( 5 ) 1434 - 1434 2022年3月

掲載種別：研究論文（学術雑誌）

アドレノメデュリンのトランスレーショナルリサーチ(会議録) 査読あり

北村和雄

日本内分泌学会雑誌 97 ( 5 ) 1430 - 1430 2022年3月

掲載種別：研究論文（学術雑誌）

アドレノメデュリンの消化管運動や炎症への役割査読あり

芦塚伸也、北村和雄

消化器病学サイエンス 6 ( 3 ) 167 - 173 2022年

掲載種別：研究論文（学術雑誌）

急性期脳梗塞に対するアドレノメデュリンの有効性・安全性の検証 : AMFIS研究査読あり

吉本武史、齊藤聡、大前勝弘、服部頼都、福間一樹、北俊弘、北村和雄、角田良介、丸山博文、山本晴子、猪原匡史

神経治療学 38 ( 6 ) ｓ279 - ｓ279 2021年10月

掲載種別：研究論文（学術雑誌）

CADASIL患者へのアドレノメデュリン投与の安全性・有効性に関する多施設共同単群試験(会議録) 査読あり

鷲田和夫、齊藤聡、田中智美、中奥由里子、大前勝弘、南学、北村和雄、冨本秀和、猪原匡史

Dementia Japan 35 ( 4 ) 635 - 635 2021年10月

掲載種別：研究論文（学術雑誌）

CADASIL患者を対象としたアドレノメデュリン静注療法による安全性および有効性に関する多施設共同単群試験査読あり

鷲田和夫、齊藤聡、田中智美、中奥由里子、大前勝弘、南学、北村和雄、冨本秀和、猪原匡史

神経治療学 38 ( 6 ) ｓ264 - ｓ264 2021年10月

掲載種別：研究論文（学術雑誌）

心臓移植予定患者のヘリ搬送時に携行する医薬品リストの整備と運用体制の構築(原著論文) 査読あり

髙橋沙季、吉川直樹、鶴田敏博、鬼塚久充、横田翼、関屋裕史、平原康寿、北村和雄、池田龍二

日本病院薬剤師会雑誌 57 ( 7 ) 771 - 775 2021年7月

掲載種別：研究論文（学術雑誌）

【血栓・塞栓症のプライマリケア】各疾患の診療　虚血性心疾患(解説) 査読あり

石川哲憲、北村和雄

臨牀と研究 98 ( 7 ) 802 - 808 2021年7月

掲載種別：研究論文（学術雑誌）

Tsuruda T., Yoshikawa N., Kai M., Yamaguchi M., Toida R., Kodama T., Kajihara K., Kawabata T., Nakamura T., Sakata K., Hatakeyama K., Gi T., Asada Y., Tono T., Kitamura K., Ikeda R.

Internal Medicine 60 ( 3 ) 423 - 429 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Internal Medicine

We herein report the cytokine expression at different stages for three patients who developed cardiac complications after immune checkpoint inhibitor (ICI) therapy. Case 1 with biopsy-proven myocarditis showed increased levels of interleukin (IL)-8, monocyte chemotactic and activating factor, and granulocyte macrophage colony-stimulating factor (GM-CSF) when he developed Takotsubo cardiomyopathy. Case 2 with subclinical myocarditis showed predominant activation of IL-8 during the progressive clinical course. Case 3 with cytokine-releasing syndrome showed substantial activations of IL-6, IL-8, GM-CSF, and interferon-γ. Our data suggest the development of unique cytokine activation in individual patients with cardiac complications after ICI therapy.

DOI： 10.2169/INTERNALMEDICINE.5317-20

Nephrotic syndrome and Giant cell arthritis concurrently occurring after percutaneous transluminal angioplasty for renal artery stenosis 査読あり

アドレノメデュリンのトランスレーショナルリサーチ査読あり

北村和雄

日本内分泌学会雑誌 97 ( 5 ) 1430 - 1430 2021年

掲載種別：研究論文（学術雑誌）

アドレノメデュリン : 基礎研究から臨床研究・医師主導治験へ査読あり

北村和雄

日本内分泌学会雑誌 97 ( 5 ) 1434 - 1434 2021年

掲載種別：研究論文（学術雑誌）

血中ナトリウム利尿ペプチド濃度と高血圧発症査読あり

加藤丈司、川越由紀子、姜丹鳳、松﨑美南、井田隆徳、北村和雄

日本内分泌学会雑誌 97 ( 5 ) 1488 - 1488 2021年

掲載種別：研究論文（学術雑誌）

トロンビン抵抗性アドレノメデュリン誘導体の開発査読あり

永田さやか、矢野弥生、北村和雄

日本内分泌学会雑誌 97 ( 5 ) 1488 - 1488 2021年

掲載種別：研究論文（学術雑誌）

アドレノメデュリン誘導体のC3分解促進効果の検討査読あり

永田さやか、川野彩、山﨑基生、北村和雄

日本内分泌学会雑誌 97 ( 1 ) 280 - 280 2021年

掲載種別：研究論文（学術雑誌）

高血圧の成因 Up date　アンジオテンシン関連ペプチドUp date　組織レニン・アンジオテンシン系とビッグアンジオテンシン-25(会議録) 査読あり

永田さやか、北村和雄

日本腎臓学会誌 62 ( 4 ) 230 - 230 2020年7月

掲載種別：研究論文（学術雑誌）

Ishizaki Y., Nishizono R., Sato Y., Ishikawa T., Kitamura K., Fujimoto S.

Clinical Nephrology 93 ( 6 ) 300 - 304 2020年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical Nephrology

An elderly Japanese woman with bilateral renal artery occlusion who developed massive proteinuria after unilateral percutaneous transluminal renal angioplasty (PTRA) is reported. She had a history of percutaneous coronary intervention and subsequently developed refractory hypertension. She was diagnosed with renovascular hypertension caused by bilateral total occlusion of the renal arteries, and underwent PTRA for the left renal artery. Nephrotic-range proteinuria from the left kidney, confirmed by split urine collection from each kidney under cytoscopic examination, and low-grade fever with positive C-reactive protein became obvious after PTRA. Giant cell arteritis (GCA) was also diagnosed by positive findings on fluorodeoxyglucose-positron emission tomography in the common carotid arteries, subclavian arteries, and aorta, but not in the renal arteries. Administration of corticosteroid and angiotensin-converting enzyme inhibitor decreased the proteinuria (> 9 - 2 g/day). Possible mechanisms for the development of nephrotic-range proteinuria and a hypothesis that GCA became obvious after PTRA are discussed.

DOI： 10.5414/CN110000

両側腎動脈狭窄症に対する治療査読あり

菊池正雄、古郷博紀、石﨑友梨、菅井亜希、新屋琴子、麻生久美子、皆川明大、西園隆三、稲垣浩子、石川哲憲、佐藤祐二、北村和雄、藤元昭一

宮崎県医師会医学会誌 44 ( 1 ) 68 - 72 2020年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Developments of human adrenomedullin-IgG1 Fc fusion proteins 査読あり

Nagata S., Yamasaki M., Kawano A., Kitamura K.

Journal of Biochemistry 25 ( 1 ) 157 - 162 2020年1月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biochemistry

Human adrenomedullin (hAM) is a hypotensive peptide hormone that exerts powerful anti-inflammatory effects. However, treatment required continuous administration of hAM, as the half-life of native hAM is quite short in blood. To resolve this problem, we designed two kinds of human IgG1 Fc fusion proteins containing either full-length hAM (IgG1-AM) or hAM residues 6-52 [IgG1-AM (6-52)]. A DNA construct was constructed by connecting DNA sequences encoding hAM and the IgG1 Fc region with a DNA sequence encoding a (GGGGS)<inf>3</inf> linker. The molecular weights of IgG1-AM and IgG1-AM (6-52) were determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and gel filtration chromatography. By protein sequencing, the N-terminal sequence of both recombinant AM-Fc fusions showed the expected human IgG1 sequence. Sufficient concentrations of both AM-Fc fusions were observed in blood 2 days after a single subcutaneous administration. IgG1-AM and IgG1-AM (6-52) stimulated cAMP production in human embryonic kidney-293 cells stably expressing the AM1 receptor. The activity of IgG1-AM (6-52) was higher than that of IgG1-AM. Treatment with IgG1-AM (6-52) inhibited blood pressure increase in spontaneously hypertensive rats. In addition, IgG1-AM (6-52) reduced total inflammation scores in the dextran sulfate sodium colitis model. Therefore, AM-IgG1 Fc fusions represent potential novel therapeutic agents.

DOI： 10.1093/jb/mvz023

Podocyte hypertrophic stress and detachment precedes hyperglycemia or albuminuria in a rat model of obesity and type2 diabetes-associated nephropathy 査読あり

中高齢発症のクローン病患者の臨床像査読あり

野田貴穂、山本章二朗、河上洋、三池忠、貴島翔子、米澤瑛美、市成直樹、坂元一樹、中村佳菜子、鈴木翔、夏田朱一郎、橋本神奈、山路卓巳、安倍弘生、芦塚伸也、田原良博、下田和哉、稲津東彦、北村和雄

日本消化器病学会雑誌 117 ( suppl-1 ) A279 - A279 2020年

掲載種別：研究論文（学術雑誌）

アドレノメデュリン査読あり

北村和雄

日本臨牀 78 ( 1 ) 335 - 342 2020年

掲載種別：研究論文（学術雑誌）

Association between body mass index (BMI) variability and plasma adrenomedullin (AM) in the general population 査読あり

加藤丈司、川越由紀子、姜丹鳳、北村和雄

Folia Endocrinologica Japonica 96 ( 4 ) 1123 - 1123 2020年

掲載種別：研究論文（学術雑誌）

ヒトIgGのFc領域を融合したアドレノメデュリン誘導体の開発査読あり

永田さやか、山﨑基生、北村和雄

日本内分泌学会雑誌 96 ( 1 ) 298 - 298 2020年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンによるIBD治療査読あり

芦塚伸也、稲津東彦、北俊弘、北村和雄

IBD Research 14 ( 3 ) 183 - 191 2020年

掲載種別：研究論文（学術雑誌）

Minakawa A., Fukuda A., Sato Y., Kikuchi M., Kitamura K., Wiggins R.C., Fujimoto S.

Scientific Reports 9 ( 1 ) 18485 2019年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Type2 diabetes-associated nephropathy is the commonest cause of renal failure. Mechanisms responsible are controversial. Leptin-deficient hyperphagic Zucker (fa/fa) rats were modeled to test the hypothesis that glomerular enlargement drives podocyte hypertrophic stress leading to accelerated podocyte detachment, podocyte depletion, albuminuria and progression. By 6weeks, prior to development of either hyperglycemia or albuminuria, fa/fa rats were hyperinsulinemic with high urinary IGF1/2 excretion, gaining weight rapidly, and had 1.6-fold greater glomerular volume than controls (P < 0.01). At this time the podocyte number per glomerulus was not yet reduced although podocytes were already hypertrophically stressed as shown by high podocyte phosphor-ribosomal S6 (a marker of mTORC1 activation), high urinary pellet podocin:nephrin mRNA ratio and accelerated podocyte detachment (high urinary pellet podocin:aquaporin2 mRNA ratio). Subsequently, fa/fa rats became both hyperglycemic and albuminuric. 24 hr urine albumin excretion correlated highly with decreasing podocyte density (R2 = 0.86), as a consequence of both increasing glomerular volume (R2 = 0.70) and decreasing podocyte number (R2 = 0.63). Glomerular podocyte loss rate was quantitatively related to podocyte detachment rate measured by urine pellet mRNAs. Glomerulosclerosis occurred when podocyte density reached <50/106um3. Reducing food intake by 40% to slow growth reduced podocyte hypertrophic stress and “froze” all elements of the progression process in place, but had small effect on hyperglycemia. Glomerular enlargement caused by high growth factor milieu starting in pre-diabetic kidneys appears to be a primary driver of albuminuria in fa/fa rats and thereby an under-recognized target for progression prevention. Progression risk could be identified prior to onset of hyperglycemia or albuminuria, and monitored non-invasively by urinary pellet podocyte mRNA markers.

DOI： 10.1038/s41598-019-54692-z

Polyethylene glycol-conjugated human adrenomedullin as a possible treatment for vascular dementia 査読あり

Nagata S., Yamasaki M., Kitamura K.

Peptides 121 170133 2019年11月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Peptides

Adrenomedullin (AM) is a multifunctional bioactive peptide. Recent studies have shown that AM has protective effects against ischemic brain damage. We recently prepared a long-acting human AM derivative that was conjugated with a 60 kDa polyethylene glycol (PEG-AM), which had an effect similar to that of native AM. In this study, we examined the effect of PEG-AM on four-vessel occlusion model rats, which exhibit vascular dementia. From day 10 to day 14 after surgery, the learning and memory abilities of the rats were examined using a Morris water maze. The rats were treated with a single subcutaneous injection of 1.0 or 10.0 nmol/kg of PEG-AM. PEG-AM treatment reduced the escape latency in the hidden platform test. Furthermore, the treatment increased the time spent in the platform quadrant in the probe test. The data showed that PEG-AM injection prevented memory loss and learning disorders in dose-dependent manner. On day 14, the immunoreactive AM concentration in plasma was 9.749 ± 2.167 pM in the high-dose group (10.0 nmol/kg) and 0.334 ± 0.073 pM in the low-dose group (1.0 nmol/kg). However, even in the low-dose group, a significant effect was observed in both tests. The present data indicate that PEG-AM is a possible therapeutic agent for the treatment of ischemic brain injury or vascular dementia.

DOI： 10.1016/j.peptides.2019.170133

Blockade of the angiotensin II type 1 receptor increases bone mineral density and left ventricular contractility in a mouse model of juvenile Paget disease 査読あり

Tsuruda T., Funamoto T., Udagawa N., Kurogi S., Nakamichi Y., Koide M., Chosa E., Asada Y., Kitamura K.

European Journal of Pharmacology 859 172519 2019年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Pharmacology

Juvenile Paget disease (JPD1), an autosomal-recessive disorder, is characterized by extremely rapid bone turnover due to osteoprotegerin deficiency. Its extra-skeletal manifestations, such as hypertension and heart failure, suggest a pathogenesis with shared skeletal and cardiovascular system components. In spite of this, the effects of anti-hypertensive drugs on bone morphometry remain unknown. We administered an angiotensin II type 1 receptor blocker, olmesartan (5 mg/kg/day) to 8-week-old male mice lacking the osteoprotegerin gene, with and without 1 μg/kg/min of angiotensin II infusion for 14 days. Olmesartan treatment decreased systolic blood pressure, and echocardiography showed increased left ventricular systolic contractility. Three-dimensional micro-computed tomography scans demonstrated that olmesartan treatment increased trabecular bone volume (sham, +176%; angiotensin II infusion, +335%), mineral density (sham, +150%; angiotensin II infusion, +313%), and trabecular number (sham, +407%; angiotensin II infusion, +622%) in the tibia. Olmesartan increased cortical mineral density (sham, +19%; angiotensin II infusion, +24%), decreased the cortical bone section area (sham, −16%; angiotensin II infusion, −18%), decreased thickness (sham, −18%; angiotensin II infusion, −31%), and decreased the lacunar area (sham, −41%; angiotensin II infusion, −27%) in the tibia. Similar trend was observed in the femur. Moreover, olmesartan decreased angiotensin II-induced increases in tartrate-resistant acid phosphatase concentrations in plasma, but it affected neither type I procollagen N-terminal propeptides, nor the receptor activator of nuclear factor kappa-B ligand. Our data suggest that blockade of the angiotensin II type 1 receptor improves bone vulnerability, and helps to maintain the heart's structural integrity in osteoprotegerin-deficient mice.

DOI： 10.1016/j.ejphar.2019.172519

Non-canonical Expression of Cardiac Troponin-T in Neuroendocrine Ethmoid Sinus Carcinoma Following Immune Checkpoint Blockade 査読あり

Tsuruda T., Sato Y., Kajihara K., Kawabata T., Kubuki Y., Komaki S., Kikuchi M., Ishikawa T., Tono T., Kitamura K.

Frontiers in Cardiovascular Medicine 6 2019年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers in Cardiovascular Medicine

We describe the case of a patient with neuroendocrine ethmoid sinus carcinoma, who exhibited markedly elevated levels of serum cardiac troponin-T and creatine kinase (CK)-MB isoenzyme without any symptom after the administration of nivolumab, immune checkpoint inhibitor. The repeated 12-leads-electrocardiogram did not show any changes in the ST-T segments or arrhythmias. The echocardiogram showed normal ranges of left ventricular contraction in the clinical course. Cardiac magnetic resonance imaging showed minimal myocardial edema and inflammation. Blood clots in the metastatic lesion of bone marrow aspirates exhibited positive staining for cardiac troponin-T and CK-MB in the cytoplasm and nucleoplasm of neoplastic cells. Although we did not perform a second cardiac magnetic resonance imaging and autopsy, we postulate that the attack of the neoplastic cells by the immune checkpoint inhibitor or the secretion from neoplastic cell-derived extracellular vesicles may have exacerbated the increase in concentrations of these molecules in the blood. Our case should warrant consideration a false-positive value of cardiac troponin-T and CK-MB can be obtained in cases with malignancy.

DOI： 10.3389/fcvm.2019.00124

血圧変動性と動脈硬化度および動脈リモデリング査読あり

北　俊弘、北村和雄

血圧 26 ( 4 ) 202 - 203 2019年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）

コントロールの難しい高血圧患者の修正可能な因子査読あり

北　俊弘、北村和雄

血圧 26 ( 8 ) 442 - 443 2019年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Efficient screening of patients with aldosterone-producing adenoma using the ACTH stimulation test 査読あり

Kita T., Furukoji E., Sakae T., Kitamura K.

Hypertension Research 42 ( 6 ) 801 - 806 2019年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

Adrenal venous sampling (AVS) is the gold standard test for distinguishing between unilateral and bilateral primary aldosteronism (PA); however, AVS requires advanced and time consuming technique. The needs for AVS have been increasing due to the increased utilization of screening for PA. An efficient selection of unilateral PA, such as aldosterone-producing adenoma (APA), before AVS is useful to avoid undesirable AVS in bilateral PA, such as idiopathic hyperaldosteronism. In this study, 40 patients who received all three confirmatory tests, including the captopril challenge test, furosemide upright test and adrenocorticotropin (ACTH) stimulation test (AST), and who were diagnosed as having PA by AVS were recruited. Subjects were diagnosed as having unilateral aldosterone excess (n = 22) or bilateral aldosterone excess (n = 18) by AVS. All patients with unilateral PA underwent an operation and were finally diagnosed with APA. Major differences were detected in serum potassium level, basal plasma aldosterone concentration (PAC), presence of adrenal tumor, and AST results between the two groups. The PAC/cortisol ratio at 120 min in the AST showed the highest diagnostic capability for distinguishing the subtypes of PA according to a receiver operating characteristic (ROC) curve analysis (area under the ROC curve was 0.956). At a cutoff value of 1.20 for the PAC/cortisol ratio at 120 min on the AST, the sensitivity was 95.5%, and the specificity was 88.9%. This sufficiently high sensitivity suggests that the PAC/cortisol ratio at 120 min in the AST could be useful for the screening of patients with PA who are suitable for AVS.

DOI： 10.1038/s41440-018-0191-5

Pre-and Postdialysis Uric Acid Difference and Risk of Long-Term All-Cause and Cardiovascular Mortalities in Japanese Hemodialysis Patients; Miyazaki Dialysis Cohort Study 査読あり

【高血圧診療の新展開】降圧薬選択の基本と併用療法査読あり

北　俊弘、北村和雄

循環器内科 85 ( 6 ) 773 - 778 2019年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Toida T., Sato Y., Komatsu H., Kitamura K., Fujimoto S.

Blood Purification 47 ( Suppl2 ) 50 - 55 2019年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Blood Purification

Background/Aims: Uric acid (UA) levels are affected by changes in dialysis; however, the relationship between the pre-and postdialysis UA difference (UAD) and mortality remains unclear. Methods: A total of 1,073 patients receiving maintenance hemodialysis (HD) were enrolled in this cohort study and followed up for 5 years. Patients were divided into quartile categories according to baseline UAD. Coxs regression analyses were used to investigate the relationship between UAD categories and all-cause and cardiovascular (CV) mortalities while adjusting for potential confounders. Results: A total of 280 patients died of all causes, including 121 CV deaths, during the follow-up. In the analysis for all-cause mortality, hazard ratios were significantly higher in the lowest UAD group (< 4.7 mg/dL) than in the highest UAD group (> 6.2 mg/dL). A correlation was not observed with CV mortality. Conclusion: UAD correlated with all-cause mortality. UAD may be the most appropriate reference for controlling UA in HD patients.

DOI： 10.1159/000496638

Grading of left ventricular diastolic dysfunction with preserved systolic function by the 2016 American Society of Echocardiography/European Association of cardiovascular imaging recommendations contributes to predicting cardiovascular events in hemodialysis patients 査読あり

尿中ビッグアンジオテンシン-25の測定系の確立と測定意義の解明査読あり

永田さやか、北村和雄

日本内分泌学会雑誌 95 ( 1 ) 377 - 377 2019年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Toida T., Toida R., Yamashita R., Komiya N., Uezono S., Komatsu H., Ishikawa T., Kitamura K., Sato Y., Fujimoto S.

CardioRenal Medicine 9 ( 3 ) 190 - 200 2019年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：CardioRenal Medicine

Background: Left ventricular diastolic dysfunction (LVDD) causes heart failure with a preserved left ventricular ejection fraction (LVEF) in the general population. Objective: To examine the relationships between the LVDD grades of the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) recommendations and several arteriosclerotic parameters and major cardiovascular events (MACE) in hemodialysis patients with preserved LVEF. Method: Sixty-three prevalent hemodialysis patients (median age [interquartile range], 69 [64-75] years, 31.7% female) with normal systolic function (LVEF > 50%) were enrolled. LVDD evaluated by echocardiography at baseline was divided into three groups according to ASE/EACVI recommendations (normal diastolic function [ND], n = 24; intermediate, n = 19; diastolic dysfunction [DD], n = 20). All patients underwent analyses of several arteriosclerotic parameters (carotid intima-media thickness [CIMT], plaque score [PS], ankle brachial index [ABI], and brachial-ankle pulse wave velocity [baPWV]). The presence or absence of postdialysis orthostatic hypotension was assessed in each dialysis session. MACE during the 1-year follow-up period was obtained from medical records. Kaplan-Meier and Cox's regression analyses were used to investigate the relationship between LVDD grades and MACE. Results: Postdialysis orthostatic hypotension and PS, but not CIMT, ABI, or baPWV, increased proportionally with LVDD grades. Eleven patients developed MACE, including 2 cardiovascular deaths. The Kaplan-Meier analysis showed that MACE frequently occurred in the DD grade (p = 0.002 by the log-rank test). Cox's regression analysis adjusted for potential confounders (age, sex, diabetes, systolic blood pressure, and body mass index) revealed that the DD grade was associated with MACE when the ND grade was set as a reference. Conclusions: In maintenance hemodialysis patients with normal ventricular systolic function, a classification of LVDD by the 2016 ASE/EACVI recommendations may be a useful tool for predicting cardiovascular events.

DOI： 10.1159/000496064

Impact of short-acting loop diuretic doses and cardiac sympathetic nerve abnormalities on outcomes of patients with reduced left ventricular function 査読あり

Onitsuka H., Koyama S., Ideguchi T., Ishikawa T., Kitamura K., Nagamachi S.

Medicine (United States) 98 ( 8 ) 2019年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Medicine (United States)

Recent studies reported that high doses of short-acting loop diuretics are associated with poor outcomes in patients with heart failure (HF). Short-acting loop diuretics have been shown to activate the renin-angiotensin system (RAS) and have no favorable effects on cardiac sympathetic nervous system (SNS) activity. The goal of this study is to investigate the relationship between daily doses of furosemide and the outcomes of patients with left ventricular dysfunction (LVD) from the viewpoint of cardiac SNS abnormalities using iodine-123-labeled metaiodobenzylguanidine (123l-MIBG) myocardial scintigraphy. We enrolled 137 hospitalized patients (62.5±14.2 years old, 103 men) with LVEF < 45% who underwent 123l-MIBG myocardial scintigraphy. A delayed heart-to-mediastinum ratio (delayed HMR) was assessed using 123l-MIBG scintigraphy. Cardiac events were defined as cardiac death or re-hospitalization due to the deterioration of HF. Cox proportional hazard analysis was used to identify predictors of cardiac events. Cardiac events occurred in 57 patients in a follow-up period of 33.1±30 months. In a multivariate Cox proportional hazard analysis, delayed HMR and furosemide doses were identified as independent predictors of cardiac events (P=.0042, P=.033, respectively). Inverse probability of treatment weighting Cox modeling showed that the use of furosemide (≥40mg /day) was associated with cardiac events with a hazard ratio of 1.96 (P=.003). In the Kaplan-Mayer analysis, the cardiac event-free survival rate was significantly lower in patients treated with high doses of furosemide (≥60mg/day vs 40-60mg/day vs <40mg/day, the Log-rank test P<.0001). In a receiver-operating characteristic (ROC) analysis, the cut-off value for cardiac events was 40mg/day of furosemide. The cardiac event-free rate was significantly lower in patients with delayed HMR <1.8 (median value) and receiving furosemide ≥40mg/day than in other patients (the Log-rank test P<.0001). Significant differences in cardiac event rates according to furosemide doses among patients with delayed HMR <1.8 were observed among patients without b-blocker therapy (P=.001), but not among those with b-blocker therapy (P=.127). The present results indicate that a relationship exists between higher doses of furosemide and poor outcomes. The prognosis of HF patients with severe cardiac SNS abnormalities receiving high-dose short-acting loop diuretics is poor.

DOI： 10.1097/MD.0000000000014657

Subcutaneously administered adrenomedullin exerts a potent therapeutic effect in a murine model of ulcerative colitis 査読あり

Kinoshita Y., Arita S., Murazoe H., Kitamura K., Ashizuka S., Inagaki-Ohara K.

Human Cell 32 ( 1 ) 12 - 21 2019年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Human Cell

Adrenomedullin (AM) exerts a potent anti-inflammatory effect. Intrarectal or consecutive intravenous administrations of AM reduce pathological manifestations in rodent colitis models. However, in clinical applications, a safer administration route that provides stronger alleviation of patient burden is preferred. We investigated whether subcutaneously administered AM is effective against dextran sulfate sodium (DSS)-induced colitis. C57BL/6J mice were administered 1% DSS in drinking water and received AM at 8, 40 or 80 nmol/kg subcutaneously once a day for 7 consecutive days. Subcutaneously administered AM significantly and dose-dependently ameliorated body weight loss, diarrhea, and histological severity of colonic inflammation in DSS-treated mice. The AM therapeutic effect was associated with the upregulation of the production of autocrine AM, and expression of cAMP, c-fos, KLF4, and downregulation of STAT3 and NF-κB p65 phosphorylation, as well as a decrease in proinflammatory cytokine expression in the colon. Subcutaneous AM treatment potently attenuated DSS-induced colitis, which suggests that AM administered subcutaneously in ulcerative colitis (UC) patients may decrease diseases burden and improve quality of life.

DOI： 10.1007/s13577-018-0219-9

Adrenomedullin: Continuing to explore cardioprotection 査読あり

Tsuruda T., Kato J., Kuwasako K., Kitamura K.

Peptides 111 47 - 54 2019年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Peptides

Adrenomedullin (AM), a peptide isolated from an extract of human pheochromocytoma, comprises 52 amino acids with an intramolecular disulfide bond and amidation at the carboxy-terminus. AM is present in various tissues and organs in rodents and humans, including the heart. The peptide concentration increases with cardiac hypertrophy, acute myocardial infarction, and overt heart failure in the plasma and the myocardium. The principal function of AM in the cardiovascular system is the regulation of the vascular tone by vasodilation and natriuresis via cyclic adenosine monophosphate-dependent or −independent mechanism. In addition, AM may possess unique properties that inhibit aldosterone secretion, oxidative stress, apoptosis, and stimulation of angiogenesis, resulting in the protection of the structure and function of the heart. The AM receptor comprises a complex between calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP) 2 or 3, and the AM-CLR/RAMP2 system is essential for heart development during embryogenesis. Small-scale clinical trials have proven the efficacy and safety of recombinant AM peptide therapy for heart failure. Gene delivery and a modified AM peptide that prolongs the half-life of the native peptide could be an innovative method to improve the efficacy and benefit of AM in clinical settings. In this review, we focus on the pathophysiological roles of AM and its receptor system in the heart and describe the advances in AM and proAM-derived peptides as diagnostic biomarkers as well as the therapeutic application of AM and modified AM for cardioprotection.

DOI： 10.1016/j.peptides.2018.03.012

Adrenomedullin: A novel therapy for intractable Crohn’s disease with a loss of response to infliximab 査読あり

Ashizuka S., Kuroishi N., Nakashima K., Inatsu H., Kita T., Kitamura K.

Internal Medicine 58 ( 11 ) 1573 - 1576 2019年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Internal Medicine

A 35-year-old man with refractory Crohn’s disease showed a loss of response to infliximab after requiring treatment with infliximab at 10 mg/kg together with steroid to maintain remission. His symptoms recurred, and colonoscopy showed extensive active ulcers in the colon. Adrenomedullin therapy was started in addition to the conventional infliximab therapy. A few days after, his symptoms went into remission. Endoscopy at 2 and 7 weeks revealed significant mucosal remission without steroid therapy. Adrenomedullin promoted mucosal healing and led to the re-induction of remission in Crohn’s disease in a patient with a loss of response to infliximab.

DOI： 10.2169/internalmedicine.1791-18

Indoleamine 2,3-dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages 査読あり

炎症性腸疾患における新規バイオマーカーとしての血中アドレノメデュリン濃度の検討査読あり

芦塚伸也、河上洋、北村和雄

日本消化器病学会雑誌 116 ( suppl-2 ) A688 - A688 2019年

掲載種別：研究論文（学術雑誌）

ペプチドホルモンの臨床展開査読あり

永田さやか、山﨑基生、北村和雄

日本プロテオーム学会大会要旨集 0 152 - 152 2019年

掲載種別：研究論文（学術雑誌）

長期的ノルアドレナリン持続投与は血圧日内変動を増大させる査読あり

姜丹鳳、川越由紀子、北村和雄、加藤丈司

日本内分泌学会雑誌 95 ( 4 ) 1599 - 1599 2019年

掲載種別：研究論文（学術雑誌）

高齢発症で長期経過を追えている潰瘍性大腸炎の1例査読あり

野田貴穂、山本章二朗、三池忠、米澤瑛美、市成直樹、坂元一樹、中村佳菜子、鈴木翔、坂口舞、夏田朱一郎、橋本神奈、安倍弘生、田原良博、下田和哉、稲津東彦、北村和雄、河上洋

日本消化器病学会九州支部例会プログラム・抄録集 114 106 - 106 2019年

掲載種別：研究論文（学術雑誌）

重症筋無力症に対する内視鏡的粘膜下層剥離術の一例経験査読あり

樽原亮、篠原実成、押川一達、米澤玲美、黒石頌子、三宮一朗、松本英丈、中島孝治、芦塚伸也、稲津東彦、北村和雄、河上洋

日本消化器病学会九州支部例会プログラム・抄録集 113 184 - 184 2019年

掲載種別：研究論文（学術雑誌）

範囲診断に難渋した胃癌の一例査読あり

篠原実成、米澤玲美、押川一達、松本英丈、中島孝治、芦塚伸也、稲津東彦、北村和雄、木脇拓道、河上洋

日本消化器病学会九州支部例会プログラム・抄録集 114 133 - 133 2019年

掲載種別：研究論文（学術雑誌）

難治性潰瘍性大腸炎に対するゴリムマブの治療状況査読あり

坂元一樹、山本章二朗、稲津東彦、芦塚伸也、小村杏奈、米澤瑛美、中村佳菜子、野田貴穂、鈴木翔、夏田朱一郎、安倍弘生、三池忠、田原良博、久保田良政、坂哲臣、下田和哉、北村和雄、河上洋

日本消化器病学会九州支部例会プログラム・抄録集 114 90 - 90 2019年

掲載種別：研究論文（学術雑誌）

インフリキシマブ誘発性ループスを発症した潰瘍性大腸炎の1例査読あり

宮後冴、芦塚伸也、山嶋友実、米澤玲美、黒木大介、松本英丈、中島孝治、稲津東彦、北村和雄、河上洋

日本消化器病学会九州支部例会プログラム・抄録集 114 106 - 106 2019年

掲載種別：研究論文（学術雑誌）

潰瘍性大腸炎に合併した重症蛋白漏出胃症の一例査読あり

吉田直樹、篠原実成、押川一達、山嶋友実、宮後冴、米澤玲美、黒石頌子、三宮一朗、三木吾郎、増田稔、星子新理、松本英丈、中島孝治、小村浩史、芦塚伸也、稲津東彦、北村和雄、河上洋

日本消化器病学会九州支部例会プログラム・抄録集 113 191 - 191 2019年

掲載種別：研究論文（学術雑誌）

ヒトIgGのFc領域融合アドレノメデュリン誘導体の開発査読あり

永田さやか、山﨑基生、北村和雄

日本内分泌学会雑誌 95 ( 4 ) 1607 - 1607 2019年

掲載種別：研究論文（学術雑誌）

【心不全(第2版)上-最新の基礎・臨床研究の進歩-】心不全の基礎研究　心不全の分子機序　神経体液性因子　アドレノメデュリン査読あり

鶴田敏博、北村和雄

日本臨牀 76 ( 9 ) 136 - 143 2018年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）

新規アンジオテンシンペプチドとは：ビッグアンジオテンシン-25と組織レニン・アンジオテンシン系査読あり

永田さやか，北村和雄

循環器内科 84 ( 4 ) 366 - 373 2018年10月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Watanabe Y., Koyama S., Yamashita A., Matsuura Y., Nishihira K., Kitamura K., Asada Y.

Research and Practice in Thrombosis and Haemostasis 2 ( 4 ) 726 - 735 2018年10月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Research and Practice in Thrombosis and Haemostasis

Background: Recent clinical studies have found that changes in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism are associated with cardiovascular events. However, the roles of the Kyn pathway on vascular wall thrombogenicity remain unknown. Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme of the Kyn pathway. Objective: The present study aimed to localize IDO1 in human coronary atherosclerotic plaques from patients with angina pectoris and define its role in plaque thrombogenicity. Methods: Immunohistochemical methods were applied to localize IDO1 in coronary atherosclerotic plaques from patients with stable (SAP) and unstable (UAP) angina pectoris. The role of IDO1 in tissue factor (TF) expression was investigated in THP-1 macrophages activated by interferon (IFN)γ and tissue necrosis factor (TNF)α. Results: We localized IDO1 mainly in CD68-positive macrophages within atherosclerotic plaques, and in close association with TF. Areas that were immunopositive for IDO1, TF, and CD3-positive T lymphocytes were significantly larger in plaques from patients with UAP than SAP. Macrophages activated by IFNγ and TNFα upregulated IDO1 expression, increased the Kyn/Trp ratio and enhanced TF expression and activity, but not TF pathway inhibitor expression. The IDO1 inhibitor epacadostat significantly reduced the Kyn/Trp ratio, TF expression and activity, as well as NF-κB (p65) binding activity in activated macrophages. Inhibition of the aryl hydrocarbon receptor that binds to Kyn, also reduced Kyn-induced TF expression in activated macrophages. Conclusion: Indoleamine 2,3-dioxygenase 1 expressed in coronary atherosclerotic plaques might contribute to thrombus formation through TF upregulation in activated macrophages.

DOI： 10.1002/rth2.12128

Interaction between cardiac myosin-binding protein C and formin Fhod3. 査読あり

Matsuyama S., Kage Y., Fujimoto N., Ushijima T., Tsuruda T., Kitamura K., Shiose A., Asada Y., Sumimoto H., Takeya R.

Proceedings of the National Academy of Sciences of the United States of America 115 ( 19 ) E4386 - E4395 2018年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1073/pnas.1716498115

クローン病診療におけるインフリキシマブ血中濃度と抗TNF抗体測定意義に関する検討査読あり

芦塚伸也、三宮一朗、久保田良政、中島孝治、三池忠、安部弥生、坂哲臣、田原良博、山本章二朗、稲津東彦、河上洋、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 112 88 - 88 2018年

掲載種別：研究論文（学術雑誌）

アンジオテンシンII (Ang II) 持続投与による血圧変動性増大に対する長時間作用型ジヒドロピリジン系カルシウム拮抗薬 (CCB) と利尿薬の効果の比較査読あり

日本内分泌学会雑誌

日本内分泌学会雑誌 94 ( 4 ) 1566 - 1566 2018年

掲載種別：研究論文（学術雑誌）

アドレノメデュリン投与が著効したインフリキシマブ治療抵抗性クローン病の一例査読あり

北俊弘、芦塚伸也、北村和雄

日本内分泌学会雑誌 94 ( 4 ) 1560 - 1560 2018年

掲載種別：研究論文（学術雑誌）

クローン病に合併した全身性エリテマトーデスの1例査読あり

福永幹、三宮一朗、篠原実成、山嶋友実、押川一達、米澤玲美、黒石頌子、仮屋暢人、松本英丈、中島孝治、芦塚伸也、稲津東彦、河上洋、北村和雄、落合祥子、皆川明大、佐藤勇一郎

日本消化器病学会九州支部例会プログラム・抄録集 111 168 - 168 2018年

掲載種別：研究論文（学術雑誌）

胃全摘術後の盲係蹄症候群に対し保存的加療と外科的治療により改善を得た一例査読あり

内山尚美、篠原実成、押川一達、山嶋友実、米澤玲美、黒石頌子、三宮一朗、松本英丈、中島孝治、芦塚伸也、稲津東彦、河上洋、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 112 149 - 149 2018年

掲載種別：研究論文（学術雑誌）

高脂餌食下での糖代謝経路阻害による生理機能への影響査読あり

鶴田敏博、ハオイーリン、北村和雄

日本内分泌学会雑誌 94 ( 4 ) 1566 - 1566 2018年

掲載種別：研究論文（学術雑誌）

内視鏡的切除を施行した十二指腸嵌頓胃粘膜下腫瘍様病変 (Inflammatory fibroid polyp疑診) の一例査読あり

小川宗一郎、米澤玲美、篠原実成、押川一達、山嶋友実、仮屋暢人、三宮一朗、松本英丈、中島孝治、芦塚伸也、稲津東彦、北村和雄、前川和也、後藤清香、河上洋

日本消化器病学会九州支部例会プログラム・抄録集 111 167 - 167 2018年

掲載種別：研究論文（学術雑誌）

虚血性心疾患診断における冠動脈領域別の位相解析指標の有用性の検討. 査読あり

寺田珠沙、長町茂樹、鬼塚久充、水谷陽一、平井俊範、北村和雄

臨床放射線 63 ( 2 ) 185 - 90 2018年

掲載種別：研究論文（学術雑誌）

周術期バイオマーカーとしてのアドレノメデュリン査読あり

丸田豊明、太田尾剛、与那覇哲、北村和雄、恒吉勇男

循環制御 39 ( 3 ) 169 - 171 2018年

掲載種別：研究論文（学術雑誌）

学習・記憶障害に対する持続性アドレノメデュリン誘導体の効果査読あり

永田さやか、山崎基生、北村和雄

日本内分泌学会雑誌 94 ( 1 ) 340 - 340 2018年

掲載種別：研究論文（学術雑誌）

Maturation of Cerebellar Purkinje Cell Population Activity during Postnatal Refinement of Climbing Fiber Network 査読あり

Good J.M., Mahoney M., Miyazaki T., Tanaka K.F., Sakimura K., Watanabe M., Kitamura K., Kano M.

Cell Reports 21 ( 8 ) 2066 - 2073 2017年11月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Cell Reports

Neural circuits undergo massive refinements during postnatal development. In the developing cerebellum, the climbing fiber (CF) to Purkinje cell (PC) network is drastically reshaped by eliminating early-formed redundant CF to PC synapses. To investigate the impact of CF network refinement on PC population activity during postnatal development, we monitored spontaneous CF responses in neighboring PCs and the activity of populations of nearby CF terminals using in vivo two-photon calcium imaging. Population activity is highly synchronized in newborn mice, and the degree of synchrony gradually declines during the first postnatal week in PCs and, to a lesser extent, in CF terminals. Knockout mice lacking P/Q-type voltage-gated calcium channel or glutamate receptor δ2, in which CF network refinement is severely impaired, exhibit an abnormally high level of synchrony in PC population activity. These results suggest that CF network refinement is a structural basis for developmental desynchronization and maturation of PC population activity. In the cerebellum, the climbing fiber to Purkinje cell network is extensively remodeled during postnatal development. Good et al. show that in vivo population activity of Purkinje cells in response to climbing fiber synaptic inputs is highly synchronized in newborn mice and massively desynchronized due to climbing fiber network refinement.

DOI： 10.1016/j.celrep.2017.10.101

Urinary podocyte and TGF-β1 mRNA as markers for disease activity and progression in anti-glomerular basement membrane nephritis 査読あり

Fukuda A, Minakawa A, Sato Y, Iwakiri T, Iwatsubo S, Komatsu H, Kikuchi M, Kitamura K, Wiggins RC, Fujimoto S

Nephrology Dialysis Transplantation 32 ( 11 ) 1818 - 1830 2017年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1093/ndt/gfx047

Corrigendum to “β-arrestins negatively control human adrenomedullin type 1-receptor internalization” [Biochem. Biophys. Res. Commun. 487 (2) (2017) 438–443] (S0006291X17307593) (10.1016/j.bbrc.2017.04.083) 査読あり

Transient Left Ventricular Contractile Dysfunction during the Treatment of Rhabdomyolysis: A Case Report and Literature Review 査読あり

Tsuruda T, Shinohara N, Ogata M, Kitamura K, Ochiai H

Internal Medicine 2017年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.2169/internalmedicine.8478-16

Plasma levels of natriuretic peptides and year-by-year blood pressure variability: a population-based study 査読あり

Kato J, Kawagoe Y, Jiang D, Kuwasako K, Shimamoto S, Igarashi K, Tokashiki M, Kitamura K

J Hum Hypertens 31 ( 8 ) 525 - 529 2017年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Kuwasako K., Kitamura K., Nagata S., Sekiguchi T., Jiang D., Murakami M., Hattori Y., Kato J.

Biochemical and Biophysical Research Communications 490 ( 3 ) 2017年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

The authors regret that the first and last names of the fifth author were retrograde. The authors would like to apologise for any inconvenience caused.

DOI： 10.1016/j.bbrc.2017.06.006

副腎静脈還流異常により診断に苦慮したアルドステロン産生腺腫の1例査読あり

新森徳長, 北俊弘, 川口隆久, 宮下和季, 栗原勲, 伊藤裕, 小黒草太, 中塚誠之, 古小路英二, 北村和雄

日本内科学会雑誌 106 ( 8 ) 1632 - 1639 2017年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本内科学会

56歳，男性．高血圧と低カリウム血症を呈し，内分泌負荷試験で原発性アルドステロン症（primary aldosteronism：PA）が強く疑われた．CT（computed tomography）で左副腎に8 mm大の腺腫を認めるも，通常の副腎静脈サンプリング（adrenal venous sampling：AVS）ではアルドステロン過剰分泌は認めなかった．CTを併用した副腎動脈造影で，左副腎腺腫から左腎被膜静脈と左腎静脈分枝への導出を同定し，アルドステロン過剰分泌を証明した．腹腔鏡下左副腎摘除術にて治癒した．副腎静脈還流異常により通常のAVSでは診断不能な症例が存在する．

DOI： 10.2169/naika.106.1632

Inhibitory effects of losartan and azelnidipine on augmentation of blood pressure variability induced by angiotensin II in rats. 査読あり

Jiang D, Kawagoe Y, Kuwasako K, Kitamura K, Kato J

Eur J Pharmacol 806 91 - 95 2017年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Anti-Inflammatory Effects of PEGylated Human Adrenomedullin in a Mouse DSS-Induced Colitis Model. 査読あり

Nagata S, Yamasaki M, Kitamura K

Drug development research 78 ( 3-4 ) 129 - 134 2017年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1002/ddr.21383

Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice 査読あり

Nakai N., Nagano M., Saitow F., Watanabe Y., Kawamura Y., Kawamoto A., Tamada K., Mizuma H., Onoe H., Watanabe Y., Monai H., Hirase H., Nakatani J., Inagaki H., Kawada T., Miyazaki T., Watanabe M., Sato Y., Okabe S., Kitamura K., Kano M., Hashimoto K., Suzuki H., Takumi T.

Science Advances 3 ( 6 ) e1603001 2017年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Science Advances

Serotonin is a critical modulator of cortical function, and its metabolism is defective in autism spectrum disorder (ASD) brain. How serotonin metabolism regulates cortical physiology and contributes to the pathological and behavioral symptoms of ASD remains unknown. We show that normal serotonin levels are essential for the maintenance of neocortical excitation/inhibition balance, correct sensory stimulus tuning, and social behavior. Conversely, low serotonin levels in 15q dup mice (a model for ASD with the human 15q11-13 duplication) result in impairment of the same phenotypes. Restoration of normal serotonin levels in 15q dup mice revealed the reversibility of a subset of ASD-related symptoms in the adult. These findings suggest that serotonin may have therapeutic potential for discrete ASD symptoms.

DOI： 10.1126/sciadv.1603001

β-arrestins negatively control human adrenomedullin type 1-receptor internalization. 査読あり

Kuwasako K, Kitamura K, Nagata S, Sekiguchi T, Danfeng J, Murakami M, Hattori Y, Kato J

Biochemical and biophysical research communications 487 ( 2 ) 438 - 443 2017年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016/j.bbrc.2017.04.083

Getting Osteoporotic Fracture Risk into Vascular Structure and Function: Do you know your FRAX® score? 招待あり査読あり

Toshihiro Tsuruda, Kazuo Kitamura

Circulation Journal 81 ( 6 ) 786 - 787 2017年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Altered glucose metabolism and hypoxic response in alloxan-induced diabetic atherosclerosis in rabbits 査読あり

Matsuura Y., Yamashita A., Zhao Y., Iwakiri T., Yamasaki K., Sugita C., Koshimoto C., Kitamura K., Kawai K., Tamaki N., Zhao S., Kuge Y., Asada Y.

PLoS ONE 12 ( 4 ) e0175976 2017年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：PLoS ONE

Diabetes mellitus accelerates atherosclerosis that causes most cardiovascular events. Several metabolic pathways are considered to contribute to the development of atherosclerosis, but comprehensive metabolic alterations to atherosclerotic arterial cells remain unknown. The present study investigated metabolic changes and their relationship to vascular histopathological changes in the atherosclerotic arteries of rabbits with alloxaninduced diabetes. Diabetic atherosclerosis was induced in rabbit ilio-femoral arteries by injecting alloxan (100 mg/kg), injuring the arteries using a balloon, and feeding with a 0.5% cholesterol diet. We histologically assessed the atherosclerotic lesion development, cellular content, pimonidazole positive-hypoxic area, the nuclear localization of hypoxiainducible factor-1α, and apoptosis. We evaluated comprehensive arterial metabolism by performing metabolomic analyses using capillary electrophoresis-time of flight mass spectrometry. We evaluated glucose uptake and its relationship to vascular hypoxia using 18F-fluorodeoxyglucose and pimonidazole. Plaque burden, macrophage content, and hypoxic areas were more prevalent in arteries with diabetic, than non-diabetic atherosclerosis. Metabolomic analyses highlighted 12 metabolites that were significantly altered between diabetic and non-diabetic atherosclerosis. A half of them were associated with glycolysis metabolites, and their levels were decreased in diabetic atherosclerosis. The uptake of glucose evaluated as 18F-fluorodeoxyglucose in atherosclerotic lesions increased according to increased macrophage content or hypoxic areas in non-diabetic, but not diabetic rabbits. Despite profound hypoxic areas, the nuclear localization of hypoxia-inducible factor-1α decreased and the number of apoptotic cells increased in diabetic atherosclerotic lesions. Altered glycolysis metabolism and an impaired response to hypoxia in atherosclerotic lesions under conditions of insulin-dependent diabetes might be involved in the development of diabetic atherosclerosis.

DOI： 10.1371/journal.pone.0175976

Relationship between hemoglobin levels corrected by interdialytic weight gain and mortality in Japanese hemodialysis patients: Miyazaki dialysis cohort study. 査読あり

Toida T, Iwakiri T, Sato Y, Komatsu H, Kitamura K, Fujimoto S

PLoS One 12 ( 1 ) e0169117 2017年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Primary cardiac leiomyosarcoma: A 27-month survival with surgery and chemotherapy 査読あり

Nakashima K., Inatsu H., Kitamura K.

Internal Medicine 56 ( 16 ) 2145 - 2149 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Internal Medicine

The patient was a 39-year-old man hospitalized due to the presence of a cardiac mass and heart failure. Emergency tumor resection and mitral valve replacement were performed. The pathological findings of the tumor led to a diagnosis of cardiac leiomyosarcoma. After the operation, multiple metastases were found. The patient underwent three courses of chemotherapies: adriamycin, ifosfamide, dacarbazine, and mesna (MAID therapy), gemcitabine plus docetaxel, and sunitinib. During MAID therapy, the patient underwent resection of gastrointestinal metastases twice due to gastrointestinal hemorrhaging. Although he died 27 months after the initial treatment, use of multimodal therapy was effective in achieving a longer survival for the patient.

DOI： 10.2169/internalmedicine.6965-15

Salvage photodynamic therapy accompanied by extended lymphadenectomy for advanced esophageal carcinoma: A case report 査読あり

Nishida T., Takeno S., Nakashima K., Kariya M., Inatsu H., Kitamura K., Nanashima A.

International Journal of Surgery Case Reports 36 155 - 160 2017年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Surgery Case Reports

Introduction Salvage surgery for locoregional failures after definitive chemoradiotherapy (dCRT) for esophageal cancer is widely practiced, but treatment options complementing it are also needed due to the high morbidity and mortality and low rate of curative resection. Presentation of case A 58-year-old man with a surgical history of right upper lobectomy for lung cancer was diagnosed as having esophageal squamous cell carcinoma. Computed tomography revealed swelling of the lesser curvature lymph node, and it had invaded the stomach, the body and tail of the pancreas and the left gastric artery, splenic artery and celiac artery. The patient underwent definitive-dose radiation with chemotherapy. Complete response was attained for the primary tumor, but the metastatic lymph node infiltrating the stomach, pancreas and major vessels remained. Therefore, the Appleby operation was proposed to the patient and subsequently performed aiming at curability. However, the primary tumor recurred 38 months after surgery, so the novel modality of photodynamic therapy using talaporfin sodium and a diode laser was performed, and a complete response was attained for this lesion. The patient is alive at 50 months after the salvage Appleby operation. Discussion and conclusion Salvage lymphadenectomy for esophageal cancer may be insufficient as a curative treatment because of regrowth of the primary lesion. However, photodynamic therapy may be applicable as a curative treatment option for recurrence of the primary lesion after salvage lymphadenectomy.

DOI： 10.1016/j.ijscr.2017.05.025

回腸結腸瘻を合併した虚血性小腸炎の1例査読あり

伊豆本心太郎、仮屋暢人、山嶋友実、押川一達、宮後冴、久保衣里奈、三宮一朗、原口大、芦塚伸也、中島孝治、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 109 164 - 164 2017年

掲載種別：研究論文（学術雑誌）

FOLFIRI + Panitumumab療法を行った虫垂杯細胞カルチノイドの1例査読あり

畑田絋志、山嶋友実、篠原実成、押川一達、米澤玲美、仮屋暢人、三宮一朗、松本英丈、中島孝治、芦塚伸也、稲津東彦、北村和雄、宮崎康幸、市原明子、池田拓人、大栗伸行、阿萬紫、佐藤勇一郎、河上洋

日本消化器病学会九州支部例会プログラム・抄録集 110 153 - 153 2017年

掲載種別：研究論文（学術雑誌）

消化器症状と両側水腎症を契機に診断された全身性エリテマトーデスの1例査読あり

島津志帆子、三宮一朗、山嶋友実、押川一達、宮後冴、久保衣里奈、仮屋暢人、原口大、芦塚伸也、中島孝治、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 109 163 - 163 2017年

掲載種別：研究論文（学術雑誌）

血管病変における血管外膜の意義査読あり

鶴田

日本臨牀 75 ( 5 ) 1076 - 1076 2017年

掲載種別：研究論文（学術雑誌）

当科にて食道癌術後に救済化学放射線治療を施行した10例の検討査読あり

中島孝治、篠原実、山嶋友実、押川一達、米澤玲美、仮屋暢人、三宮一朗、松本英丈、芦塚伸也、稲津東彦、河上洋、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 110 95 - 95 2017年

掲載種別：研究論文（学術雑誌）

EBウイルス関連リンパ増殖性疾患 (EBV-LPD) を合併した腸管ベーチェット病の一例査読あり

山嶋友実、稲津東彦、芦塚伸也、北村和雄、中島孝治、原口大、三宮一朗、仮屋暢人、久保衣里奈、宮後冴、押川一達、中村恵理子、盛口清香

日本消化器病学会九州支部例会プログラム・抄録集 109 151 - 151 2017年

掲載種別：研究論文（学術雑誌）

食道癌化学放射線療法後の局所遺残再発例に対するPDT9症例の検討査読あり

三宮一朗、篠原実成、押川一達、山嶋友実、米澤玲美、仮屋暢人、芦塚伸也、中島孝治、稲津東彦、七島篤志、河上洋、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 110 95 - 95 2017年

掲載種別：研究論文（学術雑誌）

当科における潰瘍性大腸炎に対するサーベイランス内視鏡検査の現状査読あり

三宮一朗、芦塚伸也、宮後冴、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 109 89 - 89 2017年

掲載種別：研究論文（学術雑誌）

食道癌化学放射線療法後の局所遺残再発例に対するPDT7例の検討 ~PDT導入後1年の経験~ 査読あり

三宮一朗、仮屋暢人、中島孝治、芦塚伸也、稲津東彦、河上洋、北村和雄

日本レーザー医学会誌 38 ( 3 ) 386 - 386 2017年

掲載種別：研究論文（学術雑誌）

S-1単剤治療を行なった腹膜偽粘液種の1例査読あり

後庵篤、三宮一朗、山嶋友実、押川一達、宮後冴、久保衣里奈、仮屋暢人、原口大、芦塚伸也、中島孝治、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 109 163 - 163 2017年

掲載種別：研究論文（学術雑誌）

血中ナトリウム利尿ペプチド (ANP, BNP) レベルと長期血圧変動性の関連査読あり

加藤丈司、川越由紀子、姜丹鳳、桑迫健二、渡嘉敷真理子、北村和雄

日本内分泌学会雑誌 93 ( 4 ) 1392 - 1392 2017年

掲載種別：研究論文（学術雑誌）

バリウム充填術が奏効した大腸憩室出血の1例査読あり

押川一達、山嶋友実、宮後冴、久保衣里奈、仮屋暢人、三宮一朗、原口大、芦塚伸也、中島孝治、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 109 150 - 150 2017年

掲載種別：研究論文（学術雑誌）

持続性アドレノメデュリン誘導体の創製査読あり

永田さやか、山﨑基生、北村和雄

日本内分泌学会雑誌 93 ( 4 ) 1382 - 1382 2017年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンと関連ペプチドの疾患マーカーとしての意義査読あり

北村和雄

生体の化学 67 ( 5 ) 434 - 435 2016年10月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Coexisting hyponatremiaand decline in diastolic blood pressure predispose to atrial standstill in hyperkalemic patients. 査読あり

Ideguchi T, Tsuruda T, Sato Y, Kitamura K

Circulation journal : official journal of the Japanese Circulation Society 80 ( 8 ) 1781 - 1786 2016年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Risk of Cerebral Infarction in Japanese Hemodialysis Patients: Miyazaki Dialysis Cohort Study (MID study) 査読あり

Toida T, Sato Y, Nakagawa H, Komatsu H, Uezono S, Yamada K, Ishihara T, Hisanaga S, Kitamura K, Fujimoto S

Kidney & blood pressure research 41 ( 4 ) 471 - 478 2016年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

医師国家試験過去問を活用した心臓病患者シミュレータによる医学生への心音聴診実習査読あり

小松弘幸、舟橋美保子、北村和雄、林　克裕

日本シミュレーション医療教育学会誌 4 43 - 47 2016年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Cardiac hypertrophy is exacerbated in aged mice lacking the osteoprotegerin gene. 査読あり

Hao Y, Tsuruda T, Sekita-Hatakeyama Y, Kurogi S, Kubo K, Sakamoto S, Nakamura M, Udagawa N, Sekimoto T, Hatakeyama K, Chosa E, Asada Y, Kitamura K

Cardiovascular research 110 ( 1 ) 62 - 72 2016年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Angiotensin II Stimulation of Cardiac Hypertrophy and Functional Decompensation in Osteoprotegerin-Deficient Mice. 査読あり

Tsuruda T, Sekita-Hatakeyama Y, Hao Y, Sakamoto S, Kurogi S, Nakamura M, Udagawa N, Funamoto T, Sekimoto T, Hatakeyama K, Chosa E, Kato J, Asada Y, Kitamura K

Hypertension 67 ( 5 ) 848 - 856 2016年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Multiple 18F-Fluorodeoxyglucose Positron Emission Tomography Scans Showing Progression of Abdominal Aortic Aneurysm: A Case Report 査読あり

Tsuruda T, Nagamachi S, Nishimura M, Nakamura K, Kitamura K

Medicine 2016年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1097/MD.0000000000003650

【腎保護薬update】前臨床段階の薬剤　可溶性グアニル酸シクラーゼ刺激薬査読あり

鶴田敏博、北村和雄

腎と透析 80 ( 4 ) 556 - 560 2016年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Glycaemic control is a predictor of infection-related hospitalization on haemodialysis patients: Miyazaki Dialysis Cohort study (MID study). 査読あり

Toida T, Sato Y, Nakagawa H, Komatsu H, Kikuchi M, Uezono S, Yamada K, Ishihara T, Hisanaga S, Kitamura K, Fujimoto S.

Nephrology (Carlton) 21 ( 3 ) 236 - 240 2016年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Adrenomedullin Therapy in Patients with Refractory Ulcerative Colitis: A Case Series. 査読あり

Ashizuka S, Inatsu H, Kita T, Kitamura K.

Digestive Diseases and Sciences 61 ( 3 ) 872 - 880 2016年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Inhibitory effects of two G protein-coupled receptor kinases on the cell surface expression and signaling of the human adrenomedullin receptor. 査読あり

Kuwasako K, Sekiguchi T, Nagata S, Jiang D, Hayashi H, Murakami M, Hattori Y, Kitamura K, Kato J.

Biochemical and Biophysical Research Communications 470 ( 4 ) 894 - 899 2016年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Augmented Blood Pressure Variability in Hypertension Induced by Angiotensin II in Rats. 査読あり

Jiang D, Tokashiki M, Hayashi H, Kawagoe Y, Kuwasako K, Kitamura K, Kato J.

American Journal of Hypertension 29 ( 2 ) 163 - 169 2016年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

A Baker Cyst Accompanied by Venous Thromboembolism. 査読あり

Koyama S, Matsuura Y, Ishikawa T, Kitamura K.

Internal Medicine 55 ( 2 ) 209 - 209 2016年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

心臓超音波と99mTc-ピロリン酸心筋シンチ像が診断に有用であった老人性アミロイドーシスの1例査読あり

児玉成邦、鶴田敏博、田中浩喜、小山彰平、石川哲憲、前川和也, 塩見一剛、北村和雄

宮崎医会誌 40 78 - 86 2016年

記述言語：日本語掲載種別：研究論文（学術雑誌）

血液透析患者の肝性胸水に胸膜癒着術を施行した 1 例査読あり

岩坪修司、山下靖宏、岩切太幹志、福田顕弘、辰元真理子、福留理恵、中川秀人、佐藤祐二、北村和雄、藤元昭一

透析会誌 49 ( 7 ) 511 - 516 2016年

記述言語：日本語掲載種別：研究論文（学術雑誌）

一般住民におけるナトリウム利尿ペプチド (ANP, BNP) の血漿濃度と慢性腎臓病 (CKD) 発症との関係査読あり

小川敬之、北村和雄、加藤丈司

日本内分泌学会雑誌 92 ( 3 ) 896 - 896 2016年

掲載種別：研究論文（学術雑誌）

胃粘膜にランタン沈着を認めた一例査読あり

米澤瑛美、米澤玲美、宮後冴、黒石頌子、仮屋暢人、原口大、増田稔、中島孝治、芦塚伸也、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 107 156 - 156 2016年

掲載種別：研究論文（学術雑誌）

骨粗鬆症と心不全の接点 - オステオプロテゲリンの関与査読あり

鶴田敏博、北村和雄

日本内分泌学会雑誌 92 ( 3 ) 884 - 884 2016年

掲載種別：研究論文（学術雑誌）

当科における食道ESD困難例の検討査読あり

増田稔、山嶋友実、押川一達、宮後冴、久保衣里奈、仮屋暢人、三宮一朗、原口大、三木吾郎、中島孝治、芦塚伸也、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 108 99 - 99 2016年

掲載種別：研究論文（学術雑誌）

消化管出血を契機に診断された遺伝性出血性毛細血管拡張症の1例査読あり

石崎友梨、宮後冴、押川一達、山嶋友実、久保衣里奈、仮屋暢人、三宮一朗、原口大、中島孝治、芦塚伸也、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 108 162 - 162 2016年

掲載種別：研究論文（学術雑誌）

高度の回腸狭窄を呈した特発性虚血性小腸炎の1例査読あり

新屋琴子、宮後冴、米澤玲美、黒石頌子、仮屋暢人、原口大、増田稔、中島孝治、芦塚伸也、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 107 161 - 161 2016年

掲載種別：研究論文（学術雑誌）

進行食道癌による食道気管支瘻に対してダブルステント留置によりQOLを向上できた1例査読あり

財部愛菜、原口大、宮後冴、米澤玲美、黒石頌子、仮屋暢人、増田稔、芦塚伸也、中島孝治、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 107 156 - 156 2016年

掲載種別：研究論文（学術雑誌）

5-FUを含む化学放射線療法中に狭心症発作が頻発した食道癌の1例査読あり

興梠貴俊、仮屋暢人、米澤玲美、宮後冴、黒石頌子、原口大、増田稔、中島孝治、芦塚伸也、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 107 155 - 155 2016年

掲載種別：研究論文（学術雑誌）

腸管嚢胞様気腫症を合併したクローン病の1例査読あり

岩崎あや香、米澤玲美、宮後冴、黒岩頌子、仮屋暢人、原口大、増田稔、三木吾郎、中島孝治、芦塚伸也、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 107 162 - 162 2016年

掲載種別：研究論文（学術雑誌）

尿中ビッグアンジオテンシン-25測定法の開発査読あり

永田さやか、福田顕弘、佐藤優尚、油屋順子、藤元昭一、北村和雄

日本内分泌学会雑誌 92 ( 3 ) 902 - 902 2016年

掲載種別：研究論文（学術雑誌）

アンジオテンシノーゲンの糖鎖構造解析査読あり

永田さやか、北村和雄

日本内分泌学会雑誌 92 ( 1 ) 216 - 216 2016年

掲載種別：研究論文（学術雑誌）

当科における生物学的製剤抵抗クローン病症例の検討査読あり

芦塚伸也、押川一達、山嶋友実、宮後冴、久保衣里奈、仮屋暢人、三宮一朗、原口大、三木吾郎、中島孝治、稲津東彦、北村和雄

日本消化器病学会九州支部例会プログラム・抄録集 108 75 - 75 2016年

掲載種別：研究論文（学術雑誌）

炎症性腸疾患に対するアドレノメデュリン療法の開発査読あり

芦塚伸也、稲津東彦、北村和雄

日本消化器病学会雑誌 113 ( suppl-1 ) 70 - 70 2016年

掲載種別：研究論文（学術雑誌）

Plasma levels of natriuretic peptides and development of chronic kidney disease. 査読あり

Ogawa N, Komura H, Kuwasako K, Kitamura K, Kato J.

BMC Nephrology 16 171 - 171 2015年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1186/s12882-015-0163-9

新規アンジオテンシンペプチドとは：ビッグアンジオテンシン-25と組織レニン・アンジオテンシン系査読あり

永田さやか、北村和雄

比較内分泌学 41 156 - 156 2015年9月

掲載種別：研究論文（学術雑誌）

Bench-to-bedside pharmacology of adrenomedullin 査読あり

Kato J., Kitamura K.

European Journal of Pharmacology 764 140 - 148 2015年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Pharmacology

The bioactive peptide adrenomedullin (AM) exerts pleiotropic actions in various organs and tissues. In the heart, AM has an inhibitory effect on ventricular remodeling, suppressing cardiomyocyte hypertrophy and the proliferation of cardiac fibroblasts. This pharmacological property was shown not only in rat models of acute myocardial infarction, but also clinically in patients with this cardiac disease. An originally characterized feature of AM was a potent vasodilatory effect, but this peptide was found to be important for vascular integrity and angiogenesis. AM-induced angiogenesis is involved in tumor growth, while AM inhibits apoptosis of some types of tumor cell. A unique pharmacological property is anti-inflammatory activity, which has been characterized in sepsis and inflammatory bowel diseases; thus, there is an ongoing clinical trial to test the efficacy of AM for patients with intractable ulcerative colitis. These activities are assumed to be mediated via the specific receptor formed by calcitonin receptor-like receptor and receptor activity-modifying protein 2 or 3, while some questions remain to be answered about the molecular mechanisms of this signal transduction system. Taking these findings together, AM is a bioactive peptide with pleiotropic effects, with potential as a therapeutic tool for a wide range of human diseases from myocardial infarction to malignant tumors or inflammatory bowel diseases.

DOI： 10.1016/j.ejphar.2015.06.061

Urine podocyte mRNAs mark disease activity in IgA nephropathy. 査読あり

Fukuda A, Sato Y, Iwakiri T, Komatsu H, Kikuchi M, Kitamura K, Wiggins RC, Fujimoto S.

Nephrology Dialysis Transplantation 30 ( 7 ) 1140 - 1150 2015年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1093/ndt/gfv104

Acute Renal Injury Induced by Hypersensitivity to Tolvaptan in an Elderly Patient with Congestive Heart Failure. 査読あり

Yamaguchi M, Nishihira K, Okubo T, Asada Y, Kitamura K.

Internal Medicine 54 ( 10 ) 1243 - 1246 2015年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.2169/internalmedicine.54.3308

Effect of adrenomedullin administration in two rat models of experimental inflammatory bowel disease. 査読あり

Nagata S, Hikosaka T, Kitamura K

American Journal of Life Sciences 3 ( （３－２） ) 39 - 42 2015年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Differences in 24-h blood pressure profile of Japanese hypertensive patients under ARB treatment. 査読あり

Kita T, Sakima A, Yokota N, Tamaki N, Etoh T, Shimokubo T, Nakada S, Takishita S, Ohya Y, Kitamura K.

Clinical and Experimental Hypertension 37 ( 7 ) 574 - 579 2015年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.3109/10641963.2015.1026042

Structure-function relationships between aldolase C/zebrin II expression and complex spike synchrony in the cerebellum 査読あり

I Sugihara

o Watanabe, Kenji Sakimura, Masanobu Kano, Kazuo KitaShinichiro Tsutsumi, Maya Yamazaki, Taisuke Miyazaki, Masahikmura 35 ( 2 ) 843 - 852 2015年1月

掲載種別：研究論文（学術雑誌）出版者・発行元：Society for Neuroscience

DOI： 10.1523/JNEUROSCI.2170-14

Adrenomedullin as a Potential Therapeutic Agent for Refractory Ulcerative Colitis 査読あり

Kazuo Kitamura, Shinya Ashizuka, Haruhiko Inatsu, Toshihiro Kita

Innovative Medicine 227 - 240 2015年

掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Japan

DOI： 10.1007/978-4-431-55651-0_19

Kawano S., Kawagoe Y., Kuwasako K., Shimamoto S., Igarashi K., Tokashiki M., Kitamura K., Kato J.

Endocrine Connections 4 ( 1 ) 43 - 49 2015年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Endocrine Connections

Plasmalevels of adrenomedullin(AM), a bioactivepeptide producedin adipose tissue,havebeen shown to be higher in obese patients than in non-obese patients, but little is known about gender differences in plasma AMlevels. The aims of this study were to clarify gender-related alterations in plasma AMlevels and to examine the body weight (BW) gain–plasma AM relationship in the general population.We measured plasma AMlevels of 346 local residents (62.0G8.9 years,meanGS.D.) intheKiyotakearea, Japan,whounderwentaregularhealthcheckup, by a specific fluorescence immunoassay. PlasmaAMlevels in the female residentswere lower than that in the males, and multiple regression analysis revealed a possible gender difference in plasma AM. The AM levels were significantly correlated with BMI or waist circumference in women, but such a relationship was not seen in men.When the subjects were divided into two groups by results of a questionnaire about BWgain of 10 kg or more since the age of 20 years, the plasmaAMlevel ofwomenwith BWgainS10 kgwas significantly higher than that in those without BW gain, although no difference was noted between the men with and without BW gain. In conclusion, possible gender differences were noted in the plasma AM levels and in the BWgain–plasmaAMrelationship in the general population. The plasmaAMlevels in the female residents without BW gain seem partly attributable to the lower AMof women.

DOI： 10.1530/EC-14-0131

Vascular wall hypoxia promotes arterial thrombus formation via augmentation of vascular thrombogenicity 査読あり

Matsuura Y., Yamashita A., Iwakiri T., Sugita C., Okuyama N., Kitamura K., Asada Y.

Thrombosis and Haemostasis 114 ( 1 ) 158 - 172 2015年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Thrombosis and Haemostasis

Atherosclerotic lesions represent a hypoxic milieu. However, the significance of this milieu in atherothrombosis has not been established. We aimed to assess the hypothesis that vascular wall hypoxia promotes arterial thrombus formation. We examined the relation between vascular wall hypoxia and arterial thrombus formation using a rabbit model in which arterial thrombosis was induced by 0.5 %- cholesterol diet and repeated balloon injury of femoral arteries. Vascular wall hypoxia was immunohistochemically detected by pimonidazole hydrochloride, a hypoxia marker. Rabbit neointima and THP-1 macrophages were cultured to analyse prothrombotic factor expression under hypoxic conditions (1 % O2). Prothrombotic factor expression and nuclear localisation of hypoxia-inducible factor (HIF)-1α and nuclear factor-kappa B (NF-κB) p65 were immunohistochemically assessed using human coronary atherectomy plaques. Hypoxic areas were localised in the macrophage-rich deep portion of rabbit neointima and positively correlated with the number of nuclei immunopositive for HIF-1α and NF-κB p65, and tissue factor (TF) expression. Immunopositive areas for glycoprotein IIb/IIIa and fibrin in thrombi were significantly correlated with hypoxic areas in arteries. TF and plasminogen activator inhibitor-1 (PAI-1) expression was increased in neointimal tissues and/or macrophages cultured under hypoxia, and both were suppressed by inhibitors of either HIF-1 or NF-κB. In human coronary plaques, the number of HIF-1α-immunopositive nuclei was positively correlated with that of NF-κB-immunopositive nuclei and TF-immunopositive and PAI-1-immunopositive area, and it was significantly higher in thrombotic plaques. Vascular wall hypoxia augments the thrombogenic potential of atherosclerotic plaque and thrombus formation on plaques via prothrombotic factor upregulation.

DOI： 10.1160/TH14-09-0794

潰瘍性大腸炎に対するアドレノメデュリン療法, 長期経過の検討査読あり

芦塚伸也、黒石頌子、久保絵里奈、増田稔、三木吾郎、彦坂ともみ、松本英丈、中島孝治、稲津東彦、北村和雄

日本消化器病学会雑誌 112 ( suppl-2 ) 937 - 937 2015年

掲載種別：研究論文（学術雑誌）

アンジオテンシンII持続投与高血圧ラットの血圧変動性増大査読あり

姜丹鳳、渡嘉敷真理子、林英孝、川越由紀子、桑迫健二、北村和雄、加藤丈司

日本内分泌学会雑誌 91 ( 2 ) 639 - 639 2015年

掲載種別：研究論文（学術雑誌）

重度の低K血症を伴いながら正常血圧を呈した原発性アルドステロン症の1例査読あり

渡辺雄佑、栗原勲、宮下和季、小林佐紀子、横田健一、中村俊文、井上博之、北村和雄、小黒草太、伊藤裕

日本内分泌学会雑誌 91 ( 2 ) 642 - 642 2015年

掲載種別：研究論文（学術雑誌）

N端パルミトイル化アドレノメデュリン誘導体の生理活性に関して査読あり

渡嘉敷真理子、久保恵是、桑迫健二、永田さやか、加藤丈司、北村和雄

日本内分泌学会雑誌 91 ( 2 ) 647 - 647 2015年

掲載種別：研究論文（学術雑誌）

ApoE KOマウスの動脈硬化進展における血管外膜の炎症と陽性リモデリング査読あり

坂元紀陽、鶴田敏博、畠山金太、今村卓郎、浅田祐士郎、北村和雄

日本内分泌学会雑誌 91 ( 2 ) 649 - 649 2015年

掲載種別：研究論文（学術雑誌）

難治性小腸出血にオクトレオチドが有効であった2例査読あり

久保衣里奈、黒石頌子、大野妙子、増田稔、三木吾郎、彦坂ともみ、松本英丈、芦塚伸也、中島孝治、稲津東彦、北村和雄

日本消化器病学会雑誌 112 ( suppl-2 ) 854 - 854 2015年

掲載種別：研究論文（学術雑誌）

一般住民における血中アドレノメデュリン値の性差および体重増加との関連査読あり

河野清香、川越由紀子、桑迫健二、島本怜史、五十嵐浩二、渡嘉敷真理子、北村和雄、加藤丈司

日本内分泌学会雑誌 91 ( 2 ) 647 - 647 2015年

掲載種別：研究論文（学術雑誌）

新しいアンジオテンシン関連ペプチドであるビッグアンジオテンシン-25の測定系の確立査読あり

永田さやか、福田顕弘、佐藤祐二、藤元昭一、井田隆徳、桑迫健二、渡嘉敷真理子、北村和雄

日本内分泌学会雑誌 91 ( 2 ) 643 - 643 2015年

掲載種別：研究論文（学術雑誌）

新規アンジオテンシンペプチドの同定と機能解析 : ビッグアンジオテンシン-25 査読あり

永田さやか、北村和雄

Angiotensin Research 12 ( 2 ) 88 - 94 2015年

掲載種別：研究論文（学術雑誌）

新たなアンジオテンシン関連ペプチド : ビッグアンジオテンシン-25 査読あり

永田さやか、北村和雄

日本内分泌学会雑誌 91 ( 1 ) 260 - 260 2015年

掲載種別：研究論文（学術雑誌）

抗TNFα療法施行中にIGRA陽転化を認めたクローン病3症例査読あり

稲津東彦、芦塚伸也、久保衣里奈、黒石頌子、大野妙子、増田稔、三木吾郎、彦坂ともみ　松元英丈、中島孝治、北村和雄

日本消化器病学会雑誌 112 ( suppl-2 ) 928 - 928 2015年

掲載種別：研究論文（学術雑誌）

IgA腎症を原疾患とする長期維持透析患者の特徴査読あり

小松弘幸、中川秀人、岩切太幹志、戸井田達典、福田顕弘、菊池正雄、佐藤祐二、北村和雄、藤元昭一

日本腎臓学会誌 56 56 ( 8 ) 1251 - 1259 2014年11月

記述言語：日本語掲載種別：研究論文（学術雑誌）

腎機能障害患者に対するビルダグリプチン使用経験～有効性と安全性の検討～査読あり

山下靖宏、福留慶一、上園繁弘、麻生和義、菊池正雄、佐藤祐二、北村和雄、藤元昭一

宮崎県医師会医学会誌 38 38 73 - 77 2014年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Impact of age-dependent adventitia inflammation on structural alteration of abdominal aorta in hyperlipidemic mice 査読あり

Sakamoto S., Tsuruda T., Hatakeyama K., Imamura T., Asada Y., Kitamura K.

PLoS ONE 9 ( 8 ) e105739 2014年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PLoS ONE

Background: The adventitia is suggested to contribute to vascular remodeling; however, the site-selective inflammatory responses in association with the development of atherosclerosis remain to be elucidated. Methods and Results: Wild-type or apolipoprotein E knockout male C57BL/6J background mice were fed standard chow for 16, 32, and 52 weeks, and the morphology of the aortic arch, descending aorta, and abdominal aorta was compared. Atheromatous plaque formation progressed with age, particularly in the aortic arch and abdominal aorta but not in the descending aorta. In addition, we found that the numbers of macrophages, T-lymphocytes, and microvessels, assessed by anti-F4/80, CD3, and CD31 antibodies, were higher in the adventitia of the abdominal aorta at 52 weeks. These numbers were positively correlated with plaque formation, but negatively correlated with elastin content, resulting in the enlargement of the total vessel area. In aortic tissues, interleukin-6 levels increased in the atheromatous plaque with age, whereas the level of regulated on activation, normal T cell expressed and secreted (RANTES) increased with age, and compared with other sites, it was particularly distributed in inflammatory cells in the adventitia of the abdominal aorta. Conclusion: This study suggests that adventitial inflammation contributes to the age-dependent structural alterations, and that the activation/inactivation of cytokines/chemokines is involved in the process. © 2014 Sakamoto et al.

DOI： 10.1371/journal.pone.0105739

Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients 査読あり

R Kihara , Y Nagata , H Kiyoi , T Kato , E Yamamoto , K Suzuki , F Chen 1, N Asou 3, S Ohtake 4, S Miyawaki , Y Miyazaki , T Sakura , Y Ozawa , N Usui , H Kanamori , T Kiguchi , K Imai , N Uike , F Kimura , K Kitamura, C Nakaseko , M Onizuka , A Takeshita , F Ishida , H Suzushima , Y Kato , H Miwa , Y Shiraishi , K Chiba , H Tanaka , S Miyano, S Ogawa, T Naoe

Leukemia 28 ( 8 ) 1586 - 1595 2014年8月

掲載種別：研究論文（学術雑誌）

DOI： 10.1038/leu.2014.55

Biological properties of adrenomedullin conjugated with polyethylene glycol 査読あり

Kubo K., Tokashiki M., Kuwasako K., Tamura M., Tsuda S., Kubo S., Yoshizawa-Kumagaye K., Kato J., Kitamura K.

Peptides 57 118 - 121 2014年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Peptides

Adrenomedullin (AM) is a vasodilator peptide with pleiotropic effects, including cardiovascular protection and anti-inflammation. Because of these beneficial effects, AM appears to be a promising therapeutic tool for human diseases, while intravenous injection of AM stimulates sympathetic nerve activity due to short-acting potent vasodilation, resulting in increased heart rate and renin secretion. To lessen these acute reactions, we conjugated the N-terminal of human AM peptide with polyethylene glycol (PEG), and examined the biological properties of PEGylated AM in the present study. PEGylated AM stimulated cAMP production, an intracellular second messenger of AM, in cultured human embryonic kidney cells expressing a specific AM receptor in a dose-dependent manner, as did native human AM. The pEC50 value of PEGylated AM was lower than human AM, but no difference was noted in maximum response (Emax) between the PEGylated and native peptides. Intravenous bolus injection of 10 nmol/kg PEGylated AM lowered blood pressure in anesthetized rats, but the acute reduction became significantly smaller by PEGylation as compared with native AM. Plasma half-life of PEGylated AM was significantly longer than native AM both in the first and second phases in rats. In summary, N-terminal PEGylated AM stimulated cAMP production in vitro, showing lessened acute hypotensive action and a prolonged plasma half-life in comparison with native AM peptide in vivo. © 2014 Elsevier Inc.

DOI： 10.1016/j.peptides.2014.05.005

A randomized control study on the procedure for switching Epoetin Beta (EPO) to Epoetin Beta Pegol (CERA) in the treatment of renal anemia in maintenance hemodialysis patients 査読あり

Osteoprotegerin is secreted into the coronary circulation: a possible association with the renin-angiotensin system and cardiac hypertrophy. 査読あり

Koyama S, Tsuruda T, Ideguchi T, Kawagoe J, Onitsuka H, Ishikawa T, Date H, Hatakeyama K, Asada Y, Kato J, Kitamura K

Horm Metab Res 46 2014年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Toida T., Sato Y., Shibata N., Kitamura K., Fujimoto S.

Blood Purification 38 ( 3-4 ) 174 - 179 2014年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Blood Purification

Background/Aims: We investigated the method of switching EPO to CERA that does not cause a decrease in the Hb level. Methods: Fifty EPO-treated patients were randomly divided into two groups in which CERA was administered every two weeks (Q2W) or every four weeks (Q4W). After 8 weeks of treatment, the frequency of administration was changed to Q4W in the former. Follow-up was performed for 24 weeks. Results: There was no difference in the Hb level between the two groups until 6 weeks. In the Q2W group, the Hb maintained a stable level throughout a study period. However, in the Q4W group, the Hb level was significantly lower than in the Q2W group at weeks 9, 11, and 13. Conclusion: EPO switching to CERA without a decrease in the Hb level could be achieved by administering CERA every two weeks, but not every four weeks, for a specific period after switching.

DOI： 10.1159/000368391

NT-proBNPの血液透析患者における予後予測　全死亡・脳心血管死・感染症死・腫瘍死における有用性査読あり

佐藤祐二、戸井田達典、中川秀人、菊池正雄、福田顕弘、山下靖宏、北村和雄、藤元昭一

日本透析医学会雑誌 47 2014年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）

外来高血圧患者における尿中アルブミン　54クリニック、1207例における解析査読あり

山下靖宏、海老原史高、戸井田達典、岩切太幹志、福田顕弘、中川秀人、菊池正雄、佐藤祐二、北村和雄、藤元昭一

日本腎臓学会誌 56 2014年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）

抗GBM腎炎における尿中podocyte mRNAの有用性の検討査読あり

福田顕弘、佐藤祐二, 岩切太幹志, 菊池正雄, 北村和雄, 藤元昭一

日本腎臓学会誌 56 2014年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）

レニン・アンジオテンシン系の新展開：ヒト尿中の主要なアンジオテンシン関連ペプチド「ビッグアンジオテンシン-25」の発見．査読あり

永田さやか、北村和雄

血管 37 37 73 - 79 2014年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Adrenomedullin does not contribute toward the development of abdominal aortic aneurysm in mice. 査読あり

Sakamoto S, Tsuruda T, Hatakeyama K, Shimosawa T, Asada Y, Kitamura K

Health 6 2014年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

レニン・アンジオテンシン・アルドステロン系研究の新展開、プロアンジオテンシン-12研究の最前線査読あり

加藤丈司、桑迫健二、小松洋一、永田さやか、北村和雄

Angiology Frontier 13 13 ( 1 ) 13 - 18 2014年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Association between renal vasculature changes and generalized atherosclerosis: An autopsy survey 査読あり

Iwakiri T., Sato Y., Matsuura Y., Hatakeyama K., Marutsuka K., Yamashita A., Fujimoto S., Kitamura K., Asada Y.

Journal of Atherosclerosis and Thrombosis 21 ( 2 ) 99 - 107 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Aim: To examine the association between renal vasculature changes and generalized atherosclerosis using autopsy cases. Methods: We histologically examined 107 autopsy patients (mean age, 68.4 years; 64% men; 81% non-CVD) to investigate the association between renal vasculature changes and generalized atherosclerosis. We measured the intima/media (I/M) ratio for the renal, intrarenal and systemic arteries (coronary, cerebral, common carotid and common iliac), calculated the rates of arteriolar hyalinization and global glomerulosclerosis and evaluated the frequency of advanced lesions (AHA classification ≥IV) in the systemic arteries. Results: The I/M ratios of the renal and intrarenal arteries and the rate of global glomerulosclerosis increased with age, while the rates of arteriolar hyalinization and global glomerulosclerosis were associated with diabetes and hypertension (all p<0.05). The I/M ratio of the coronary artery was independently associated with the rate of global glomerulosclerosis (p<0.05). The frequency of advanced atherosclerotic lesions in the coronary and cerebral arteries was also correlated with the I/M ratio of the renal artery and rates of arteriolar hyalinization and global glomerulosclerosis (all p<0.05). The frequency of advanced lesions in the cerebral and common carotid arteries was independently associated with the I/M ratio of the renal artery and the rate of renal arteriolar hyalinization (odds ratio (OR) with [95% confidence interval]; 5.09 [1.15-27.9] and 4.11 [1.38-13.9], respectively). Conclusions: The results of this study demonstrated that pathological changes in four portions of the renal vasculature differ. Renal vasculature changes except the intrarenal arteries were significantly associated with those observed in the cerebral, common carotid and coronary arteries.

DOI： 10.5551/jat.19869

Association between adiponectin production in coronary circulation and future cardiovascular events in patients with coronary artery disease

Kawagoe J., Ishikawa T., Iwakiri H., Date H., Imamura T., Kitamura K.

International Heart Journal 55 ( 3 ) 239 - 243 2014年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：International Heart Journal

Adiponectin has antiatherosclerotic properties and is also produced in the local coronary circulation. We previously reported that signifi cantly less adiponectin was produced in the coronary circulation of patients with than without coronary artery disease (CAD). The goal of this study was to determine whether adiponectin production in the coronary circulation could predict future cardiovascular events in patients with CAD. Forty-eight CAD patients whose left anterior descending coronary arteries required percutaneous coronary intervention (PCI) were enrolled. The amount of adiponectin production in the coronary circulation was defi ned as the plasma adiponectin level at the great cardiac vein minus that at the orifi ce of the left coronary artery. All patients were divided by adiponectin production level in the coronary circulation into the adiponectin-positive production group (> 0 μg/ mL) and adiponectin-negative production group (≤ 0 μg/mL). Median follow-up period was 66 months (maximum, 108 months). The primary endpoint was the combined occurrence of major adverse cardiovascular events (MACE), including rehospitalization due to unstable angina, heart failure, nonfatal myocardial infarction, revascularization with PCI or coronary artery bypass grafting, ischemic stroke, and cardiovascular death. Sixteen MACE occurred. The incidence of MACE was signifi cantly higher in the adiponectin-negative production group than in the adiponectin-positive production group (P = 0.02). In multivariate analysis, adiponectin-negative production was a predictor of MACE (P = 0.03). Kaplan-Meier analysis revealed that the MACE-free rate was signifi cantly lower in the adiponectin-negative production group than in the adiponectin-positive production group. Adiponectin production in the coronary circulation with CAD may be associated with MACE.

DOI： 10.1536/ihj.13-287

Inhibited cardiac hypertrophy in proadrenomedullin NH2-Terminal 20 peptide-transgenic rat with unilateral ... 査読あり

Yuan-NingCao、北村和雄、桑迫健二、加藤丈司、西平賢作、浅田祐士郎、江藤胤尚

Journal of Adaptation Medicine 9 ( 1 ) 30 - 30 2014年

掲載種別：研究論文（学術雑誌）

活動性潰瘍性大腸炎の入院治療に伴う合併症に関する検討査読あり

芦塚伸也、三宮一朗、増田稔、三木吾郎、星子新理、松本英丈、中島孝治、稲津東彦、北村和雄

日本消化器病学会雑誌 111 ( suppl-2 ) 888 - 888 2014年

掲載種別：研究論文（学術雑誌）

一般住民におけるアドレノメデュリンとナトリウム利尿ペプチドの血中レベルと慢性腎臓病発症査読あり

加藤丈司、桑迫健二、北村和雄

日本内分泌学会雑誌 90 ( 2 ) 751 - 751 2014年

掲載種別：研究論文（学術雑誌）

ビッグアンジオテンシン-25 : ヒト尿中の主要なアンジオテンシン関連ペプチド査読あり

永田さやか、北村和雄

最新医学 69 ( 11月増刊 ) 2276 - 2286 2014年

掲載種別：研究論文（学術雑誌）

Long-term survival of patients with IgA nephropathy after dialysis therapy. 査読あり

Komatsu H, Kikuchi M, Nakagawa H, Fukuda A, Iwakiri T, Toida T, Sato Y, Kitamura K, Fujimoto S

Kidney Blood Press Res 37 ( 6 ) 649 - 656 2013年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Big angiotensin-25: A novel glycosylated angiotensin-related peptide isolated from human urine. 査読あり

Nagata S, Hatakeyama K, Asami M, Tokashiki M, Hibino H, Nishiuchi Y, Kuwasako K, Kato J, Asada Y, Kitamura K

Biochem Biophys Res Commun 441 ( 4 ) 757 - 762 2013年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Adrenomedullin as a potential therapeutic agent for inflammatory bowel disease 査読あり

Ashizuka S., Inatsu H., Inagaki-Ohara K., Kita T., Kitamura K.

Current Protein and Peptide Science 14 ( 4 ) 246 - 255 2013年11月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Current Protein and Peptide Science

Adrenomedullin (AM) was originally isolated from human pheochromocytoma as a biologically active peptide with potent vasodilating action but is now known to exert a wide range of physiological effects, including cardiovascular protection, neovascularization, and apoptosis suppression. A variety of tissues, including the gastrointestinal tract, have been shown to constitutively produce AM. Pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-1, and lipopolysaccharides, induce the production and secretion of AM. Conversely, AM induces the downregulation of inflammatory cytokines in cultured cells. Furthermore, AM downregulates inflammatory processes in a variety of different colitis models, including acetic acid-induced colitis and dextran sulfate sodium-induced colitis. AM exerts antiinflammatory and antibacterial effects and stimulates mucosal regeneration for the maintenance of the colonic epithelial barrier. Here, we describe the first use of AM to treat patients with refractory ulcerative colitis. The results strongly suggest that AM has potential as a new therapeutic agent for the treatment of refractory ulcerative colitis. © 2013 Bentham Science Publishers.

DOI： 10.2174/13892037113149990044

Gender difference in relationship between body mass index and development of chronic kidney disease 査読あり

Komura H, Nomura I, Kitamura K, Kuwasako K, Kato J

BMC Res Notes 13 463 - 463 2013年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Efficacy of alogliptin, a dipeptidyl peptidase-4 inhibitor, on glucose parameters, the activity of the advanced glycation end product (AGE) - receptor for AGE (RAGE) axis and albuminuria in Japanese type 2 diabetes. 査読あり

Sakata K, Hayakawa M, Yano Y, Tamaki N, Yokota N, Eto T, Watanabe R, Hirayama N, Matsuo T, Kuroki K, Sagara S, Mishima O, Koga M, Nagata N, Nishino Y, Kitamura K, Kario K, Takeuchi M, Yamagishi S

Diabetes Metab Res Rev 29 ( 8 ) 624 - 630 2013年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

ストローマからみた心血管病「ストローマをターゲットとした心血管病の治療」査読あり

鶴田敏博、北村和雄

循環器内科 (Cardioangiology) 74 125 - 131 2013年8月

掲載種別：研究論文（学術雑誌）

ストローマからみた心血管病　序文査読あり

北村和雄、鶴田敏博

循環器内科 (Cardioangiology) 74 123 - 124 2013年8月

掲載種別：研究論文（学術雑誌）

Functions of third extracellular loop and helix 8 of Family B GPCRs complexed with RAMPs and characteristics of their receptor trafficking. 査読あり

Curr Protein Pept Sci

Curr Protein Pept Sci 14 ( 5 ) 416 - 428 2013年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Disruption of cerebellar microzonal organization in GluD2 (Glurδ2) knockout mouse 査読あり

Hashizume M., Miyazaki T., Sakimura K., Watanabe M., Kitamura K., Kano M.

Frontiers in Neural Circuits 7 ( JUL ) 130 2013年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers in Neural Circuits

Cerebellar cortex has an elaborate rostrocaudal organization comprised of numerous microzones. Purkinje cells (PCs) in the same microzone show synchronous activity of complex spikes (CSs) evoked by excitatory inputs from climbing fibers (CFs) that arise from neurons in the inferior olive (IO). The synchronous CS activity is considered to depend on electrical coupling among IO neurons and anatomical organization of the olivo-cerebellar projection. To determine how the CF-PC wiring contributes to the formation of microzone, we examined the synchronous CS activities between neighboring PCs in the glutamate receptor δ2 knockout (GluD2 KO) mouse in which exuberant surplus CFs make ectopic innervations onto distal dendrites of PCs. We performed in vivo two-photon calcium imaging for PC populations to detect CF inputs. Neighboring PCs in GluD2 KO mice showed higher synchrony of calcium transients than those in wild-type (control) mice. Moreover, the synchrony in GluD2 KO mice hardly declined with mediolateral separation between PCs up to ~200 μm, which was in marked contrast to the falloff of the synchrony in control mice. The enhanced synchrony was only partially affected by the blockade of gap junctional coupling. On the other hand, transverse CF collaterals in GluD2 KO mice extended beyond the border of microzone and formed locally clustered ectopic synapses onto dendrites of neighboring PCs. Furthermore, PCs in GluD2 KO mice exhibited clustered firing (Cf), the characteristic CF response that was not found in PCs of wild-type mice. Importantly, Cf was often associated with localized calcium transients in distal dendrites of PCs, which are likely to contribute to the enhanced synchrony of calcium signals in GluD2 KO mice. Thus, our results indicate that CF signals in GluD2 KO mice propagate across multiple microzones, and that proper formation of longitudinal olivo-cerebellar projection is essential for the spatiotemporal organization of CS activity in the cerebellum. © 2013 Hashizume, Miyazaki, Sakimura, Watanabe, Kitamura and Kano.

DOI： 10.3389/fncir.2013.00130

Validation of a newly proposed histopathological classification in Japanese patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis. 査読あり

Iwakiri T, Fujimoto S, Kitagawa K, Furuichi K, Yamahana J, Matsuura Y, Yamashita A, Uezono S, Shimao Y, Hisanaga S, Tokura T, Wada T, Kitamura K, Asada Y

BMC Nephrol 14 ( 1 ) 125 - 125 2013年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Reduced fractional shortening of right ventricular outflow tract is associated with adverse outcomes in patients with left ventricular dysfunction. 査読あり

Yamaguchi M, Tsuruda T, Watanabe Y, Onitsuka H, Furukawa K, Ideguchi T, Kawagoe J, Ishikawa T, Kato J, Takenaga M, Kitamura K

Cardiovasc Ultrasound 11 ( 1 ) 19 - 19 2013年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Autocrine effects of neuromedin B stimulate the proliferation of rat primary osteoblasts. 査読あり

Saito H, Nakamachi T, Inoue K, Ikeda R, Kitamura K, Minamino N, Shioda S, Miyata A

J Endocrinol 217 ( 2 ) 141 - 150 2013年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Hepatocyte growth factor activator inhibitor type 1 is a suppressor of intestinal tumorigenesis 査読あり

Hoshiko S., Kawaguchi M., Fukushima T., Haruyama Y., Yorita K., Tanaka H., Seiki M., Inatsu H., Kitamura K., Kataoka H.

Cancer Research 73 ( 8 ) 2659 - 2670 2013年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Research

Hepatocyte growth factor activator inhibitor type 1 (HAI-1/SPINT1) is a membrane-bound serine protease inhibitor expressed on the surface of epithelial cells. Although HAI-1/SPINT1 is abundantly expressed in the intestinal epithelium, its role in intestinal tumorigenesis is not known. In this study, we investigated the role of Hai-1/Spint1 in intestinal tumorigenesis using mouse models. The membranous Hai-1/Spint1 immunoreactivity was decreased in murine ApcMin/+ tumors and also in carcinogen (azoxymethane treatment followed by dextran sodium sulfate administration)-induced colon tumors compared with the adjacent non-neoplastic epithelium. The decreased immunoreactivity appeared to be due to sheddase activity of membrane-type 1 matrix metalloprotease. Then, we examined the effect of intestine-specific deletion of Spint1 gene on ApcMin/+ mice. The loss of Hai-1/Spint1 significantly accelerated tumor formation in ApcMin/+ mice and shortened their survival periods. Activation of HGF was enhanced in Hai-1/Spint1-deficient ApcMin/+ intestine. Gene expression profiling revealed upregulation of the Wnt/b-catenin signaling circuit, claudin-2 expression, and angiogenesis not only in tumor tissue but also in the background mucosa without macroscopic tumors in Hai-1/Spint1-deficient ApcMin/+ intestine. Intestinal deletion of Spint1 also enhanced the susceptibility to carcinogen-induced colon tumorigenicity of wild-type Apc mice. Our findings suggest that HAI-1/SPINT1 has a crucial role in suppressing intestinal tumorigenesis, which implies a novel link between epithelial cell surface serine protease inhibitors and protection from carcinogenic stimuli. © 2013 American Association for Cancer Research.

DOI： 10.1158/0008-5472.CAN-12-3337

Organized thrombus in aspirated coronary materials can predict in-hospital mortality of patients with acute myocardial infarction. 査読あり

Nishihira K, Hatakeyama K, Shibata Y, Kitamura K, Asada Y

Circ J 77 ( 5 ) 1275 - 1280 2013年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Adrenomedullin: A novel therapy for intractable ulcerative colitis. 査読あり

Ashizuka S, Kita T, Inatsu H, Kitamura K

Inflamm Bowel Dis 19 ( 2 ) 26 - 27 2013年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1002/ibd.22891.

Electrocardiographic assessment of incident atrial fibrillation in hemodialysis patients. 査読あり

Nishi K, Fujimoto S, Hisanaga S, Ogawa O, Kitamura K

Ther Apher Dial 17 ( 1 ) 16 - 23 2013年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Hemodynamic and hormonal changes to dual renin-angiotensin system inhibition in experimental hypertension. 査読あり

Moniwa N, Varagic J, Ahmad S, VonCannon JL, Simington SW, Wang H, Groban L, Brosnihan KB, Nagata S, Kato J, Kitamura K, Gomez RA, Lopez ML, Ferrario CM

Hypertension 61 ( 2 ) 417 - 424 2013年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Glucose metabolism in macrophages contributes to the development of atherosclerosis in apolipoprotein E knockout ... 査読あり

カク異琳、鶴田敏博、関田陽子、坂元紀陽、畠山金太、浅田祐士郎、北村和雄

日本内分泌学会雑誌 89 ( 2 ) 756 - 756 2013年

掲載種別：研究論文（学術雑誌）

産褥期発症の特発性冠動脈解離による急性心筋梗塞に対して冠動脈ステント留置術を行った1例査読あり

和田美沙、鬼塚久充、久保恵是、井手口武史、川越純志、鶴田敏博、石川哲憲、今村卓郎、古田賢、古川誠志、鮫島浩、北村和雄

心臓 45 ( 12 ) 1577 - 1583 2013年

掲載種別：研究論文（学術雑誌）

ヒト尿中に存在する主要アンジオテンシン関連ペプチド「Big angiotensin-25」の単離・同定査読あり

北村和雄、永田さやか

日本内分泌学会雑誌 89 ( 2 ) 720 - 720 2013年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンの展開研究査読あり

北村和雄

心臓 45 ( 12 ) 1496 - 1502 2013年

掲載種別：研究論文（学術雑誌）

心房性ナトリウム利尿ペプチドが発見されるのを見ていて感じたこと査読あり

北村和雄

心臓 45 ( 5 ) 491 - 491 2013年

掲載種別：研究論文（学術雑誌）

降圧因子"アドレノメデュリン"の研究査読あり

北村和雄

血圧 20 ( 1 ) 155 - 155 2013年

掲載種別：研究論文（学術雑誌）

動脈硬化バイオマーカー測定とその臨床的意義 CRP, SAA, ペントラキシン3 査読あり

石川哲憲、今村卓郎、浅田祐士郎、北村和雄

日本臨牀 71 ( 3 ) 444 - 449 2013年

掲載種別：研究論文（学術雑誌）

Adrenomedullin does not contribute toward the development of abdominal aortic aneurysm in mice 査読あり

坂元紀陽、鶴田敏博、畠山金太、下澤達雄、浅田祐士郎、北村和雄

日本内分泌学会雑誌 89 ( 2 ) 747 - 747 2013年

掲載種別：研究論文（学術雑誌）

2つのアドレノメデュリン受容体のユニークな活性化機構査読あり

桑迫健二、北村和雄、永田さやか、加藤丈司

日本薬理学会部会（日本薬理学雑誌） 141 ( 3 ) 22 - 22 2013年

掲載種別：研究論文（学術雑誌）

ステロイド依存性ネフローゼ症候群に対するACTH製剤の有効性：古くて新しい治療査読あり

菊池正雄、佐藤祐二、北村和雄、藤元昭一

日本内分泌学会雑誌 89 ( 2 ) 759 - 759 2013年

掲載種別：研究論文（学術雑誌）

肥満の有無による降圧併用療法の効果およびアルドステロン濃度変化の差異査読あり

加藤丈司、桑迫健二、北俊弘、北村和雄

日本内分泌学会雑誌 89 ( 1 ) 342 - 342 2013年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンを用いた潰瘍性大腸炎に対する新規治療薬の開発査読あり

芦塚伸也、稲津東彦、北俊弘、北村和雄

日本内分泌学会雑誌 89 ( 2 ) 748 - 748 2013年

掲載種別：研究論文（学術雑誌）

潰瘍性大腸炎に対するアドレノメデュリン療法 (続報) 査読あり

芦塚伸也、仮屋暢人、三宮一朗、原口大、三木吾郎、星子新理、松本英丈、中島孝治、稲津東彦、北村和雄

日本消化器病学会雑誌 110 ( suppl-2 ) 933 - 933 2013年

掲載種別：研究論文（学術雑誌）

Advanced diffuse malignant peritoneal mesothelioma responding to palliative chemotherapy 査読あり

Nakashima K., Inatsu H., Kitamura K., Hikosaka T., Hoshiko S., Ashiduka S.

Clinical Journal of Gastroenterology 5 ( 6 ) 373 - 376 2012年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical Journal of Gastroenterology

A 64-year-old man diagnosed with advanced malignant peritoneal mesothelioma by laparoscopic biopsy was treated with systemic chemotherapy. The patient underwent first-line chemotherapy with pemetrexed plus cisplatin for 11 months, then second-line chemotherapy with gemcitabine plus vinorelbine for 6 months, and third-line chemotherapy with CPT-11 for 4 months. After third-line chemotherapy failed, he received palliative treatment. Although the tumor continued to grow, and he died 24 months after initiation of treatment, chemotherapy prolonged the survival time and improved his quality of life. © 2012 Springer Japan.

DOI： 10.1007/s12328-012-0334-1

Differential blood pressure reductions by angiotensin receptor blocker plus calcium channel blocker or diuretic in elderly hypertension with or without obesity. 「"jointly worked"」査読あり

Kato J, Yokota N, Tamaki N, Kariya S, Kita T, Ayabe T, Eto T, Kitamura K

J Am Soc Hypertens 6 ( 6 ) 393 - 398 2012年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016

Usefulness of carotid intima-media thickness measurement as an indicator of generalizedatherosclerosis: findings from autopsy analysis.「"jointly worked"」査読あり

Iwakiri?T,?Yano Y,?Sato Y,?Hatakeyama K,?Marutsuka K,?Fujimoto S,?Kitamura K,?Kario K,?Asada Y

Atherosclerosis 225 ( 2 ) 359 - 362 2012年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016

高血圧治療の新戦略?ARB/Ca拮抗薬配合剤をどう使うか?．（共著）査読あり

北村和雄,横田直人,早田泰英,江藤琢磨,田口利文

Medical Tribune 1 - 4 2012年10月

記述言語：日本語掲載種別：研究論文（その他学術会議資料等）

実地臨床のおける使用成績から、ARB/利尿薬合剤が適した患者像を探る．（共著）査読あり

北村和雄,浦田秀則,野出孝一

PREMINENT(MSD) 1 - 4 2012年10月

記述言語：日本語掲載種別：研究論文（その他学術会議資料等）

Effect of lanthanum carbonate vs. calcium carbonate on serum calcium in hemodialysis patients: A crossover study 査読あり

Toida T., Fukudome K., Fujimoto S., Yamada K., Sato Y., Chiyotanda S., Kitamura K.

Clinical Nephrology 78 ( 3 ) 216 - 223 2012年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical Nephrology

Background: Lanthanum carbonate (LC) is a non-calcium-containing phosphate binder and shows a comparable effect with other phosphate binders on hyperphosphatemia in dialysis patients. LC also contributes to a reduced oral calcium load compared with calcium carbonate(CaC)treatment. However, no crossover studies which compare the influence on serum calcium level between treatments with LC and CaC in hemodialysis (HD) patients have been carried out. Methods: After washout for 2 weeks, 50 patients on HD were randomized (1 1) to receive LC or CaC for 3 months.Thereafter, patients underwent a second 2-week washout period and were switched to the alternative binder for the next 3 months. Mineral and bone metabolism markers were measured with the changes of vitamin D doses. Results: The serum phosphate level showed a similar decrease from baseline to 3 months in both groups. During the study periods, hypercalcemia was observed only in patients taking CaC. The dose of vitamin D analogue was increased more frequently in the patients of the LC group compared with LC group. The iPTH level showed a significant decrease in the CaC group, but not in the LC group. Serum levels of BAP, TRAP5b, and ALP were significantly elevated in the LC group, whereas the FGF-23 level showed a significant decrease. Conclusion: LC effectively reduced the serum phosphate level (like CaC) and allowed the vitamin D analogue dosage to be increased without hypercalcemia in HD patients. LC is one of the useful phosphate binders without hypercalcemia.(UMIN-CTR registration number:UMIN000002331). © 2012 Dustri-Verlag Dr. K. Feistle.

DOI： 10.5414/CN107257

Reprint of “Adrenomedullin: A Novel Hypotensive Peptide Isolated from Human Pheochromocytoma” 査読あり

Kitamura K.

Biochemical and Biophysical Research Communications 425 ( 3 ) 548 - 555 2012年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

DOI： 10.1016/j.bbrc.2012.08.022

Paucity of CD34-positive cells and increased expression of high-mobility group box 1 in coronary thrombus with type 2 diabetes mellitus.「"jointly worked"」査読あり

Yamashita A, Nishihira K, Matsuura Y, Ito T, Kawahara K, Hatakeyama K, Hashiguchi T, Maruyama I, Yagi H, Matsumoto M, Fujimura Y, Kitamura K, Shibata Y, Asada Y

Atherosclerosis 224 ( 2 ) 511 - 514 2012年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016

Different distribution of pentraxin 3 and C-reactive protein in coronary atherosclerotic plaques.「"jointly worked"」査読あり

Matsuura Y, Hatakeyama K, Imamura T, Tsuruda T, Shibata Y, Kodama T, Kitamura K, Asada Y

J Atheroscler Thromb 19 ( 9 ) 837 - 845 2012年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.5551

Comparison of the effects of intravenous methylprednisolone pulse versus oral prednisolone therapies on the first attack of minimal-change nephrotic syndrome in adults. 「"jointly worked"」査読あり

Fukudome K, Fujimoto S, Sato Y, Kitamura K

Nephrology (Carlton) 17 ( 3 ) 263 - 268 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1111

Characterization of the single transmembrane domain of human receptor activity-modifying protein 3 in adrenomedullin receptor internalization. 「"jointly worked"」査読あり

Kuwasako K, Kitamura K, Nagata S, Nozaki N, Kato J

Biochem Biophys Res Commun 420 ( 3 ) 582 - 587 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016

Effects of proangiotensin-12 infused continuously over 14days in conscious rats.「"jointly worked"」査読あり

Komatsu Y, Kida N, Nozaki N, Kuwasako K, Nagata S, Kitamura K, Kato J

Eur J Pharmacol 683 ( 1 ) 186 - 189 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016

The third extracellular loop of the human calcitonin receptor-like receptor is crucial for the activation of adrenomedullin signalling. 「"jointly worked"」査読あり

Kuwasako K, Hay DL, Nagata S, Hikosaka T, Kitamura K, Kato J

Brit J Pharmacol 166 ( 1 ) 137 - 150 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1111

GABAergic Inhibition Regulates Developmental Synapse Elimination in the Cerebellum 査読あり

Nakayama H., Miyazaki T., Kitamura K., Hashimoto K., Yanagawa Y., Obata K., Sakimura K., Watanabe M., Kano M.

Neuron 74 ( 2 ) 384 - 396 2012年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Neuron

Functional neural circuit formation during development involves massive elimination of redundant synapses. In the cerebellum, one-to-one connection from excitatory climbing fiber (CF) to Purkinje cell (PC) is established by elimination of early-formed surplus CFs. This process depends on glutamatergic excitatory inputs, but contribution of GABAergic transmission remains unclear. Here, we demonstrate impaired CF synapse elimination in mouse models with diminished GABAergic transmission by mutation of a single allele for the GABA synthesizing enzyme GAD67, by conditional deletion of GAD67 from PCs and GABAergic interneurons or by pharmacological inhibition of cerebellar GAD activity. The impaired CF synapse elimination was rescued by enhancing GABA A receptor sensitivity in the cerebellum by locally applied diazepam. Our electrophysiological and Ca 2+ imaging data suggest that GABA A receptor-mediated inhibition onto the PC soma from molecular layer interneurons influences CF-induced Ca 2+ transients in the soma and regulates CF synapse elimination from postnatal day 10 (P10) to around P16. Nakayama et al. find that GABAergic inhibition onto Purkinje cell somata from molecular layer interneurons suppresses climbing fiber-induced Ca 2+ transients and regulates elimination of redundant climbing fiber inputs during postnatal cerebellar development. © 2012 Elsevier Inc.

DOI： 10.1016/j.neuron.2012.02.032

Three-year safety and effectiveness of fixed-dose losartan/hydrochlorothiazide combination therapy in Japanese patients with hypertension under clinical setting (PALM-1 Extension Study).「"jointly worked"」査読あり

Kita T, Yokota N, Ichiki Y, Ayabe T, Etoh T, Tamaki N, Kato J, Eto T, Kitamura K

Clin Exp　Hypertens 34 ( 7 ) 498 - 503 2012年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.3109

Inhibition of development of abdominal aortic aneurysm by glycolysis restriction.「"jointly worked"」査読あり

Tsuruda T, Hatakeyama K, Nagamachi S, Sekita Y, Sakamoto S, Endo GJ, Nishimura M, Matsuyama M, Yoshimura K, Sato Y, Onitsuka T, Imamura T, Asada Y, Kitamura K

Arterioscler Thromb Vasc Biol 32 ( 6 ) 1410 - 1417 2012年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1161

メタボリックシンドローム対策としての特定健診の有用性?清武町研究―．（共著）査読あり

野崎尚美,木田信章,桑迫健二,北村和雄,加藤丈司

宮崎県医師会医学会誌 36 ( 1 ) 14 - 18 2012年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system.「"jointly worked"」査読あり

Nagata S, Kato J, Kuwasako K, Asami M, Kitamura K

Hypertens Res 35 ( 2 ) 234 - 238 2012年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1038

管理不良高血圧患者に対するロサルタンからロサルタン／ヒドロクロロチアジド配合薬への切り替えによる長期（３年間）の降圧効果と安全性：PALM-1 extension研究．（共著）査読あり

北　俊弘,横田直人,市来能成,綾部隆夫,江藤琢磨,玉置　昇,加藤丈司,江藤胤尚,北村和雄

Progress in Medicine 32 ( 2 ) 117 - 121 2012年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Tonsillectomy delays progression of advanced IgA nephropathy to end-stage kidney disease.「"jointly worked"」査読あり

Komatsu H, Fujimoto S, Kikuchi M, Sato Y, Kitamura K

Ren Fail 34 ( 4 ) 448 - 453 2012年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.3109

Sarcoidosis manifesting as cardiac sarcoidosis and massive splenomegaly. 「"jointly worked"」査読あり

Kawano S, Kato J, Kawano N, Yoshimura Y, Masuyama H, Fukunaga T, Shimao Y, Mihara K, Ueda A, Toyoda K, Imamura T, Kitamura K

Intern Med 51 ( 1 ) 65 - 69 2012年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.2169

心血管機能を制御するG蛋白共役型受容体の新たな分子調節機構と役割の解明．（共著）査読あり

桑迫健二,北村和雄,永田さやか,加藤丈司

医科学応用研究財団研究報告 29 226 - 229 2012年1月

記述言語：日本語掲載種別：研究論文（その他学術会議資料等）

Postinfarction dissecting intramyocardial haematoma in a patient treated with immunosuppressant 査読あり

Sakata K., Tsuruda T., Imamura T., Kitamura K.

BMJ Case Reports 32 ( 1 ) 2012年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：BMJ Case Reports

DOI： 10.1136/bcr-2012-006904

Postsynaptic P/Q-type Ca2+ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum 査読あり

アンジオテンシンII産生におけるプロアンジオテンシン-12の役割査読あり

永田さやか、桑迫健二、北村和雄

日本内分泌学会雑誌 88 ( 1 ) 340 - 340 2012年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンの診断薬・治療薬としての可能性査読あり

北村和雄

日本内分泌学会雑誌 88 ( 2 ) 797 - 797 2012年

掲載種別：研究論文（学術雑誌）

両腕の血圧差と血管疾患および死亡のリスク査読あり

北俊弘、北村和雄

血圧 19 ( 10 ) 854 - 855 2012年

掲載種別：研究論文（学術雑誌）

糖尿病合併高血圧と血圧日内変動査読あり

北俊弘、北村和雄

血圧 19 ( 4 ) 344 - 345 2012年

掲載種別：研究論文（学術雑誌）

当科にて経験した好酸球性消化管病変を有する5例の検討査読あり

原口大、稲津東彦、中島孝治、芦塚伸也、松本英丈、星子新理、三木吾郎、三宮一朗、彦坂ともみ、片山陽平、北村和雄

日本消化器病学会雑誌 109 ( suppl-2 ) 862 - 862 2012年

掲載種別：研究論文（学術雑誌）

CRT-D植込みを契機に頻回作動を呈し, ステロイド投与にて改善した心サルコイドーシスの1例査読あり

川越純志、和田美沙、西山美保、井手口武史、鬼塚久充、鶴田敏博、石川哲憲、今村卓郎、北村和雄

Journal of Arrhythmia 28 ( suppl ) 342 - 342 2012年

掲載種別：研究論文（学術雑誌）

維持透析患者における炭酸ランタン(LC)内服継続と炭酸カルシウム(CaC)単剤内服継続の比較検討査読あり

戸井田達典、福留慶一、千代反田晋、佐藤祐二、北村和雄、藤元昭一

Therapeutic Research 33 ( 66 ) 929 - 933 2012年

掲載種別：研究論文（学術雑誌）

当科にて経験した膵・消化管神経内分泌癌5例の検討査読あり

原口大、稲津東彦、中島孝治、芦塚伸也、松本英丈、星子新理、三木吾郎、三宮一朗、彦坂ともみ、片山陽平、北村和雄

日本消化器病学会雑誌 109 ( suppl-2 ) 872 - 872 2012年

掲載種別：研究論文（学術雑誌）

G蛋白共役型受容体キナーゼ (GRK) によるアドレノメデュリン (AM) 査読あり

桑迫健二、北村和雄、永田さやか、加藤丈司

日本内分泌学会雑誌 88 ( 1 ) 372 - 372 2012年

掲載種別：研究論文（学術雑誌）

1型アドレノメデュリン受容体複合体のユニークな分子機構と循環制御査読あり

桑迫健二、北村和雄、永田さやか、加藤丈司

日本薬理学雑誌 140 ( 1 ) 8 - 13 2012年

掲載種別：研究論文（学術雑誌）

1型アドレノメデュリン受容体の細胞内ヘリックス8の役割査読あり

桑迫健二、北村和雄、永田さやか、彦坂ともみ、野崎尚美、加藤丈司

日本薬理学会部会（日本薬理学雑誌） 139 ( 3 ) 36 - 36 2012年

掲載種別：研究論文（学術雑誌）

ネフローゼ症候群における脂質の検討査読あり

菊池正雄、藤元昭一、岩坪修

Therapeutic Research 33 ( 2 ) 183 - 185 2012年

掲載種別：研究論文（学術雑誌）

ARBとカルシウム拮抗薬または利尿薬の併用降圧療法の比較：肥満の有無による降圧効果とアルドステロン濃度変化の差異査読あり

加藤丈司、桑迫健二、北俊弘、北村和雄

日本内分泌学会雑誌 88 ( 2 ) 829 - 829 2012年

掲載種別：研究論文（学術雑誌）

Presence of older thrombus in patients with late and very late drug-eluting stent thrombosis.「"jointly worked"」査読あり

Nishihira K, Hatakeyama K, Kuriyama N, Nomura K, Fukushima Y, Inoue Y, Nakama T, Mine D, Sagara S, Ashikaga K, Matsuyama A, Kitamura K, Shibata Y, Asada Y

Cardiol 59 ( 1 ) 57 - 63 2011年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016

Adrenomedullin production is increased in colorectal adenocarcinomas; its relation to matrix metalloproteinase-9.「"jointly worked"」査読あり

Hikosaka T, Tsuruda T, Nagata S, Kuwasako K, Tsuchiya K, Hoshiko S, Inatsu H, Chijiiwa K, Kitamura K

Peptides 32 ( 9 ) 1825 - 1831 2011年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： "

一般住民における血中アルドステロン値の規定因子および血中アルドステロン値とインスリン感受性との関連．（共著）査読あり

野村郁夫，加藤丈司，北村和雄

血圧 18 ( 8 ) 771 - 773 2011年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Hashimoto K., Tsujita M., Miyazaki T., Kitamura K., Yamazaki M., Shin H.S., Watanabe M., Sakimura K., Kano M.

Proceedings of the National Academy of Sciences of the United States of America 108 ( 24 ) 9987 - 9992 2011年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America

Neural circuits are initially redundant but rearranged through activity-dependent synapse elimination during postnatal development. This process is crucial for shaping mature neural circuits and for proper brain function. At birth, Purkinje cells (PCs) in the cere-bellum are innervated by multiple climbing fibers (CFs) with similar synaptic strengths. During postnatal development, a single CF is selectively strengthened in each PC through synaptic competition, the strengthened single CF undergoes translocation to a PC dendrite, and massive elimination of redundant CF synapses follows. To investigate the cellular mechanisms of this activity-dependent synaptic refinement, we generated mice with PC-selective deletion of the Ca v2.1 P/Q-type Ca2+ channel, the major voltage-dependent Ca2+ channel in PCs. In the PC-selective Cav2.1 knockout mice, Ca2+ transients induced by spontaneous CF inputs are markedly reduced in PCs in vivo. Not a single but multiple CFs were equally strengthened in each PC from postnatal day 5 (P5) to P8, multiple CFs underwent translocation to PC dendrites, and subsequent synapse elimination until around P12 was severely impaired. Thus, P/ Q-type Ca2+ channels in postsynaptic PCs mediate synaptic competition among multiple CFs and trigger synapse elimination in developing cerebellum.

DOI： 10.1073/pnas.1101488108

Shared and separate functions of the RAMP-based adrenomedullin receptors. 「"jointly worked"」査読あり

Kuwasako K, Kitamura K, Nagata S, Hikosaka T, Takei Y, Kato J

Peptides 32 ( 7 ) 1540 - 1550 2011年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016

Clinical features and outcomes of eosinophilic myocarditis patients treated with prednisolone at a single institution over a 27-year period.「"jointly worked"」査読あり

Kawano S, Kato J, Kawano N, Yoshimura Y, Masuyama H, Fukunaga T, Sato Y, Maruyama H, Mihara K, Ueda A, Toyoda K, Imamura T, Kitamura K

Internal Medicine 50 ( 9 ) 975 - 981 2011年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.2169

Associations of plasma pentraxin 3 and monocyte chemoattractant protein-1 concentrations with cardiovascular disease in patients with chronic kidney disease. 「"jointly worked"」査読あり

Nishi K, Imamura T, Kitamura K, Ogawa T, Fujimoto S, Kakitsubata Y, Ishikawa T, Asada Y, Kodama T

Renal Failure 33 ( 4 ) 398 - 404 2011年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.3109

卒前臨床実習における心臓病患者シミュレータを用いた診察実習査読あり

小松弘幸, 有村保次, 今村卓郎, 北村和雄, 岡山昭彦, 林克裕

医学教育 42 ( 2 ) 55 - 63 2011年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本医学教育学会

心臓病患者シミュレータは全国の医学教育機関で最も普及している医療シミュレータの一つであるが，学習到達目標を明確にした上での有効な活用方法は十分検討されていない．本研究では，共用試験OSCE後の医学生に対する明確な到達目標の設定とシミュレータ演習を取り入れた学習方法を提案し，その教育効果についても検討した． 1）対象は本学医学科5年生94名で，到達目標は順序立てた診察技能の習得と正常心音および代表的心疾患の判別とし，講義とシミュレータ演習の前後でチェックリストを用いた評価を行った． 2）実習前後で，総スコア（14点満点）は2.2±0.9点から11.4±1.5点へ有意に上昇した（p<0.001）．心疾患の病態の違いによる実習後スコアの差は見られなかった． 3）実習前に対象者の50％以上が実施できた項目は，聴診器の正確な当て方と心雑音の最強点の指摘のみであったが，実習後は対象者の98％が診察所見を順序立てて述べられ，94％が設定された心疾患の病態を的確に推測できた． 4）到達目標を絞ったシミュレータ演習は，限られた時間と人的資源で診察技能の向上に寄与しうる．今後は，実習後の定着度の再評価や反復学習プログラムの確立が課題である．

DOI： 10.11307/mededjapan.42.55

活動期潰瘍性大腸炎寛解導入療法としてのアドレノメデュリン持続静注療法の経験査読あり

稲津東彦、芦塚伸也、北村和雄

日本消化器病学会雑誌 108 ( suppl-2 ) 862 - 862 2011年

掲載種別：研究論文（学術雑誌）

卒前臨床実習における心臓病患者シミュレータを用いた診察実習査読あり

小松弘幸, 有村保次, 今村卓郎, 北村和雄, 岡山昭彦, 林克裕

医学教育 42 ( 2 ) 55 - 63 2011年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本医学教育学会

DOI： 10.11307/mededjapan.42.55

Cardiovascular event rates in patients with cerebrovascular disease and atherothrombosis at other vascular locations: Results from 1-year outcomes in the Japanese REACH Registry 査読あり

O07-4 一般住民における血中アルドステロン値の規定因子および血中アルドステロン値とインスリン感受性との関連査読あり

野村郁夫、加藤丈司、北村和雄

日本内分泌学会雑誌 87 ( 2 ) 779 - 779 2011年

掲載種別：研究論文（学術雑誌）

一般住民における血中アルドステロン値の規定因子および血中アルドステロン値とインスリン感受性との関連査読あり

野村郁夫、加藤丈司、北村和雄

血圧 18 ( 8 ) 771 - 773 2011年

掲載種別：研究論文（学術雑誌）

循環器疾患研究を支えた人々松尾壽之査読あり

北村和雄

CARDIAC PRACTICE 22 ( 4 ) 336 - 337 2011年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンの内分泌・代謝系へのユニークな作用査読あり

北俊弘、北村和雄

実験医学 29 ( 5 ) 844 - 849 2011年

掲載種別：研究論文（学術雑誌）

血中NT-proBNP値と生命予後査読あり

北俊弘、北村和雄

血圧 18 ( 10 ) 952 - 953 2011年

掲載種別：研究論文（学術雑誌）

マクロファージの糖代謝エネルギー制御により腹部大動脈瘤の進展を抑制できるかもしれない査読あり

鶴田敏博、北村和雄

日本内分泌学会雑誌 87 ( 2 ) 785 - 785 2011年

掲載種別：研究論文（学術雑誌）

腹部大動脈瘤の病態解明と細胞内エネルギー制御による内科的治療法の基盤確立査読あり

鶴田敏博、北村和雄

日本内分泌学会雑誌 87 ( 1 ) 178 - 178 2011年

掲載種別：研究論文（学術雑誌）

マクロファージ・血管構築細胞群査読あり

鶴田敏博、畠山金太、北村和雄

日本臨牀 69 ( 1 ) 45 - 49 2011年

掲載種別：研究論文（学術雑誌）

Hepatocyte growth factor activator inhibitor type 1(HAI-1)の欠失はAPC Min／＋マウスの腸管腫瘍形成を促進する査読あり

星子新理、川口真紀子、頼田顕辞、福島剛、彦坂ともみ、中野みち子、三宮一朗、三木吾郎、松本英丈、芦塚伸也、中島孝治、稲津東彦、北村和雄、片岡寛章

日本消化器病学会雑誌 108 ( suppl-2 ) 848 - 848 2011年

掲載種別：研究論文（学術雑誌）

二次性高血圧査読あり

加藤丈司、北村和雄

臨牀と研究 88 ( 2 ) 205 - 208 2011年

掲載種別：研究論文（学術雑誌）

Comparison of combination therapies, including the angiotensin receptor blocker olmesartan and either a calcium channel blocker or a thiazide diuretic, in elderly patients with hypertension. 「"jointly worked"」査読あり

Kato J, Yokota N, Tamaki N, Kariya S, Kita T, Ayabe T, Eto T, Kitamura K

Hypertension Research 34 ( 3 ) 331 - 335 2010年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1038

Repeated sirolimus-eluting stent implantation to treat sirolimus-eluting stent and bare-metal stent restenosis.「"jointly worked"」査読あり

Nishihira K, Shibata Y, Ishikawa T, Nomura K, Nakama T, Mine D, Inoue Y, Ashikaga K, Kuriyama N, Matsuyama A, Imamura T, Asada Y, Kitamura K

Circulation Journal 74 2329 - 2333 2010年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016

Structure-function analysis of helix 8 of human calcitonin receptor-like receptor within the adrenomedullin 1 receptor. 「"jointly worked"」査読あり

Kuwasako K, Kitamura K, Nagata S, Hikosaka T, Kato J

Peptides 32 ( 1 ) 144 - 149 2010年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016

Reciprocal contribution of pentraxin 3 and C-reactive protein to obesity and metabolic syndrome. 「"jointly worked"」査読あり

Ogawa T, Kawano Y, Imamura T, Kawakita K, Sagara M, Matsuo T, Kakitsubata Y, Ishikawa T, Kitamura K, Hatakeyama K, Asada Y, Kodama T

Obesity 18 1871 - 1874 2010年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1038

Disturbed blood flow induces erosive injury to smooth muscle cell-rich neointima and promotes thrombus formation in rabbit femoral artery. 「"jointly worked"」査読あり

Sumi T, Yamashita A, Matsuda S, Goto S, Nishihira K, Furukoji E, Sugimura H, Kawahara H, Imamura T, Kitamura K, Tamura S, Asada Y

J Thromb Haemost 8 1394 - 1402 2010年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1111

Hemodynamic and hormonal effects of exogenous adrenomedullin administration in humans and relationship to insulin resistance. 「"jointly worked"」査読あり

Kita T, Suzuki Y, Kitamura K

Hypertension Research 33 314 - 319 2010年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1038

One-year effectiveness and safety of open-label losartan/hydrochlorothiazide combination therapy in Japanese patients with hypertension uncontrolled with ARBs or ACE inhibitors. 「"jointly worked"」査読あり

Kita T, Yokota N, Ichiki Y, Ayabe T, Etoh T, Tamaki N, Kato J, Eto T, Kitamura K

Hypertension Research 33 320 - 325 2010年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1038

Aldosterone antisecretagogue and antihypertensive actions of adrenomedullin in patients with primary aldosteronism. 「"jointly worked"」査読あり

Kita T, Tokashiki M, Kitamura K

Hypertension Research 33 374 - 379 2010年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1038

Effects of mineralocorticoid and angiotensin II receptor blockers on proteinuria and glomerular podocyte protein expression in a model of minimal change nephrotic syndrome.「"jointly worked"」査読あり

Fukuda A, Fujimoto S, Iwatsubo S, Kawachi H, Kitamura K

Nephrology 15 321 - 326 2010年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1111

Stromal cell biology -a way to understand the evolution of cardiovascular diseases.「"jointly worked"」査読あり

Tsuruda T, Imamura T, Hatakeyama K, Asada Y, Kitamura K

Circulation Journal 74 1042 - 1050 2010年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1253

Plasma and tissue levels of proangiotensin-12 and components of the renin-angiotensin system (RAS) following low- or high-salt feeding in rats. 「"jointly worked"」査読あり

Nagata S, Kato J, Kuwasako K, Kitamura K

Peptides 31 889 - 892 2010年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016

Function of the cytoplasmic tail of human calcitonin receptor-like receptor in complex with receptor activity-modifying protein 2. 「"jointly worked"」査読あり

Kuwasako K, Kitamura K, Nagata S, Hikosaka T, Kato J

Biochemical and Biophysical Research Communications 392 380 - 385 2010年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016

アドレノメデュリン受容体の機能と役割査読あり

桑迫健二、加藤丈司、北村和雄

医学のあゆみ 233 ( 9 ) 851 - 856 2010年

掲載種別：研究論文（学術雑誌）

アドレノメデュリン査読あり

北村和雄

日本臨牀 68 ( 7 ) 630 - 632 2010年

掲載種別：研究論文（学術雑誌）

ARB/利尿薬合剤の降圧効果と安全性査読あり

北俊弘、北村和雄

血圧 17 ( 12 ) 1028 - 1032 2010年

掲載種別：研究論文（学術雑誌）

大腸MALT lymphoma術後11年目にdiffuse large B cell lymphomaを認めた一例査読あり

中島孝治、彦坂ともみ、星子新理、松本英丈、芦塚伸也、早稲田文子、押川勝太郎、稲津東彦、北村和雄、岩切太幹志、丸塚浩助

日本消化器病学会雑誌 107 ( suppl-2.2 ) 827 - 827 2010年

掲載種別：研究論文（学術雑誌）

メタボリック症候群とペントラキシン3 査読あり

小川恒夫、今村卓郎、北村和雄

生物試料分析 33 ( 4 ) 339 - 346 2010年

掲載種別：研究論文（学術雑誌）

Uchiyama S., Goto S., Matsumoto M., Nagai R., Origasa H., Yamazaki T., Shigematsu H., Shimada K., Yamada N., Bhatt D.L., Steg P.G., Ikeda Y.

Journal of the Neurological Sciences 287 ( 1-2 ) 45 - 51 2009年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of the Neurological Sciences

The REduction of Atherothrombosis for Continued Health (REACH) Registry is a large, international, prospective cohort of patients with atherothrombosis or multiple (≥ 3) risk factors (MRFs) for atherothrombosis. Japanese patients (n = 5193) were enrolled into the REACH registry between August and December 2004. One-year event rate in patients with cerebrovascular disease (CVD) was compared with that of patients with symptomatic atherothrombosis at other locations. After one year (n = 5021), patients with CVD (n = 1962) experienced a higher rate of non-fatal strokes than patients with coronary artery disease (CAD), peripheral artery disease (PAD) or MRFs alone (2.77% vs. 1.28%, 2.07% and 1.56%, respectively), but a lower rate of non-fatal myocardial infarction (0.45% vs. 1.31%, 0.77% and 0.66%, respectively). Patients with CVD plus disease in ≥ 1 other vascular bed had higher rates of cardiovascular events than patients with CVD alone. Overall, event rates including non-fatal stroke, non-fatal myocardial infarction and cardiovascular death were higher for patients with CVD and PAD than for patients with CVD and CAD. Asymptomatic carotid stenosis ≥ 70% and ankle-brachial index < 0.9 were significant predisposing factors for stroke. Patients with CVD and co-existing atherothrombotic diseases had a high risk of recurrent events, including events arising in other vascular beds than originally diagnosed. © 2009 Elsevier B.V.

DOI： 10.1016/j.jns.2009.09.011

Thrombin generation by intimal tissue factor contributes to thrombus formation on macrophage-rich neointima but not normal intima of hyperlipidemic rabbits 査読あり

Adrenomedullin treatment reduces intestinal inflammation and maintains epithelial barrier function in mice administered dextran sulphate sodium. "jointly worked" 査読あり

Ashizuka S, Inagaki-Ohara K, Kuwasako K, Kato J, Inatsu H, Kitamura K

Microbiol Immunol 53 ( 10 ) 573 - 581 2009年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1111/j.1348-0421.2009.00159.x

Yamashita A., Matsuda S., Matsumoto T., Moriguchi-Goto S., Takahashi M., Sugita C., Sumi T., Imamura T., Shima M., Kitamura K., Asada Y.

Atherosclerosis 206 ( 2 ) 418 - 426 2009年10月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Atherosclerosis

Arterial thrombosis occurs in atherosclerotic, but rarely in non-atherosclerotic arteries. The present study investigates how hyperlipidemic condition affects thrombus formation on macrophage-rich neointima or normal intima in rabbits. Rabbits were fed with a 0.5% cholesterol diet, and then the femoral artery on one side of each rabbit was injured with a balloon catheter. Three weeks later, bilateral femoral arteries were similarly injured with a balloon catheter to produce thrombi on neointima and normal intima. We compared the expression and activity of intimal tissue factor (TF) as well as thrombus size and composition between these femoral arteries. 0.5% cholesterol diet combined with a balloon injury induced macrophage-rich neointima in injured arteries. The whole blood coagulation activity or plasma thrombin generation activity did not differ after consuming the 0.5% cholesterol diet for 4 weeks, and an anti-TF antibody did not affect the measured parameters. TF activities were increased in the neointima/media compared with normal intima/media. Balloon injury induced large platelet-fibrin thrombi on macrophage-rich neointima, whereas small platelet thrombi were produced in normal arteries even under hyperlipidemic conditions. Recombinant human tissue factor pathway inhibitor (25 μg/(kg min)) and argatroban (100 μg/(kg min)), a specific thrombin inhibitor, significantly reduced thrombus formation on induced neointima, but not on normal intima. Thrombin generation mediated by TF in intima contributes to thrombus formation on macrophage-rich neointima, but not on normal intima. The TF content in disrupted atherosclerotic plaques might play a more important role than hyperlipidemia in the development of atherothrombosis. © 2009 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.atherosclerosis.2009.03.014

Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS) 査読あり

Increased plasma levels of the mature and intermediate forms of adrenomedullin in obesity.　"jointly worked" 査読あり

Nomura I, Kato J, Tokashiki M, Kitamura K

Regulatory Peptides 158 ( (1-3) ) 127 - 131 2009年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016/j.regpep.2009.08.003

Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1α in rat heart. "jointly worked" 査読あり

Tsuruda T, Hatakeyama K, Masuyama H, Sekita Y, Imamura T, Asada Y, Kitamura K

Tsuruda T, Hatakeyama K, Masuyama H, Sekita Y, Imamura T, Asada Y, Kitamura K 297 ( 4 ) 1274 - 1280 2009年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1152/ajpheart.00503.2009.

Flow cytometric analysis of the calcitonin receptor-like receptor domains responsible for cell-surface translocation of receptor activity-modifying proteins.　"jointly worked" 査読あり

Kuwasako K, Kitamura K, Nagata S, Kato J

Biochemical and Biophysical Research Communications 384 ( 2 ) 249 - 254 2009年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016/j.bbrc.2009.04.097

Pressure-independent effects of pharmacological stimulation of soluble guanylate cyclase on fibrosis in pressure-overloaded rat heart. "jointly worked" 査読あり

Masuyama H, Tsuruda T, Sekita Y, Hatakeyama K, Imamura T, Kato J, Asada Y, Stasch JP, Kitamura K

Hypertension Research 32 ( 7 ) 597 - 603 2009年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1038/hr.2009.64

Association between body mass index and chronic kidney disease: a population-based, cross-sectional study of a Japanese community.　 "jointly worked" 査読あり

Nomura I, Kato J, Kitamura K

Nomura I, Kato J, Kitamura K 5 ( 1 ) 315 - 320 2009年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.2147/vhrm.s5522

Interleukin-10 correlates with oxidized low density lipoprotein in coronary culprit plaques.　"jointly worked" 査読あり

Nishihira K, Imamura T, Ishikawa T, Yamashita A, Shibata Y, Itabe H, Kitamura K, Asada Y

Thrombosis research 124 ( 3 ) 335 - 337 2009年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Differential regulation of angiotensin-(1-12) in plasma and cardiac tissue in response to bilateral nephrectomy. "jointly worked" 査読あり

Ferrario CM, Varagic J, Habibi J, Nagata S, Kato J, Chappell MC, Trask AJ, Kitamura K, Whaley-Connell A, Sowers JR

Am J Physiol Heart Circ Physiol 296 ( 4 ) 1184 - 1192 2009年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1152/ajpheart.01114.2008.

Effects of uroguanylin on natriuresis in experimental nephrotic rats. "jointly worked" 査読あり

Baba A, Fujimoto S, Kikuchi M, Kita T, Kitamura K

Nephrology 14 ( 1 ) 80 - 85 2009年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1111/j.1440-1797.2008.01006.x

Recent therapeutic strategies improve renal outcome in patients with IgA nephropathy.　"jointly worked" 査読あり

Komatsu H, Fujimoto S, Hara S, Fukuda A, Fukudome K, Yamada K, Sato Y, Kitamura K

American Journal of Nephrology 30 ( 1 ) 19 - 25 2009年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1159/000197116

Effect of adrenomedullin on the cerebral circulation: relevance to primary headache disorders. "jointly worked" 査読あり

Petersen KA, Birk S, Kitamura K, Olesen J

Petersen KA, Birk S, Kitamura K, Olesen J 29 ( 1 ) 23 - 30 2009年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1111/j.1468-2982.2008.01695.x

Minimal change nephrotic syndrome complicated with recurrence of malignant thymoma: an interesting case with remission due to steroid therapy of both nephrotic syndrome and thymoma] 査読あり

Akihiro Fukuda 1, Yuji Sato, Shuji Iwatsubo, Hiroyuki Komatsu, Ryousuke Nishiura, Keiichi Fukudome, Kazuhiro Yamada, Seiichiro Hara, Shouichi Fujimoto, Kazuo Kitamura

Nihon Jinzo Gakkai Shi 51 ( 2 ) 130 - 137 2009年

掲載種別：研究論文（学術雑誌）

食塩摂取量の変化に伴う血中と組織中プロアンジオテンシン-12(proang-12)およびレニン・アンジオテンシン(RA)系因子の変化査読あり

永田さやか、加藤丈司、北村和雄

日本内分泌学会雑誌 85 ( 1 ) 374 - 374 2009年

掲載種別：研究論文（学術雑誌）

地域住民における血中アルドステロンとbody mass index(BMI)およびインスリン値との関連査読あり

野村郁夫、加藤丈司、北村和雄

日本内分泌学会雑誌 85 ( 2 ) 716 - 716 2009年

掲載種別：研究論文（学術雑誌）

話題のホルモン・受容体・酵素: 最近の知見からアドレノメデュリン(AM), PAMPとその受容体査読あり

北村和雄

Heart View 13 ( 12 ) 69 - 75 2009年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンの発見査読あり

北村和雄

日本臨牀 67 ( 6 ) 67 - 72 2009年

掲載種別：研究論文（学術雑誌）

大動脈瘤と炎症細胞(マスト細胞とマクロファージ) 査読あり

鶴田敏博、北村和雄

血管医学 10 ( 3 ) 221 - 229 2009年

掲載種別：研究論文（学術雑誌）

第16回腹部大動脈瘤の発症・進展とアドレノメデュリン査読あり

鶴田敏博、北村和雄

Vascular Medicine 5 ( 3 ) 166 - 172 2009年

掲載種別：研究論文（学術雑誌）

直腸MALTリンパ腫疑診症例から直腸炎型潰瘍性大腸炎へと変化した一例査読あり

中島孝治、彦坂ともみ、星子新理、松本英丈、芦塚伸也、早稲田文子、押川勝太郎、稲津東彦、北村和雄、丸塚浩助、堺雅彦

日本消化器病学会雑誌 106 ( suppl-1.2 ) 484 - 484 2009年

掲載種別：研究論文（学術雑誌）

術前S-1+CDDP療法が奏効した進行胃癌の1例査読あり

中島孝治、彦坂ともみ、星子新理、松本英丈、芦塚伸也、早稲田文子、押川勝太郎、稲津東彦、北村和雄、河野文彰、関屋亮、鬼塚敏男、片岡寛章

日本消化器病学会雑誌 106 ( suppl-2.2 ) 790 - 790 2009年

掲載種別：研究論文（学術雑誌）

盲腸, 上行結腸への浸潤伸展がみられた虫垂杯細胞カルチノイドの一例査読あり

星子新理、彦坂ともみ、早稲田文子、松本英丈、中島孝治、芦塚伸也、押川勝太郎、稲津東彦、北村和雄、日高秀樹、佛坂正幸、千々岩一男、梅北佳子、田中弘之、片岡寛章

日本消化器病学会雑誌 106 ( suppl-2.2 ) 402 - 402 2009年

掲載種別：研究論文（学術雑誌）

5-FU/CDDP併用化学放射線療法にてCRが得られた進行期食道腺癌の1例査読あり

三木吾郎、押川勝太郎、芦塚伸也、中島孝治、早稲田文子、大塚正晃、彦坂ともみ、稲津東彦、北村和雄、田井博、鶴身小都絵

日本消化器病学会雑誌 106 ( suppl-2.2 ) 762 - 762 2009年

掲載種別：研究論文（学術雑誌）

小腸内視鏡で確認しえた心臓原発平滑筋肉腫多発消化管転移の一例査読あり

原口大、彦坂ともみ、星子新理、松本英丈、早稲田文子、芦塚伸也、中島孝治、押川勝太郎、稲津東彦、北村和雄、松田俊太郎、丸塚浩助

日本消化器病学会雑誌 106 ( suppl-2.2 ) 815 - 815 2009年

掲載種別：研究論文（学術雑誌）

原因候補遺伝子アドレノメデュリン遺伝子査読あり

桑迫健二、加藤丈司、北村和雄

日本臨牀 67 ( 6 ) 400 - 404 2009年

掲載種別：研究論文（学術雑誌）

JATOS Study Group

Hypertension Research 31 ( 12 ) 2115 - 2127 2008年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

The benefits of lowering a systolic blood pressure below 140 mmHg in elderly hypertension remain controversial. This study is a prospective, randomized, open-label study with blinded assessment of endpoints to compare the 2-year effect of strict treatment to maintain systolic blood pressure below 140 mmHg with that of mild treatment to maintain systolic blood pressure below 160 but at or above 140 mmHg in elderly hypertensive patients. Patients with essential hypertension (65-85 years old, with a pretreatment systolic blood pressure of above 160 mmHg) were randomly assigned to receive strict treatment (n=2,212) or mild treatment (n=2,206). The baseline drug was efonidipine hydrochloride, a long-acting calcium antagonist. The primary endpoint was the combined incidence of cardiovascular disease and renal failure, and the secondary endpoints were total deaths and any safety problems. Although final blood pressures (systolic/diastolic) were significantly lower in the strict-treatment group compared with the mild-treatment group (135.9/ 74.8 vs. 145.6/78.1 mmHg; p<0.001), the incidence of the primary endpoint was similar in the two groups (86 patients in each group; p=0.99). Total deaths were 54 in the strict-treatment group vs. 42 in the mild-treatment group (p=0.22), and treatment was withdrawn because of adverse events in 36 patients in each group (p=0.99). An interaction between age and treatment for the primary endpoints (p=0.03) was seen. Complex clinical features associated with aging seem to have obscured the difference in effect between the two treatments. Further studies are needed to assess the optimal treatment strategy for hypertension in the elderly.

DOI： 10.1291/hypres.31.2115

Therapeutic efficacy of intra-articular adrenomedullin injection in antigen-induced arthritis in rabbits. "jointly worked" 査読あり

Okura T, Marutsuka K, Hamada H, Sekimoto T, Fukushima T, Asada Y, Kitamura K, Chosa E

Arthritis Res Ther 10 ( 6 ) R133 2008年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1186/ar2550.

Functions of the extracellular histidine residues of receptor activity-modifying proteins vary within adrenomedullin receptors. "jointly worked" 査読あり

Kuwasako K, Kitamura K, Nagata S, Kato J

Biochem Biophys Res Commun 377 ( 1 ) 109 - 113 2008年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1.16/J.BBRC.2008.09.105

Long-term therapy with nifedine-CR improves arterio-sclerosis related markers in patients with untreated essential hypertension. "jointly worked" 査読あり

Kita T, Tokashiki M, Kitamura K

The Open Hypertension Journal 1 1 - 6 2008年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Elevated osteoprotegerin levels predict cardiovascular events in new hemodialysis patients.　"jointly worked" 査読あり

Nishiura R, Fujimoto S, Sato Y, Yamada K, Hisanaga S, Hara S, Nakao H, Kitamura K

American Journal of Nephrology 29 ( 3 ) 257 - 263 2008年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1159/000157629

Serotonin induces vasoconstriction of smooth muscle cell-rich neointima through 5-hydroxytryptamine2A receptor in rabbit femoral arteries. "jointly worked" 査読あり

Nishihira K, Yamashita A, Tanaka N, Moriguchi-Goto S, Imamura T, Ishida T, Kawashima S, Yamamoto R, Kitamura K, Asada Y

J Thromb Haemost 6 ( 7 ) 1207 - 1214 2008年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1111/j.1538-7836.2008.02996.x

Adrenomedullin 2/intermedin-like immunoreactivity in the hypothalamus and brainstem of rats. "jointly worked" 査読あり

Hashimoto H, Kitamura K, Kawasaki M, Saito T, Suzuki H, Otsubo H, Ohbuchi T, Yokoyama T, Fujihara H, Takei Y, Ueta Y

Auton Neurosci 139 ( 1-2 ) 46 - 54 2008年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016/j.autneu.2008.01.003

Effect of tonsillectomy plus steroid pulse therapy on clinical remission of IgA nephropathy: a controlled study. "jointly worked" 査読あり

Komatsu H, Fujimoto S, Hara S, Sato Y, Yamada K, Kitamura K

Clin J Am Soc Nephrol 3 ( 5 ) 1301 - 1307 2008年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.2215/CJN.00310108

Thioredoxin in coronary culprit lesions: Possible relationship to oxidative stress and intraplaque hemorrhage. "jointly worked" 査読あり

Nishihira K, Yamashita A, Imamura T, Hatakeyama K, Sato Y, Nakamura H, Yodoi J, Ogawa H, Kitamura K, Asada Y

Atherosclerosis 201 ( 2 ) 360 - 367 2008年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1016/J.ATHEROSCLEROSIS.2008.03.005

Reciprocal production of adiponectin and C-reactive protein in coronary circulation of patients with and without coronary artery disease."jointly worked" 査読あり

Kawagoe J, Imamura T, Date H, Ideguchi T, Koyama S, Nagoshi Y, Tatsumoto M, Onitsuka H, Iwakiri H, Kitamura K

Horm Metab Res 40 ( 8 ) 578 - 580 2008年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1055/s-2008-1073150

Adventitial mast cells contribute to pathogenesis in the progression of abdominal aortic aneurysm. "jointly worked" 査読あり

Tsuruda T, Kato J, Hatakeyama K, Kojima K, Yano M, Yano Y, Nakamura K, Nakamura-Uchiyama F, Matsushima Y, Imamura T, Onitsuka T, Asada Y, Nawa Y, Eto T, Kitamura K

Circ Res 102 ( 11 ) 1368 - 1377 2008年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1161/CIRCRESAHA.108.173682

Localization of the novel angiotensin peptide, angiotensin-(1-12), in heart and kidney of hypertensive and normotensive rats. "jointly worked" 査読あり

Jessup JA, Trask AJ, Chappell MC, Nagata S, Kato J, Kitamura K, Ferrario CM

Am J Physiol Heart Circ Physiol 294 ( 6 ) H2614 - H2618 2008年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1152/ajpheart.91521.2007

降圧治療中の高血圧患者の実態と積極的降圧治療の有効性と安全性に関する調査．（共著）査読あり

北　俊弘,横田直人,市来能成,綾部隆夫,加藤丈司,江藤胤尚,北村和雄

Progress in Medicine 28 ( 5 ) 1173 - 1177 2008年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Exfoliation of gastric pit-parietal cells into the gastric lumen associated with a stimulation of isolated rat gastric mucosa in vitro: a morphological study by the application of cryotechniques. "jointly worked" 査読あり

Aoyama F, Sawaguchi A, Ide S, Kitamura K, Suganuma T

Histochem Cell Biol 129 ( 6 ) 785 - 793 2008年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1007/s00418-008-0403-1

各種腎機能評価法の比較検討．(共著）査読あり

岩坪修司,藤元昭一,福田顕弘,西桂子,馬場明子,中川真菜,福留理恵,福留慶一,山田和弘,原誠一郎,北村和雄

宮崎医学会誌 31 116 - 119 2008年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Adrenomedullinは実験大腸炎に対して抗炎症作用を有する査読あり

芦塚伸也、彦坂ともみ、田中規幹、松本英丈、早稲田文子、押川勝太郎、大塚正晃、稲津東彦、北村和雄

日本消化器病学会雑誌 105 ( suppl-2.2 ) 796 - 796 2008年

掲載種別：研究論文（学術雑誌）

薬剤誘発性高血圧査読あり

北村和雄

宮崎医学会誌 32 1 - 5 2008年

掲載種別：研究論文（学術雑誌）

潰瘍性大腸炎に対する白血球除去療法(LCAP)抗凝固剤としての低分子ヘパリンの有効性と安全性に対する検討査読あり

彦坂ともみ、芦塚伸也、松本英丈、早稲田文子、大塚正晃、押川勝太郎、稲津東彦、北村和雄

日本消化器病学会雑誌 105 ( suppl-2.2 ) 808 - 808 2008年

掲載種別：研究論文（学術雑誌）

心筋梗塞ラットにおけるカンデサルタンとアドレノメデュリン(AM)の併用効果査読あり

陳広亜、北村和雄、加藤丈司

日本内分泌学会雑誌 84 ( 2 ) 681 - 681 2008年

掲載種別：研究論文（学術雑誌）

ネフローゼ症候群の合併症査読あり

岩切太幹志、藤元昭一、北村和雄

臨牀と研究 85 ( 11 ) 1641 - 1647 2008年

掲載種別：研究論文（学術雑誌）

プロアンジオテンシン-12 査読あり

永田

分子心血管病 9 ( 3 ) 288 - 292 2008年

掲載種別：研究論文（学術雑誌）

Combined use of brain natriuretic peptide and C-reactive protein for predicting cardiovascular risk in outpatients with type 2 diabetes mellitus. 査読あり

Tsuruda T, Kato J, Sumi T, Mishima K, Masuyama H, Nakao H, Imamura T, Eto T, Kitamura K

Vascular Health and Risk Management 3 417 - 423 2007年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Outcome of ANCA-associated primary renal vasculitis in miyazaki prefecture. 査読あり

Uezono S, Sato Y, Hara S, Hisanaga S, Fukudome K, Fujimoto S, Nakao H, Kitamura K, Kobayashi S, Suzuki K, Hashimoto H, Nunoi H

Intern Med 46 815 - 822 2007年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Expression of interleukin-18 in coronary plaque obtained by atherectomy from patients with stable and unstable angina. 査読あり

Nishihira K, Imamura T, Hatakeyama K, Yamashita A, Shibata Y, Date H, Manabe I, Nagai R, Kitamura K, Asada Y

Thromb Res 121 275 - 279 2007年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

組織アンジオテンシンの分子型の検討とproangiotensin-12の発見査読あり

永田さやか、加藤丈司、南野直人、北村和雄、江藤胤尚

日本内分泌学会雑誌 83 ( 1 ) 107 - 107 2007年

掲載種別：研究論文（学術雑誌）

不全心の分子機構に関する最新の基礎研究神経体液性因子の活性化の分子機構と作用アドレノメデュリン査読あり

北村和雄

日本臨牀 65 ( 4 ) 170 - 174 2007年

掲載種別：研究論文（学術雑誌）

Ca拮抗薬の心血管作用を再考する査読あり

松﨑益徳、北村和雄、宮崎俊一、楽木宏実、村上達明

日本内分泌学会雑誌 83 ( 2 ) 413 - 413 2007年

掲載種別：研究論文（学術雑誌）

ラット脳内におけるアドレノメデュリン2の局在と中枢性オキシトシン分泌作用における特異的受容体の検討査読あり

橋本弘史、兵藤晋、藤原広明、樋口隆、北村和雄、竹井祥郎、上田陽一

日本内分泌学会雑誌 83 ( 1 ) 107 - 107 2007年

掲載種別：研究論文（学術雑誌）

レニン・アンジオテンシン系の新たなペプチドproangiotensin-12の単離同定と組織濃度の検討査読あり

永田さやか、加藤丈司、北村和雄

日本内分泌学会雑誌 83 ( 2 ) 580 - 580 2007年

掲載種別：研究論文（学術雑誌）

Isolation and identification of proangiotensin-12, a possible component of the renin-angiotensin system 査読あり

Nagata S., Kato J., Sasaki K., Minamino N., Eto T., Kitamura K.

Biochemical and Biophysical Research Communications 350 ( 4 ) 1026 - 1031 2006年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

The renin-angiotensin (RA) system plays an important role in regulating blood pressure and fluid balance. In the search for bioactive peptides with an antibody binding to the N-terminal portion of angiotensin II (Ang II), we isolated a new angiotensinogen-derived peptide from the rat small intestine. Consisting of 12 amino acids, this peptide was termed proangiotensin-12 based on its possible role of an Ang II precursor. Proangiotensin-12 constricted aortic strips and, when infused intravenously, raised blood pressure in rats, while both the vasoconstrictor and pressor response to proangiotensin-12 were abolished by captopril and by CV-11974, an Ang II type I receptor blocker. Proangiotensin-12 is abundant in a wide range of organs and tissues including the small intestine, spleen, kidneys, and liver of rats. The identification of proangiotensin-12 suggests a processing cascade of the RA system, different from the cleavage of angiotensinogen to Ang I by renin. © 2006.

DOI： 10.1016/j.bbrc.2006.09.146

Adrenomedullin And Its Related Peptides 査読あり

Kitamura K., Kato J.

Handbook of Biologically Active Peptides 1163 - 1168 2006年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Handbook of Biologically Active Peptides

Adrenomedullin (AM) is a potent vasodilator peptide that exerts major effects on cardiovascular function. AM, initially isolated from human pheochromocytoma tissue, is biosynthesized in a wide variety of organs and cells. The basic characteristic effect of AM is a potent, long-lasting hypotension that is dose-dependent in several species, including humans. AM dilates resistance vessels in the kidney, brain, lung, hind limbs, and mesentery in animals. In addition to AM, proadrenomedullin N-terminal 20 peptide (PAMP) is found to be processedfrom the AM precursor. Both AM and PAMP show hypotensive effects in anesthetized rats but exhibit different hypotensive mechanisms. Further, AM possesses multiple biological effects closely related to cardiovascular homeostasis. Plasma AM concentration is increased in patients with several cardiovascular diseases such as hypertension, congestive heart failure, renal failure, and septic shock. It has been recognized that AM is one of the important vasoactive peptides involved in the physiology and pathophysiology of circulation and body fluid control. © 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/B978-012369442-3/50162-8

Soluble guanylate cyclase stimulation on cardiovascular remodeling in angiotensin II-induced hypertensive rats 査読あり

Masuyama H., Tsuruda T., Kato J., Imamura T., Asada Y., Stasch J.P., Kitamura K., Eto T.

Hypertension 48 ( 5 ) 972 - 978 2006年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension

It is unknown whether long-term pharmacological stimulation of soluble guanylate cyclase (sGC), elevating intracellular cGMP levels, has a beneficial effect on hypertension. The purpose of this study is to investigate the effects of BAY41-2272, an orally available sGC stimulator, on cardiovascular remodeling in hypertensive rats. Eight-week-old male Wistar rats with hypertension induced by angiotensin II infused subcutaneously at 250 ng/kg per minute were treated orally with a low ([L] 2 mg/kg per day) or high ([H] 10 mg/kg per day) dose of BAY41-2272 for 14 days. BAY41-2272-H partially suppressed the rise in blood pressure and reduced the heart weight (4.20±0.34 versus 3.68±0.20 mg/g; P<0.01), whereas BAY41-2272-L had no effect. However, both doses decreased the angiotensin II-induced left ventricular accumulation of collagen in the perivascular area (L, -20%, P<0.05; H, -30%, P<0.01) and myocardial interstitium (L, -21%, P<0.05; H, -38%, P<0.01), reducing the number of activated fibroblasts surrounding coronary arteries (L, -74%; H, -79%; P<0.05). BAY41-2272 downregulated the angiotensin II-induced left ventricular gene expression of type 1 collagen (L, -41%, P<0.05; H, -49%, P<0.01) and transforming growth factor-β1 (L, -49%, P<0.05; H, -65%, P<0.01). cGMP levels were elevated by BAY41-2272 not only in the left ventricle, but also in cultured cardiac fibroblasts, resulting in reduced thymidine incorporation into the cells. Thus, stimulation of sGC by BAY41-2272 attenuates fibrosis of the left ventricle in rats with angiotensin II-induced hypertension partly in a pressure-independent manner, suggesting an important role for sGC generating cGMP in inhibiting cardiovascular remodeling. © 2006 American Heart Association, Inc.

DOI： 10.1161/01.HYP.0000241087.12492.47

Bone and bone related biochemical examinations. Hormone and hormone related substances. Calcitonin gene-related peptide (CGRP) 査読あり

Kenji Kuwasako 1, Kazuo Kitamura

Clin Calcium 16 ( 6 ) 905 - 912 2006年6月

掲載種別：研究論文（学術雑誌）

Adrenomedullin in mast cells of abdominal aortic aneurysm 査読あり

Tsuruda T., Kato J., Hatakeyama K., Yamashita A., Nakamura K., Imamura T., Kitamura K., Onitsuka T., Asada Y., Eto T.

Cardiovascular Research 70 ( 1 ) 158 - 164 2006年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：Cardiovascular Research

Objectives: Produced by vascular walls, adrenomedullin (AM) exerts antifibrotic actions in the process of cardiovascular remodeling. The purpose of this study was to examine the pathophysiological role of AM in the development of human abdominal aortic aneurysm (AAA). Methods and results: Immunohistochemical analyses revealed that vascular smooth muscle cells in the media were positive for AM in the early stage of atherosclerotic aorta. Intense immunoreactivity was observed in mast cells of the outer media and adventitia of AAA, and the number of mast cells was greater (p < 0.01) in AAA than in atherosclerotic aorta without any aneurysmal change. To determine the role of AM in mast cells, we examined cultured human mast cell leukemia line-1 (HMC-1) and fibroblasts isolated from AAA patients. Cultured HMC-1 cells were found to express preproAM gene and release AM peptide into the cultured media. When assessed by collagenase-sensitive [3H]proline incorporation and procollagen type I C-peptide secretion, collagen synthesis in co-culture of HMC-1 and the fibroblasts was reduced by 10- 6 mol/L synthetic AM, while conversely, it increased following blockade of the action of endogenous AM with 10 μg/mL anti-AM monoclonal antibody. Conclusion: The present study suggests an anti-fibrotic role for AM released from mast cells, providing new insight into the biological actions of mast cell-derived AM in the development of AAA. © 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.cardiores.2006.02.003

Functions of the cytoplasmic tails of the human receptor activity-modifying protein components of calcitonin gene-related peptide and adrenomedullin receptors 査読あり

レニン・アンジオテンシン系阻害薬を再考する査読あり

北村和雄

臨床のあゆみ 69 24 - 25 2006年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Plasma adrenomedullin level and development of hypertension 査読あり

Kato J, Kitamura K, Eto T

J Hum Hypertens 20 566 - 570 2006年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Increased production of adrenomedullin in glomeruli from anti-glomerular basement membrane (GBM) glomerulonephritis rats treated with methylprednisolone. 査読あり

Iwatsubo S, Fujimoto S, Matsumoto M, Sato Y, Hara S, Kitamura K, Eto T

Nephron Exp Nephrol 104 e41 - e47 2006年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

長期のベニジピン療法により降圧を超えた動脈硬化度の改善が得られる査読あり

北　俊弘、鈴木良彦、江藤胤尚、北村和雄

Arterial Stiffness 10 48 - 49 2006年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Kuwasako K., Cao Y.N., Chu C.P., Iwatsubo S., Eto T., Kitamura K.

Journal of Biological Chemistry 281 ( 11 ) 7205 - 7213 2006年3月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biological Chemistry

Receptor activity-modifying proteins (RAMPs) enable calcitonin receptor-like receptor (CRLR) to function as a calcitonin gene-related peptide receptor (CRLR/RAMP1) or an adrenomedullin (AM) receptor (CRLR/RAMP2 or -3). Here we investigated the functions of the cytoplasmic C-terminal tails (C-tails) of human RAMP1, -2, and -3 (hRAMP1, -2, and -3) by cotransfecting their C-terminal deletion or progressive truncation mutants into HEK293 cells stably expressing hCRLR. Deletion of the C-tail from hRAMP1 had little effect on the surface expression, function, or intracellular trafficking of the mutant heterodimers. By contrast, deletion of the C-tail from hRAMP2 disrupted transport of hCRLR to the cell surface, resulting in significant reductions in 125I-hAM binding and evoked cAMP accumulation. The transfection efficiency for the hRAMP2 mutant was comparable with that for wild-type hRAMP2; moreover, immunocytochemical analysis showed that the mutant hRAMP2 remained within the endoplasmic reticulum. FACS analysis revealed that deleting the C-tail from hRAMP3 markedly enhances AM-evoked internalization of the mutant heterodimers, although there was no change in agonist affinity. Truncating the C-tails by removing the six C-terminal amino acids of hRAMP2 and -3 or exchanging their C-tails with one another had no effect on surface expression, agonist affinity, or internalization of hCRLR, which suggests that the highly conserved Ser-Lys sequence within hRAMP C-tails is involved in cellular trafficking of the two AM receptors. Notably, deleting the respective C-tails from hRAMPs had no effect on lysosomal sorting of hCRLR. Thus, the respective C-tails of hRAMP2 and -3 differentially affect hCRLR surface delivery and internalization. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI： 10.1074/jbc.M511147200

Overexpression of proadrenomedullin N-terminal 20 peptide blunts blood pressure rise and attenuates myocardial hypertrophy and fibrosis in hypertensive rats 査読あり

テルミサルタンが、あらゆる臓器障害に先行して起こる血管内皮機能障害の指標であるNOを増加させたことは、きわめて意義深い査読あり

北村和雄

Medical Tribune 2006年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）

第14回(最終回) アドレノメデュリン査読あり

加藤丈司、北村和雄、江藤胤尚

血圧 13 ( 2 ) 225 - 227 2006年

掲載種別：研究論文（学術雑誌）

PAMP単独過剰発現ラットの開発とPAMPの血管新生作用査読あり

北村和雄、Yuan-NingCao、江藤胤尚

日本内分泌学会雑誌 82 ( 1 ) 116 - 116 2006年

掲載種別：研究論文（学術雑誌）

アドレノメデュリン査読あり

北村和雄

日本臨牀 64 ( 2 ) 217 - 221 2006年

掲載種別：研究論文（学術雑誌）

降圧因子としてのアドレノメデュリンとPAMP 査読あり

北村和雄

循環制御 27 ( 4 ) 312 - 316 2006年

掲載種別：研究論文（学術雑誌）

糖尿病患者の心血管発症イベントの抑制を目指して:BNPとCRPのイベント発症予測因子としての有用性査読あり

鶴田敏博、加藤丈司、隅専浩、三嶋和也、今村卓郎、北村和雄、江藤胤尚

日本内分泌学会雑誌 82 ( 2 ) 506 - 506 2006年

掲載種別：研究論文（学術雑誌）

閉塞性動脈血栓の形成における5-HT2A受容体の関与‐家兎動脈硬化性血栓モデルでの検討査読あり

西平賢作、山下篤、田中直子、川本理一朗、今村卓郎、山本隆一、北村和雄、浅田祐士郎

血圧 13 ( 9 ) 951 - 954 2006年

掲載種別：研究論文（学術雑誌）

Long-term anti-hypertensive therapy with benidipine improves arterial stiffness over blood pressure lowering 査読あり

北　俊弘,Suzuki Y,江藤　胤尚,北村　和雄

Hypertens Res 28 959 - 964 2005年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Adrenomedullin a protective factor for blood vessels 査読あり

加藤　丈司,鶴田　敏博,北　俊弘,北村　和雄,江藤　胤尚

Arterioscler Thromb Vasc Biol 25 2480 - 2487 2005年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Effect of adrenomedullin administration on acetic acid-induced colitis in rats 査読あり

芦塚　伸也,石川　直人,加藤　丈司,山家　純一,稲津　東彦,北村　和雄,江藤　胤尚

Peptides 26 2610 - 2615 2005年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Adrenomedullin release in the rat mesenteric resistance artery 査読あり

Akiyama S,Hobara N,Naruo N,Hashida S,北村　和雄,江藤　胤尚,Kawasaki H

Peptides 26 2222 - 2230 2005年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cao Y.N., Kuwasako K., Kato J., Nishihira K., Asada Y., Eto T., Kitamura K.

FEBS Letters 579 ( 22 ) 4997 - 5001 2005年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：FEBS Letters

We developed a transgenic (Tg) rat model that overexpresses human proadrenomedullin N-terminal 20 peptide (PAMP) only and then compared the effects of unilateral nephrectomy followed by a high salt diet for five weeks in Tg and wild-type rats. We found that systolic blood pressure was significantly lower in Tg UNX rats and cardiac hypertrophy and myocardial fibrosis was also attenuated in Tg rats. Evaluation of gene expression showed suppression of cardiac local renin-angiotensin system (RAS) in Tg rat. These results suggest that in addition to reducing blood pressure, PAMP suppresses cardiac hypertrophy through negative regulation of the local cardiac RAS. © 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.febslet.2005.08.007

アドレノメデュリンと血庄調節異常査読あり

加藤丈司、北村和雄、江藤胤尚

生活習慣病の最前線. Molecular medicine : 分子生物学から臨床へ 42 ( 1 ) 234 - 237 2005年9月

掲載種別：研究論文（学術雑誌）

Beyond vasodilation: The antioxidant effect of adrenomedullin in Dahl salt-sensitive rat aorta 査読あり

Cao Y.N., Kuwasako K., Kato J., Yanagita T., Tsuruda T., Kawano J., Nagoshi Y., Chen A.F., Wada A., Suganuma T., Eto T., Kitamura K.

Biochemical and Biophysical Research Communications 332 ( 3 ) 866 - 872 2005年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

We have investigated the antioxidant effect of adrenomedullin (AM) on endothelial function in the Dahl salt-sensitive (DS) rat hypertension model. Dahl salt-resistant (DR) and DS rats were fed an 8% NaCl diet. In addition, the DS rats were subcutaneously infused with either saline or recombinant human AM for 4 weeks. Although systolic blood pressures measured weekly in AM- and saline-infused rats did not significantly differ, aortic O2- levels were significantly (P < 0.01) higher in the latter. Likewise, both endothelial nitric oxide synthase (eNOS) mRNA and protein were significantly higher in saline-infused DS rats. Infusion of AM reduced both O2- and eNOS expression to levels comparable to those seen in DR rats. AM infusion also upregulated the gene expression of guanosine-5′-triphosphate cyclohydrolase I and downregulated the expression of p22phox, suggesting that AM increased the NOS coupling and bioavailability of NO. AM possesses significant antioxidant properties that improve endothelial function. © 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.05.034

Angiotensin II stimulates cardiac adrenomedullin production and causes accumulation of mature adrenomedullin independently of hemodynamic stress in vivo 査読あり

鬼塚　久充,今村　卓郎,山家　純一,桑迫　健二,北村　和雄,江藤　胤尚

Horm Metab Res 37 281 - 285 2005年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Antifibrotic effect of adrenomedullin on coronary adventitia in angiotensin II-induced hypertensive rats 査読あり

Tsuruda T., Kato J., Hatakeyama K., Masuyama H., Cao Y.N., Imamura T., Kitamura K., Asada Y., Eto T.

Cardiovascular Research 65 ( 4 ) 921 - 929 2005年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Cardiovascular Research

Objective: The extracellular matrix (ECM) determines the structural integrity of the heart and vasculature, participating in cardiovascular remodeling. We previously reported that adrenomedullin (AM) inhibited cellular proliferation and protein synthesis of cardiac fibroblasts; however, the precise mechanisms of AM actions as an antifibrotic factor remain unknown. The purpose of this study was to examine the biological actions of AM against the profibrotic factor angiotensin II (Ang II) in coronary adventitia. Methods and results: Rats with hypertension induced by Ang II infusion were administered 0.06 μg/kg/min recombinant human AM subcutaneously for 14 days. The AM infusion significantly (p<0.05) reduced the Ang II-induced increase of coronary adventitial fibroblasts expressing Ki-67 and α-smooth muscle actin (α-SMA) in the left ventricle, by 65%, and 62%, respectively, without affecting systolic blood pressure, left ventricle/body weight, or cross-sectional area of myocardial fibers. Collagen deposition of coronary arteries was reduced by the AM infusion (-24%, p<0.01), and these effects of AM were accompanied by significant reductions in gene expression of type 1 collagen (-49%, p<0.05) and transforming growth factor-β1 (TGF-β1) (-55%, p<0.01). In cultured cardiac fibroblasts, 10-7 mol/L AM exerted an inhibitory effect on TGF-β1-induced α-SMA expression (p<0.01) that was mimicked by 8-bromo-cAMP and attenuated by the protein kinase A inhibitor H-89. Conclusion: AM decreased Ang II-induced collagen deposition surrounding the coronary arteries, inhibiting myofibroblast differentiation and expressions of ECM-related genes in rats. The present findings further support the biological action of AM as an antifibrotic factor in vascular remodeling. © 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.cardiores.2004.11.004

Adrenomedullin alleviates not only neointimal formation but also perivascular hyperplasia following arterial injury in rats 査読あり

アドレノメデュリンの測定と血中濃度All of adrenomedullin (2005). Adrenomedullin assay and its plasma level. 査読あり

加藤丈司、北村和雄

ホルモンと臨牀 53 ( 3 ) 269 - 274 2005年3月

掲載種別：研究論文（学術雑誌）

Atrial and brain natriuretic peptides as markers of cardiac load and volume retention in primary aldosteronism 査読あり

加藤　丈司,江藤　琢磨,北村　和雄,江藤　胤尚

Am J Hypertens 18 354 - 357 2005年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

心血管作動物質と循環器疾患－最近の話題－　アドレノメデュリンの循環器系における役割査読あり

北村和雄

循環器内科 57 ( 2 ) 134 - 140 2005年2月

掲載種別：研究論文（学術雑誌）

Tsuruda T., Kato J., Matsui E., Hatakeyama K., Masuyama H., Imamura T., Kitamura K., Asada Y., Eto T.

European Journal of Pharmacology 508 ( 1-3 ) 201 - 204 2005年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Pharmacology

Producing components of the extracellular matrix, the vascular adventitia has been recognized as an important modulator of the vascular remodeling process, which determines the vessel architecture. In this study, we examined the effect of the vasodilator peptide adrenomedullin on vascular remodeling induced by balloon injury of rat carotid arteries. Endothelial denudation with wall stretch by ballooning not only induced neointimal formation accompanied with a reduced ratio of the lumen to vessel area, but also increased the fibroblast number and collagen deposition in the adventitial layer. When compared with the saline infusion, intravenous adrenomedullin infusion at 200 ng/h for 14 days suppressed the neointimal formation (-33%, P=0.033), reversing the ratio of lumen to vessel ratio (P=0.030), without affecting systolic blood pressure. Moreover, the adrenomedullin infusion decreased the number of adventitial fibroblasts (-41%, P<0.001) and the collagen deposition (-36%, P=0.006) in the adventitial layer of the injured artery. In conclusion, the intravenous adrenomedullin infusion effectively attenuates vascular remodeling following the arterial injury via suppression of hyperplasia in the intima and adventitia, suggesting a potential of adrenomedullin as a therapeutic tool against vascular remodeling. © 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejphar.2004.12.019

Inhibited cardiac hypertrophy in proadrenomedullin NH2-Terminal 20 peptide-transgenic rat with unilateral ... 査読あり

Yuan-NingCao、北村和雄、桑迫健二、加藤丈司、西平賢作、浅田祐士郎、江藤胤尚

Journal of Adaptation Medicine 9 ( 1 ) 30 - 30 2005年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンの臨床応用査読あり

北村和雄

最新医学 60 ( 7 ) 1600 - 1605 2005年

掲載種別：研究論文（学術雑誌）

内分泌学的検査　アドレノメデュリン査読あり

北村和雄、江藤胤尚

日本臨牀 63 ( 8 ) 592 - 594 2005年

掲載種別：研究論文（学術雑誌）

アドレノメデュリン研究の新展開（座談会）査読あり

北村和雄、下澤達雄、伊藤裕、永谷憲歳

分子心血管病 6 ( 5 ) 447 - 458 2005年

掲載種別：研究論文（学術雑誌）

総論：アドレノメデュリンと関連ペプチドの構造と作用査読あり

北村和雄

分子心血管病 6 ( 5 ) 459 - 463 2005年

掲載種別：研究論文（学術雑誌）

新たな循環調節因子の研究を推進することで医学と医療の発展に貢献する-宮崎大学医学部内科学第一講座高血圧研究室査読あり

北村和雄

分子心血管病 6 ( 1 ) 105 - 108 2005年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンの最近の知見査読あり

北村和雄

日本妊娠高血圧学会雑誌 13 9 - 13 2005年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンの最近の知見　Recent advancement in adrenomedullin science 査読あり

北村和雄

日本妊娠高血圧学会プログラム・抄集 26 17 - 17 2005年

掲載種別：研究論文（学術雑誌）

アドレノメデュリン(AM)とアドレノメデュリン2(AM2)のラットにおける組織中および血中濃度の比較査読あり

北村和雄、渡嘉敷真理子、Yuan-NingCao、加藤丈司、江藤胤尚

適応医学 9 ( 1 ) 30 - 30 2005年

掲載種別：研究論文（学術雑誌）

アドレノメデュリン(AM)とアドレノメデュリン2(AM2)のラット組織中と血中濃度の比較査読あり

北村和雄、江藤胤尚

日本内分泌学会雑誌 81 ( 1 ) 182 - 182 2005年

掲載種別：研究論文（学術雑誌）

Adrenomedullin Alleviates Not Only Neointimal Formation But Also Perivascular Hyperplasia Following Arterial Injury ... 査読あり

鶴田敏博、加藤丈司、松井英三郎、畠山金太、増山浩幸、今村卓郎、北村和雄、浅田祐士郎、江藤胤尚

Journal of Adaptation Medicine 9 ( 1 ) 31 - 31 2005年

掲載種別：研究論文（学術雑誌）

カルシトニン遺伝子関連ペプチド受容体の特徴査読あり

桑迫健二、北村和雄桑迫、江藤胤尚

日本臨牀 63 ( 10 ) 254 - 259 2005年

掲載種別：研究論文（学術雑誌）

アドレノメデュリン受容体の薬理学的特徴および病態生理学的意義査読あり

桑迫健二、北村和雄

分子心血管病 6 ( 5 ) 471 - 478 2005年

掲載種別：研究論文（学術雑誌）

原発性アルドステロン症患者(PA)の前負荷や後負荷と血中ANPおよびBNP濃度査読あり

加藤丈司、北村和雄、江藤胤尚

日本内分泌学会雑誌 81 ( 2 ) 564 - 564 2005年

掲載種別：研究論文（学術雑誌）

心血管に対するストレスと降圧因子アドレノメデュリン査読あり

加藤丈司、北村和雄、江藤胤尚

適応医学 9 ( 2 ) 30 - 36 2005年

掲載種別：研究論文（学術雑誌）

心血管に対するストレスと降圧系ペプチド査読あり

加藤丈司、北村和雄、江藤胤尚

適応医学 9 ( 1 ) 20 - 20 2005年

掲載種別：研究論文（学術雑誌）

Adrenomedullin induces matrix metalloproteinase-2 activity in rat aortic adventitial fibroblasts. 査読あり

加藤　丈司,畠山　金太,今村　卓郎,北村　和雄,浅田　祐士郎,江藤　胤尚

Biochem Biophys Res Commun. 3 ( 325 ) 80 - 84 2004年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Adrenomedullin and receptor activity modifying proteins in glomeruli with Thy.1 glomerulonephritis 査読あり

Matsumoto Michitaka,藤元　昭一,岩坪　修司,佐藤　祐二,原　誠一郎,北村　和雄,江藤　胤尚

Clin Exper Nephrol 8 316 - 321 2004年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Adrenomedullin receptors: pharmacological features and possible pathophysiological roles 査読あり

桑迫　健二,曹　袁寧,名越　康子,北村　和雄,江藤　胤尚

Peptides 25 2003 - 2012 2004年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Adrenomedullin as a sensitive marker for coronary and peripheral arterial complications in patients with atherosclerotic risks 査読あり

鈴木　良彦,Horio Takeshi,Nonogi Hiroshi,Hayashi Tokio,北村　和雄,江藤　胤尚,Kangawa Kenji,Kawano Yuhei

Peptides 25 1321 - 1326 2004年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Adrenomedullin administration immediately after myocardial infarction ameliorates progression of heart failure in rats. 査読あり

加藤　丈司,北村　和雄,鬼塚　久充,今村　卓郎,丸塚　浩助,浅田　祐士郎,江藤　胤尚

Circulation. 27 ( 110 ) 426 - 431 2004年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Tumor necrosis factor-α downregulates adrenomedullin receptors in human coronary artery smooth muscle cells 査読あり

名越　康子,桑迫　健二,曹　袁寧,今村　卓郎,北村　和雄,江藤　胤尚

Peptides 25 1115 - 1121 2004年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Differential gene expression of adrenomedullin receptors in pressure-and volume-overloaded heart-role of angiotensin II 査読あり

鬼塚　久充,今村　卓郎,伊藤　薫,桑迫　健二,Yamakawa Hiroshi,Hirano Shuji,北村　和雄,江藤　胤尚

Peptides 25 1107 - 1114 2004年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

降圧に働く内分泌因子査読あり

北村和雄

ホルモンと臨牀 52 ( 5 ) 401 - 408 2004年5月

掲載種別：研究論文（学術雑誌）

Characterization of the human calcitonin gene-related peptide receptor subtypes associated with receptor activity-modifying proteins 査読あり

桑迫　健二,曹　袁寧,名越　康子,鶴田　敏博,北村　和雄,江藤　胤尚

Mol Pharmacol 65 207 - 213 2004年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Adrenomedullin administration immediately after myocardial infarction ameliorates progression of heart failure in rats. 査読あり

中村　亮斉,加藤　丈司,北村　和雄,鬼塚　久充,今村　卓郎,丸塚　浩助,浅田　祐士郎,寒川　賢治,江藤　胤尚

Circulation 110 ( 4 ) 426 - 431 2004年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Disassociated increases of adrenomedullin in the rat cerebrospinal fluid and plasma after salt loading and systemic administration of lipopolysaccharide 査読あり

Chen Lei,Hashida Seiichi,北村　和雄,江藤　胤尚,Kangawa Kenji,Serino Ryota,Kis Bela,Yamashita Hiroshi,Ueta Yoichi

Peptides 25 609 - 614 2004年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Plasma adrenomedullin concentration is increased in patients with peripheral arterial occlusive disease associated with vascular inflammation 査読あり

鈴木　良彦,Horio Takeshi,Hayashi Tokio,Nonogi Hiroshi,北村　和雄,江藤　胤尚,Kangawa Kenji,Kawano Yuhei

Regul Pept 118 99 - 104 2004年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Effects of c-reactive protein on atherogenic mediators and adrenomedullin in human coronary artery endothelial and smooth muscle cells 査読あり

名越　康子,桑迫　健二,曹　袁寧,北村　和雄,江藤　胤尚

Biochem Biophys Res Commun 314 1057 - 1063 2004年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Development of an ultrasensitive enzyme immunoassay for human proadrenomedullin N-terminal 20 peptide and direct measurement of two molecular forms of PAMP in plasma from healthy subjects and patients with cardiovascular disease 査読あり

橋田　誠一,北村　和雄,長友美達,柴田　剛徳,今村　卓郎,山田　和弘,藤元　昭一,加藤　丈司,森下　和広,江藤　胤尚

Clin Biochem 37 ( 1 ) 14 - 21 2004年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

病態と疾患からみたアドレノメデュリン心不全査読あり

加藤丈司、北村和雄、江藤胤尚

日本臨牀 62 ( 9 ) 269 - 272 2004年

掲載種別：研究論文（学術雑誌）

腫瘍壊死因子(TNF)-αはヒト冠動脈平滑筋細胞のアドレノメデュリン(AM)受容体をdown regulationする査読あり

名越康子、桑迫健二、曹袁寧、北村和雄、今村卓郎、江藤胤尚

日本内分泌学会雑誌 80 ( 2 ) 492 - 492 2004年

掲載種別：研究論文（学術雑誌）

ヒト冠動脈の培養内皮および平骨筋細胞に発現している動脈硬化促進因子とアドレノメデュリンに対するC反応性蛋白の効果査読あり

名越康子、桑迫健二、曹袁寧、北村和雄、今村卓郎、江藤胤尚

臨床高血圧 10 ( 2 ) 136 - 137 2004年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンと関連ペプチドの基礎研究と臨床応用の可能性査読あり

北村和雄、江藤胤尚

日本内分泌学会雑誌 80 ( 1 ) 38 - 38 2004年

掲載種別：研究論文（学術雑誌）

治療抵抗性高血圧に低用量スピロノラクトンが有用である査読あり

北村和雄

臨床高血圧 10 ( 2 ) 132 - 133 2004年

掲載種別：研究論文（学術雑誌）

血中DRPは高血圧発症のリスクと関係がある査読あり

北村和雄

臨床高血圧 10 ( 2 ) 134 - 135 2004年

掲載種別：研究論文（学術雑誌）

ほ乳類に存在する新たなアドレノメデュリン：強力な心血管・腎の調節因子査読あり

北村和雄

臨床高血圧 10 ( 2 ) 130 - 131 2004年

掲載種別：研究論文（学術雑誌）

基礎研究の進展アドレノメデュリンとPAMPの測定法査読あり

北村和雄

日本臨牀 62 ( 9 ) 216 - 219219 2004年

掲載種別：研究論文（学術雑誌）

基礎研究の進展 PAMP : アドレノメデュリン前駆体より生合成される新しい降圧ペプチド査読あり

北村和雄

日本臨牀 62 ( 9 ) 203 - 206206 2004年

掲載種別：研究論文（学術雑誌）

基礎研究の進展アドレノメデュリンの構造, 遺伝子, 生合成査読あり

北村和雄

日本臨牀 62 ( 9 ) 184 - 188 2004年

掲載種別：研究論文（学術雑誌）

高血圧性臓器障害に関する基礎研究　アドレノメデュリン査読あり

北村和雄、江藤胤尚

日本臨牀 62 ( 3 ) 239 - 242 2004年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンは線維芽細胞の活性化とTransforming Growth Factor-β1の発現を抑制することにより冠動脈マトリックスリモデリングを抑制する査読あり

鶴田敏博、畠山金太、増山浩幸、加藤丈司、今村卓郎、北村和雄、浅田裕士郎、江藤胤尚

日本内分泌学会雑誌 80 ( 2 ) 493 - 493 2004年

掲載種別：研究論文（学術雑誌）

特論アドレノメデュリンの心筋梗塞後リモデリングへの臨床応用査読あり

中村亮斉、加藤丈司、北村和雄、今村卓郎、江藤胤尚

日本臨牀 62 ( 9 ) 302 - 306 2004年

掲載種別：研究論文（学術雑誌）

Human Adrenomedullin(hAM)およびHuman Proadrenomedullin N-termimal 20 peptide(hPAMP)の超高感度測定法の関発と臨床応用査読あり

橋田誠一、北村和雄、森下和広、江藤胤尚、

日本内分泌学会雑誌 80 ( 1 ) 197 - 197 2004年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンの臨床的意義と新たな研究展開査読あり

加藤丈司、北村和雄、江藤胤尚

日本内分泌学会雑誌 80 ( 1 ) 72 - 72 2004年

掲載種別：研究論文（学術雑誌）

Increased plasma and joint tissue adrenomedullin concentrations in patients with rheumatoid arthritis compared to those with osteoarthritis 査読あり

Chosa Etsuo,Hamada Hiroaki,北村　和雄,江藤　胤尚,Tajima Naoya

J Rheumatol 30 2553 - 2556 2003年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Plasma adrenomedullin is closely correlated with pulse wave velocity in middle-aged and elderly patients 査読あり

Kita T., Kitamura K., Hashida S., Morishita K., Eto T.

Hypertension Research 26 ( 11 ) 887 - 893 2003年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

Arterial stiffness as measured by pulse wave velocity (PWV) is a major predictor of cardiovascular disease. Adrenomedullin (AM), a hypotensive peptide, works as a compensatory factor for arterial sclerosis. The aim of this study was to investigate the relationship between PWV and the plasma concentration of AM in risk-loading patients. One hundred and twenty-six inpatients aged 30 to 75 years with or without varying degrees of atherosclerosis were investigated. Patients with heart and/or renal failure were excluded. The PWV was measured using an automatic waveform analyzer, and the plasma AM level was measured using a newly developed, hypersensitive immunoenzymometric assay system. The PWV increased with the increasing number of cardiovascular risk factors and organ damage in the patients. A positive correlation between the PWV and AM level was observed (r=0.375, p<0.0001, n=126). Seventy-four patients were receiving antihypertensive medications; medication did not affect the correlation. Multivariate regression analysis revealed that the PWV was significantly and independently associated with age, systolic blood pressure, and AM level. These results indicate that the plasma AM concentration could serve as a marker of advanced arterial sclerosis as estimated by increased PWV.

DOI： 10.1291/hypres.26.887

Chronic salt loading upregulates expression of adrenomedullin and its receptors in adrenal glands and kidneys of the rat 査読あり

Cao Y.N., Kitamura K., Kato J., Kuwasako K., Ito K., Onitsuka H., Nagoshi Y., Uemura T., Kita T., Eto T.

Hypertension 42 ( 3 ) 369 - 372 2003年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension

The vasodilator peptide adrenomedullin (AM) elicits diuresis and natriuresis and inhibits aldosterone secretion. The aim of this study was to better understand the role of AM in maintaining water and electrolyte balance during chronic salt loading. Male Wistar rats were divided into a high salt (HS) group that received a diet containing 8% sodium chloride (NaCl) and a normal salt group that received a diet containing 0.4% NaCl. Plasma AM concentrations as well as expression of AM mRNA in the adrenal gland and kidney were then measured after 3, 7, 14, and 28 days. After 28 days, sodium and water excretion were significantly higher in HS rats than in control, although blood pressure and fluid volume were not significantly affected. Moreover, although plasma AM remained unchanged for up to 14 days, it was increased 2.5-fold in HS rats after 28 days on a high salt diet, and there were corresponding 3-fold and 1.5-fold increases in the levels of AM mRNA in the adrenal gland and kidney, respectively. At the same time, expression of calcitonin receptor-like receptor mRNA was significantly upregulated in both kidney and adrenal gland, as was expression of receptor activity-modify protein 1 (RAMP1) and RAMP2 mRNA in the adrenals and expression of RAMP3 in kidneys. Taken together, these results suggest that AM plays a role in the regulation of water and electrolyte balance in animals chronically ingesting high levels of salt.

DOI： 10.1161/01.HYP.0000088560.10830.37

Angiotensin II modulates gene expression of adrenomedullin receptor components in rat cardiomyocytes 査読あり

Mishima K., Kato J., Kuwasako K., Imamura T., Kitamura K., Eto T.

Life Sciences 73 ( 13 ) 1629 - 1635 2003年8月

掲載種別：研究論文（学術雑誌）出版者・発行元：Life Sciences

Both adrenomedullin (AM) and angiotensin II (Ang II) are locally-acting hormones in the cardiac ventricles. Previously we reported that AM inhibits Ang II-induced hypertrophy of cultured rat neonatal cardiomyocytes. In this study, we examined whether Ang II affects the gene expression of the AM receptor components of calcitonin-receptor-like receptor (CRLR) and receptor-activity-modifying protein (RAMP) in rat cardiomyocytes. The mRNA levels of RAMP1 and RAMP3 were significantly elevated following 24-h treatment with Ang II without a change of those of RAMP2 and CRLR. AM increased the intracellular cAMP level and the cAMP accumulation by AM was significantly amplified by the 24-h preincubation with Ang II. The effects of Ang II on RAMP1 and RAMP3 expression were abolished by an Ang II type 1 (AT1) receptor antagonist, but not by an AT2 receptor antagonist. Thus, Ang II modulates gene expression of the AM receptor components via AT1 receptor, suggesting alteration of AM actions by Ang II in cultured rat cardiomyocytes. © 2003 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0024-3205(03)00484-3

Identification of the human receptor activity-modifying protein 1 domains responsible for agonist binding specificity 査読あり

Kuwasako K., Kitamura K., Nagoshi Y., Cao Y.N., Eto T.

Journal of Biological Chemistry 278 ( 25 ) 22623 - 22630 2003年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biological Chemistry

When co-expressed with receptor activity-modifying protein (RAMP) 1, calcitonin receptor-like receptor (CRLR) can function as a receptor for both calcitonin gene-related peptide (CGRP) and adrenomedullin (AM). To investigate the structural determinants of ligand binding specificity, we examined the extracellular domain of human (h) RAMP1 using various deletion mutants. Co-expression of the hRAMP1 mutants with hCRLR in HEK-293 cells revealed that deletion of residues 91-94, 96-100, or 101-103 blocked [125I]CGRP binding and completely abolished intracellular cAMP accumulation normally elicited by CGRP or AM. On the other hand, the deletion of residues 78-80 or 88-90 significantly attenuated only AM-evoked responses. In all of these cases, the receptor heterodimers were fully expressed at the cell surface. Substituting alanine for residues 91-103 one at a time had little effect on CGRP-induced responses, indicating that although this segment is essential for high affinity agonist binding to the receptors, none of the residues directly interacts with either CGRP or AM. This finding suggests that RAMPs probably determine ligand specificity by contributing to the structure of the ligand-binding pocket or by allosteric modulation of the conformation of the receptor. Interestingly, the L94A mutant up-regulated surface expression of the receptor heterodimer to a greater degree than wild-type hRAMP1, thereby increasing CGRP binding and signaling. L94A also significantly increased cell surface expression of the hRAMP1 deletion mutant D101-103 when co-transfected with hCRLR, and expression of a L94A/D101-103 double mutant markedly attenuated the activity of endogenous RAMP1 in HEK-293T cells.

DOI： 10.1074/jbc.M302571200

Glycine-extended adrenomedullin exerts vasodilator effect through amidation in the rat aorta 査読あり

Cao Y.N., Kitamura K., Ito K., Kato J., Hashida S., Morishita K., Eto T.

Regulatory Peptides 113 ( 1-3 ) 109 - 114 2003年5月

掲載種別：研究論文（学術雑誌）出版者・発行元：Regulatory Peptides

Human adrenomedullin (hAM) is an endogenous peptide that has potent vasodilator activity. Mature AM is biosynthesized from its intermediate form, glycine-extended AM (AM-gly), by carboxy-terminal amidation. AM-gly is generally considered to be biologically inactive but is a major molecular form in human and rat plasma. The present study demonstrated that recombinant human AM-gly (hAM-gly) elicits potent vasodilator effect on isolated rat aorta. In aortic rings, hAM-gly produced dose-dependent (0.1-100 nM) relaxation in phenylephrine-precontracted strips (pD2 8.4±0.5). The vasorelaxant potency of hAM-gly was comparable to that of hAM (pD2 8.6±0.2) but hAM-gly took a significantly (P<0.01) longer time to reach the maximal relaxation compared with hAM (Tmax 23±4 vs. 5±2 min). Vasorelaxant responses to hAM-gly were abolished by endothelial removal. Nω-nitro-L-arginine (L-NNA) and AM(22-52) significantly (P<0.01) reduced the vasodilator effect of hAM-gly. Furthermore, 4-phenyl-3-butenoic acid (PBA), an alpha-amidation enzyme inhibitor, significantly (P<0.05) inhibited the vasorelaxant responses to hAM-gly without any effect on the hAM-induced relaxation, suggesting the possible process of amidation in the rat aorta. We further clarified that the aorta has the ability to convert exogenous hAM-gly to mature hAM and the conversion is inhibited by PBA. These results suggest that the circulating AM-gly may play a role in regulating vascular tone and increased plasma AM-gly may be involved in the pathophysiology of cardiovascular diseases. © 2003 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0167-0115(03)00002-8

Two cases of pheochromocytoma associated with tetralogy of fallot 査読あり

Kita T., Imamura T., Date H., Kitamura K., Moriguchi S., Sato Y., Asada Y., Eto T.

Hypertension Research 26 ( 5 ) 433 - 437 2003年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

We report two cases of pheochromocytoma combined with tetralogy of Fallot who showed different clinical courses. Case 1 was a 45-year-old woman with a history of radical operation for tetralogy of Fallot at 20 years of age. She presented with sudden hypertensive attack, and was diagnosed with pheochromocytoma of the left adrenal gland. She was treated surgically, and her high plasma noradrenaline level normalized. Case 2 was a 41-year-old woman who had been suffering from severe cyanosis due to tetralogy of Fallot throughout her life. A palliative operation had been performed at 7 years of age, but a radical operation had not been performed. She has had resistant hypertension since 38 years of age. She was diagnosed as having pheochromocytoma of the left adrenal gland at 41 years of age, but surgery was not performed. She was pharmacologically treated with doxazosin, followed by bisoprolol. Her symptoms somewhat improved, although she continued to have high plasma levels of noradrenaline and adrenomedullin. The combination of pheochromocytoma with tetralogy of Fallot or cyanotic congenital heart disease is rare; however, pheochromocytoma and congenital heart disease might be related through chronic hypoxia and/or gene abnormalities. The presence of pheochromocytoma worsens the hemodynamic state in patients with congenital heart disease regardless of whether radical surgery for congenital heart disease had been performed. Differential diagnosis of pheochromocytoma could be paramount in congenital heart disease patients who show unexpected or unusual symptoms.

DOI： 10.1291/hypres.26.433

Regulation of production and secretion of adrenomedullin in the cardiovascular system 査読あり

Eto T., Kato J., Kitamura K.

Regulatory Peptides 112 ( 1-3 ) 61 - 69 2003年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：Regulatory Peptides

Adrenomedullin (AM) has multi-functional properties, of which the vasodilatory hypotensive effect is the most characteristic. AM and its gene are ubiquitous in a variety of tissues and organs, in the cardiovascular system, as well as the adrenal medulla. AM secretion, especially in cardiovascular tissues, is regulated mainly by mechanical stressors such as shear stress, inflammatory cytokines such as interleukin (IL)-1, tumor necrosis factor (TNF), and lipopolysaccharide (LPS), hormones such as angiotensin (Ang) II and endothelin (ET)-1, and metabolic factors such as hypoxia, ischemia, or hyperglycemia. Elevation of plasma AM due to overproduction in response to one or more of these stimuli in pathological conditions may explain the raised plasma AM levels present in cardiovascular and renal diseases such as congestive heart failure, myocardial infarction, hypertension, chronic renal failure, stroke, diabetes mellitus, and septic shock. In addition to shear stress, stretching of cardiomyocytes may be another mechanical stimulus for AM synthesis and secretion. Our recent studies have shown the importance of aldosterone and additional hormonal factor on AM secretion in vascular wall. © 2003 Published by Elsevier Science B.V.

DOI： 10.1016/S0167-0115(03)00023-5

Expression of adrenomedullin and its receptor by chondrocyte phenotype cells 査読あり

Chosa E., Hamada H., Kitamura K., Kuwasako K., Yanagita T., Eto T., Tajima N.

Biochemical and Biophysical Research Communications 303 ( 1 ) 379 - 386 2003年3月

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

For clarifying a process of de-differentiation in culturing chondrocytes, the present study was undertaken to investigate the secretion of adrenomedullin (AM) by chondrocyte phenotype cells and whether or not AM effects this proliferation in a cAMP-dependent fashion. Chondrocyte phenotype cells expressed AM and the AM receptor, and secreted high concentration of AM into the culture medium. When added to cultures, AM increased the intracellular cAMP level and decreased the number of these cells in a similar concentration-dependent fashion. Addition of forskolin and dibutyryl-cAMP caused a significant decrease in the number of these cells. Furthermore, the effect of AM was inhibited by a cAMP-dependent protein kinase A inhibitor (H89). The present findings indicate that AM has an autocrine/paracrine type of anti-proliferative effect on these cells mediated via a cAMP-dependent pathway and raise the possibility that AM plays a role in the local modulation of a process of de-differentiation by culturing chondrocyte phenotype cells. © 2003 Elsevier Science (USA). All rights reserved.

DOI： 10.1016/S0006-291X(03)00347-4

Novel calcitonin-(8-32)-sensitive adrenomedullin receptors derived from co-expression of calcitonin receptor with receptor activity-modifying proteins 査読あり

Kuwasako K., Kitamura K., Nagoshi Y., Eto T.

Biochemical and Biophysical Research Communications 301 ( 2 ) 460 - 464 2003年2月

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

We tested whether heterodimers comprised of calcitonin (CT) receptor lacking the 16-amino acid insert in intracellular domain 1 (CTRI1-) and receptor activity-modifying protein (RAMP) can function not only as calcitonin gene-related peptide (CGRP) receptors but also as adrenomedullin (AM) receptors. Whether transfected alone or together with RAMP, human (h)CTRI1- appeared mainly at the surface of HEK-293 cells. Expression of CTRI1- alone led to significant increases in cAMP in response to hCGRP or hAM, though both peptides remained about 100-fold less potent than hCT. However, the apparent potency of AM, like that of CGRP, approached that of CT when CTRI1- was co-expressed with RAMP. CGRP- or AM-evoked cAMP production was strongly inhibited by salmon CT-(8-32), a selective amylin receptor antagonist, but not by hCGRP-(8-37) or hAM-(22-52), antagonists of CGRP and AM receptors, respectively. Moreover, the inhibitory effects of CT-(8-32) were much stronger in cells co-expressing CTRI1- and RAMP than in cells expressing CTRI1- alone. Co-expression of CTRI1- with RAMP thus appears to produce functional CT-(8-32)-sensitive AM receptors. © 2003 Elsevier Science (USA). All rights reserved.

DOI： 10.1016/S0006-291X(02)03072-3

Direct measurement of glycine-extended adrenomedullin in plasma and tissue using an ultrasensitive immune complex transfer enzyme immunoassay in rats 査読あり

Yamaga J., Hashida S., Kitamura K., Tokashiki M., Aoki T., Inatsu H., Ishikawa N., Kangawa K., Morishita K., Eto T.

Hypertension Research 26 ( SUPPL. ) S45 - S53 2003年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

The mature form of the vasodilator peptide adrenomedullin (AM-m) is synthesized from a glycine-extended precursor (AM-Gly) by enzymatic amidation. We have developed a highly sensitive enzyme immunoassay (Immune Complex Transfer Enzyme Immunoassay; ICTEIA) that enables us to measure levels of AM-Gly in plasma and tissue directly. The detection limit of this assay is 1 amol/assay, and the intra- and inter-assay precision are 4.5-14.1% and 9.9-20.5%, respectively. Dilution curves for plasma samples showed good linearity, and the analytical recovery was 107-116.6%. Using ICTEIA, we determined that the plasma concentration of immunoreactive AM-Gly is substantially higher than that of AM-m (5.22±2.56 vs. 1.21± 0.79 fmol/ml). In contrast, levels of AM-Gly were much lower than those of AM-m in the lung, heart, kidney, adrenal gland and liver. We also evaluated AM-Gly and AM-m levels in rats in a morbid state induced by intraperitoneal administration of lipopolysaccharide (LPS). In most tissues, levels of AM-m and AM-Gly were both increased by LPS; however, AM-Gly/AM-m ratios were not significantly affected, which suggests that AM-Gly is rapidly converted to AM-m in tissue.

DOI： 10.1291/hypres.26.S45

Adrenomedullin: A possible autocrine or paracrine hormone in the cardiac ventricles 査読あり

Kato J., Tsuruda T., Kitamura K., Eto T.

Hypertension Research 26 ( SUPPL. ) S113 - S119 2003年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

Adrenomedullin (AM), a potent vasodilator peptide originally isolated from pheochromocytoma, is expressed in cardiovascular tissues such as those of the cardiac atria and ventricles. Cell culture experiments have shown that AM peptide is synthesized and secreted from cardiac myocytes and fibroblasts of neonatal rats. Humoral factors, such as angiotensin II (Ang II) and endothelin-1 (ET-1), and mechanical stress due to pressure and volume overload to the heart have been shown to be involved in AM expression of the myocardium in both in vitro and in vivo studies. The effects of AM on cardiomyocytes and cardiac fibroblasts have been examined in in vitro studies, with the result that AM was shown to exert inhibitory actions on myocyte hypertrophy and on proliferation and collagen production of cardiac fibroblasts in an autocrine or paracrine manner. In rats, experimental therapeutic intervention consisting of transfer of the AM gene or of recombinant AM appears to partly inhibit the progression of cardiac hypertrophy and remodeling. It has been shown that the calcitonin receptor-like receptor (CRLR) and receptor-activity-modifying protein (RAMP) act together to function as AM receptors, although in this regard there are a number of issues, including the cellular mechanism of AM actions, that remain to be addressed. In addition, the role of proadrenomedullin N-terminal 20 peptide (PAMP), which is derived from preproAM, is another topic for future experiments. Collectively, the research data accumulating in this area suggest that AM plays a role as an autocrine or paracrine hormone in the cardiac ventricles, and that AM might be utilized as a therapeutic tool in the treatment of hypertensive or ischemic heart disease.

DOI： 10.1291/hypres.26.S113

The function of extracellular cysteines in the human adrenomedullin receptor 査読あり

Kuwasako K., Kitamura K., Uemura T., Nagoshi Y., Kato J., Eto T.

Hypertension Research 26 ( SUPPL. ) S25 - S31 2003年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

When co-expressed with receptor activity-modifying protein (RAMP) 2, calcitonin receptor-like receptor (CRLR) functions as an adrenomedullin (AM) receptor (CRLR/RAMP2). In the present study, we examined the function of the cysteine (C) residues in the extracellular loops of human (h)CRLR (C212, C225 and C282) and in the extracellular domain of hRAMP2 (C68, C84, C99 and C131). Using site-directed mutagenesis, the cysteine residues were substituted, one at a time, with alanine (A). Co-expression in HEK293 cells of hRAMP2 with the hCRLR C212A or C282A mutant significantly reduced the 50% of effective concentration (EC50) for AM-evoked cyclic adenosine monophosphate (cAMP) production, despite full cell surface expression of the receptor heterodimer. Co-expression of the C225A mutant had no effect on [125I]AM binding or receptor signaling. These results suggest that the cysteine residues in the first (C212) and the second (C282) extracellular loops form a disulfide bond that is important for stabilizing the receptor in the correct conformation for ligand binding and activation. Cells expressing hCRLR with an hRAMP2 mutant (C68A, C84A, C99A or C131A) showed no specific AM binding or AM-stimulated cAMP accumulation. Though abundant in the intracellular compartment, these receptors were not detected at the cell surface, suggesting that all four cysteine residues are essential for efficient transport to the plasma membrane. Cysteine residues in the extracellular loops of hCRLR and in the extracellular domain of hRAMP2 thus appear to play distinct roles in the cell surface expression and function of the receptor heterodimer.

DOI： 10.1291/hypres.26.S25

Plasma levels of proadrenomedullin N-terminal 20 peptide and adrenomedullin in patients undergoing hemodialysis. 査読あり

Tokura T., Kinoshita H., Fujimoto S., Kitamura K., Eto T.

Nephron. Clinical practice 95 ( 2 ) 47 - 54 2003年

掲載種別：研究論文（学術雑誌）出版者・発行元：Nephron. Clinical practice

BACKGROUND: Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide present in the precursor of adrenomedullin (AM), a vasodilative and natriuretic peptide. However, the profile of PAMP in hemodialyzed (HD) patients has not been determined. METHODS: We measured plasma levels of PAMP, total AM (tAM) and a mature form of AM (mAM, the biologically active form) in HD patients (n = 31) and in normal controls (n = 21). RESULTS: Plasma concentrations of PAMP before HD were significantly higher than those in controls (4.02 +/- 0.24 vs. 1.64 +/- 0.12 fmol/ml, p < 0.001) and decreased to the control level after HD (2.17 +/- 0.18 vs. 1.64 +/- 0.12 fmol/ml; NS). The plasma PAMP level before HD significantly correlated with weight gain during HD sessions (r = 0.41, p < 0.05), but not with predialysis blood pressure. The concentrations of mAM before and after HD were significantly higher than those in controls. The plasma mAM level before HD significantly correlated with weight gain during HD sessions, but not with predialysis blood pressure. The plasma level of PAMP did not correlate with that of mAM in HD patients. CONCLUSION: PAMP and AM may be involved in the regulation of blood volume in patients undergoing HD. Copyright 2003 S. Karger AG, Basel

DOI： 10.1159/000073670

Increased adrenomedullin concentration in cerebrospinal fluid in patients with septic shock 査読あり

Naoto Nagata 1, Johji Kato, Kazuo Kitamura, Mari Kawamoto, Hirosi Katsuki, Masaharu Yamaga, Tanenao Eto, Shingo Tateyama, Mayumi Takasaki

J Med 34 ( 1-6 ) 59 - 66 2003年

掲載種別：研究論文（学術雑誌）

ヒトにおけるアドレノメデュリンの心機能改善効果の検討査読あり

鈴木良彦、北俊弘、北村和雄、江藤胤尚、

日本内分泌学会雑誌 79 ( 2 ) 523 - 523 2003年

掲載種別：研究論文（学術雑誌）

心筋梗塞(MI)急性期のアドレノメデュリン(AM)投与は慢性期の心機能低下を抑制する査読あり

中村

日本内分泌学会雑誌 79 ( 2 ) 523 - 523 2003年

掲載種別：研究論文（学術雑誌）

受容体活性調節蛋白(RAMP)とカルシトニン受容体(CTR)で形成されるカルシトニン遺伝子関連ペプチド(CGRP)受容体の薬理学的特徴査読あり

桑迫健二、名越康子、曹遠寧、鶴田敏博、北村和雄、江藤胤尚

日本内分泌学会雑誌 79 ( 2 ) 542 - 542 2003年

掲載種別：研究論文（学術雑誌）

Beneficial effects of adrenomedullin on left ventricular remodeling after myocardial infarction in rats 査読あり

Nakamura R., Kato J., Kitamura K., Onitsuka H., Imamura T., Marutsuka K., Asada Y., Kangawa K., Eto T.

Cardiovascular Research 56 ( 3 ) 373 - 380 2002年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：Cardiovascular Research

Objective: We previously reported that plasma adrenomedullin (AM) levels increase in patients with acute myocardial infarction (MI) and AM inhibits growth of rat cardiac myocytes and fibroblasts. The aim of this study was to examine the effects of long-term administration of AM on left ventricular (LV) remodeling, hemodynamic and hormonal parameters in a rat model of MI. Methods: Rats with MI induced by left coronary ligation were intravenously infused with 1.0 μg/h of recombinant human AM or saline by osmotic mini-pump. After infusion for 4 weeks, hemodynamic and hormonal studies were performed, and the myocyte size and collagen volume in non-infarct LV area were quantified morphometrically. Results: When compared with the MI rats infused with saline, continuous infusion of AM reduced the heart weight/body weight (4.4±0.2 vs. 3.6±0.1 g/kg, P<0.01), myocyte size (922±23 vs. 868±10 μm2, P<0.05) and collagen volume fraction of non-infarct LV area (7.6±0.8 vs. 4.8±0.5%, P<0.05), without affecting the infarct size. The AM infusion had no significant effect on the arterial pressure, but decreased the LV end-diastolic pressure (8.8±1.8 vs. 4.4±0.5 mmHg, P<0.05) in the MI rats. The plasma level of endogenous rat AM in the MI rats infused with human AM was reduced by 27% (P<0.05), with a slight reduction of plasma atrial natriuretic peptide, compared with the control. Conclusions: Continuous administration of AM had beneficial effects on LV remodeling and hemodynamics in MI rats, suggesting the possibility that this peptide could be a useful therapeutic tool for acute MI. © 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0008-6363(02)00594-1

Adrenomedullin stimulates the growth of cultured normal human osteoblasts as an autocrine/paracine regulator 査読あり

Hamada H., Kitamura K., Chosa E., Eto T., Tajima N.

Peptides 23 ( 12 ) 2163 - 2168 2002年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：Peptides

Adrenomedullin (AM) is a 52 amino acid peptide that is synthesized in a variety of tissues, including the vessels and bones. This study showed that normal human osteoblast (NHOst) secreted immunoreactive AM and that AM stimulated intracellular cAMP production in these cells. An anti-AM monoclonal antibody, which inhibited endogenous AM, caused the number of NHOst to decrease. The effect of a low concentration AM was inhibited by addition of a cAMP-dependent protein kinase A inhibitor (H89). These data suggest that AM is an autocrine or paracrine regulator that promotes the proliferation of NHOst via the cAMP pathway. © 2002 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0196-9781(02)00259-0

Large-scale production of functional human adrenomedullin: Expression, cleavage, amidation, and purification 査読あり

Mitsuda Y., Takimoto A., Kamitani S., Kitamura K., Sakata T., Mitsushima K.

Protein Expression and Purification 25 ( 3 ) 448 - 455 2002年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：Protein Expression and Purification

Human adrenomedullin (hAM) is a 52-amino-acid regulatory peptide containing a six-membered ring structure and an amidated C-terminus, features that are essential for its biological activity. Here, we describe a simple and effective protocol for producing large quantities of highly pure, functional recombinant hAM. A peptide precursor (hAM-Gly) was expressed in Escherichia coli as a fusion protein with thioredoxin and collected as inclusion bodies. The fusion protein was then digested with BLase, a glutamate-specific endopeptidase, to prepare hAM-Gly. The essential ring structure formed spontaneously, while the terminal amide was generated by conversion of the added glycine residue using peptidylglycine α-amidating enzyme. The low solubility of hAM-Gly enabled the use of a selective precipitation/extraction method to generate a product that was 80-90% pure, which was sufficient to proceed with the α-amidating enzyme reaction. The resultant hAM was then purified further by column chromatography. The final yield was about 82 mg/L of bacterial culture, and the purity, determined by reverse phase HPLC, was >99:5%. The recombinant hAM was biologically active, eliciting concentration-dependent increases in cAMP in CHO-K1 cells expressing a specific hAM receptor and hypotensive responses when intravenously injected into rats. This new approach to the synthesis of hAM is simpler and more cost-effective for large-scale production than chemical synthesis. It therefore represents a new powerful tool that has the potential to facilitate analysis of the structure and function of hAM, as well as the development of new therapeutic protocols for the treatment of ailments such as hypertension. © 2002 Elsevier Science (USA). All rights reserved.

DOI： 10.1016/S1046-5928(02)00030-X

Plasma levels of adrenomedullin and atrial and brain natriuretic peptides in the general population: Their relations to age and pulse pressure 査読あり

Kato J., Kitamura K., Uemura T., Kuwasako K., Kita T., Kangawa K., Eto T.

Hypertension Research 25 ( 6 ) 887 - 892 2002年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

Adrenomedullin (AM) and atrial and brain natriuretic peptides (ANP and BNP) exert vasodilator and natriuretic actions and are thought to share roles in counteracting the progression of hypertension or heart failure as circulating or locally-acting hormones. However, little data is available with regard to their roles in subjects who have no apparent cardiovascular diseases. The present study was carried out to identify the factors that affect plasma levels of AM, ANP and BNP in the general population. We measured the plasma levels of AM, ANP and BNP in 184 local residents who had a scheduled regular health checkup, and compared the findings with those for other clinical parameters. Univariate analyses showed that the plasma levels of AM, ANP and BNP were significantly correlated with age. The plasma levels of ANP and BNP were also significantly correlated with systolic blood pressure (SBP) and with pulse pressure (PP), an indicator of the stiffness of the great vessels. Multivariate analyses conducted using a stepwise method revealed that age was a significant, independent variable for the plasma levels of AM, ANP and BNP. In addition, PP was a significant factor for the plasma levels of ANP and BNP, while the plasma AM was significantly associated with body mass index (BMI). Thus, the plasma levels of AM, ANP and BNP all increased in association with aging, and those of ANP and BNP increased in association with PP, suggesting possible relationships between the plasma levels and age-related changes in the cardiovascular system.

DOI： 10.1291/hypres.25.887

The calcitonin receptor-like receptor/receptor activity-modifying protein 1 heterodimer can function as a calcitonin gene-related peptide-(8-37)-sensitive adrenomedullin receptor 査読あり

Nagoshi Y., Kuwasako K., Ito K., Uemura T., Kato J., Kitamura K., Eto T.

European Journal of Pharmacology 450 ( 3 ) 237 - 243 2002年8月

掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Pharmacology

The receptor activity-modifying protein (RAMP)/calcitonin receptor-like (CRL) receptor heterodimer is thought to function as a receptor for either a calcitonin gene-related peptide (CGRP) (CRL receptor/RAMP1) or adrenomedullin (CRL receptor/RAMP2 or -3), depending on the RAMP isoform present. We examined the receptor specificity of adrenomedullin-induced increases in cAMP in human embryonic kidney (HEK)293 cells coexpressing human CRL receptor and human RAMP1 or RAMP2. In cells expressing CRL receptor/RAMP1, adrenomedulin-induced increases in cAMP were comparable to those induced by α-CGRP, and the CGRP receptor antagonist α-CGRP-(8-37), but not the adrenomedullin receptor antagonist adrenomedullin-(22-52), blocked the adrenomedullin-evoked responses. Cells expressing CRL receptor/RAMP2 responded more selectively to adrenomedullin; in this case, the effect was blocked by adrenomedullin-(22-52) but not by α-CGRP-(8-37). Real-time quantitative polymerase chain reaction confirmed that cotransfection of CRL receptor and RAMP1 had no effect on the endogenous expression of RAMP2. Thus, CRL receptor/RAMP1 likely functions as an adrenomedullin receptor as well as a CGRP receptor, which may explain why many of the actions of adrenomedullin are potently antagonized by α-CGRP-(8-37). © 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0014-2999(02)02184-2

Identification of amidicin: A novel peptide with C-terminal amide structure isolated from porcine cardiac atrium 査読あり

Ishiyama Y., Kitamura K., Eto T.

Biochemical and Biophysical Research Communications 293 ( 2 ) 741 - 746 2002年7月

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

Using a novel method employing a V8 protease digestion coupled with ethyl acetate extraction, we have purified a peptide with C-terminal amide structure from porcine cardiac atrium. The peptide was determined to be Ala-Val-Leu-Gly-Leu-CONH2. According to the sequence, we have raised an antibody and established the radioimmunoassay. Using this radioimmunoassay, we have isolated a novel 14 amino acid peptide where C-terminus was amidated. This peptide was termed amidicin. Amidicin is widely distributed in porcine tissue and is especially abundant in pituitary gland, cardiac ventricle, and spleen. © 2002 Elsevier Science (USA). All rights reserved.

DOI： 10.1016/S0006-291X(02)00284-X

Expression and immunohistochemical localization of adrenomedullin in the mouse cochlea 査読あり

Tono T., Shimozono M., Kawano H., Asada Y., Kitamura K., Komune S.

ORL 64 ( 3 ) 169 - 172 2002年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：ORL

Adrenomedullin (AM) is a novel hypotensive and vasodilator peptide. It has been shown that AM is biosynthesized in various organs and cells and is suggested to play multiple roles including electrolyte homeostasis and body fluid control. The present study describes for the first time the presence of mRNA for AM and AM-like immunoreactivity in the cochlea. A reverse transcription-polymerase chain reaction (RT-PCR) performed with gene-specific AM primer on total RNA extracted from mouse cochlea revealed a PCR product of the expected size. Immunohistochemical examination showed positive immunostaining in vascular smooth muscle cells of the modiolar arterioles and in the stria vascularis of the cochlea. These results suggest that AM may play a role in the regulation not only of cochlear hemodynamics but also of cochlear fluid dynamics. Copyright © 2002 S. Karger AG, Basel.

DOI： 10.1159/000058020

Aldosterone augments adrenomedullin production without stimulating pro-adrenomedullin N-terminal 20 peptide secretion in vascular smooth muscle cells 査読あり

Uemura T., Kato J., Kuwasako K., Kitamura K., Kangawa K., Eto T.

Journal of Hypertension 20 ( 6 ) 1209 - 1214 2002年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Hypertension

Objective: Both adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP), processed from the same precursor of prepro-adrenomedullin (preproAM), have differential biological properties; AM dilates blood vessels and presumably affects the vascular remodeling, while PAMP inhibits catecholamine secretion. Since aldosterone has been shown to be involved in vascular remodeling, we examined the effects of aldosterone on AM and PAMP secretion and preproAM gene expression in human aortic vascular smooth muscle cells (VSMC). Methods: AM and PAMP secreted from human VSMC incubated with aldosterone were measured by radioimmunoassay, and preproAM gene expression was evaluated by quantitative polymerase chain reaction. Results: Cultured human VSMC secreted both AM and PAMP into the media, while the secretion rate of AM was much higher than that of PAMP. Aldosterone increased preproAM gene expression in the cultured VSMC in a dose-dependent fashion following incubation for 48 h, with a concomitant increase in AM secretion from the cells, but PAMP secretion remained unchanged. Aldosterone-stimulated AM secretion was significantly reduced by spironolactone. Reverse-phase high-performance liquid chromatography analyses showed that immunoreactive AM secreted from the VSMC untreated or treated with aldosterone emerged at the point of human AM(1-52)-NH2. Conclusions: AM production was stimulated by aldosterone in cultured human VSMC without an increase in PAMP secretion, suggesting a possible role of AM in modulating vascular remodeling by aldosterone. © 2002 Lippincott Williams & Wilkins.

DOI： 10.1097/00004872-200206000-00035

Rat RAMP domains involved in adrenomedullin binding specificity 査読あり

Kuwasako K., Kitamura K., Onitsuka H., Uemura T., Nagoshi Y., Kato J., Eto T.

FEBS Letters 519 ( 1-3 ) 113 - 116 2002年5月

掲載種別：研究論文（学術雑誌）出版者・発行元：FEBS Letters

When coexpressed with receptor activity-modifying protein (RAMP)2 or -3, calcitonin receptor-like receptor (CRLR) functions as an adrenomedullin (AM) receptor (CRLR/RAMP2 or -3). Coexpression of rat (r)CRLR with rRAMP deletion mutants in HEK293T cells revealed that deletion of residues 93-99 from rRAMP2 or residues 58-64 from rRAMP3 significantly inhibits high-affinity [125I]AM binding and AM-evoked cAMP production, despite full cell surface expression of the receptor heterodimer. Apparently, these two seven-residue segments are key determinants of high-affinity agonist binding to rAM receptors and of receptor functionality. Consequently, their deletion yields peptides that are able to serve as negative regulators of AM receptor function. © 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0014-5793(02)02721-7

Rapid increase in cardiac adrenomedullin gene expression caused by acute pressure overload: Effect of the renin-angiotensin system on gene expression 査読あり

Hirano S., Imamura T., Onitsuka H., Matsuo T., Kitamura K., Koiwaya Y., Eto T.

Circulation Journal 66 ( 4 ) 397 - 402 2002年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Circulation Journal

To determine whether acute pressure overload (POL) can stimulate adrenomedullin (AM) production, the response of ventricular AM gene expression and plasma AM concentration to aortic banding was investigated in the rat. Furthermore, any link between AM expression and the renin-angiotensin system (RAS) enhanced by acute POL was examined using: a Ca channel blocker (manidipine), an angiotensin II type I receptor antagonist (candesartan), and an angiotensin-converting enzyme inhibitor (quinapril). Rats with acute POL produced by suprarenal aortic banding were studied 1, 5 and 14 days after surgery. Plasma AM concentrations in banded rats at day 1 increased 1.49-fold (p<0.01), then gradually declined to near the control level at day 14. Plasma AM concentrations correlated with plasma renin activity (PRA) (p<0.001). Adrenomedullin mRNA expression in the left ventricle (LV) increased 1.35-fold (p<0.05) at day 1. This increase was not significant at either 5 or 14 days after surgery. Adrenomedullin mRNA expression in the right ventricle on days 1 and 5 increased by 1.46-fold (p<0.05) and 1.52-fold (p<0.05), respectively. Candesartan, quinapril and manidipine reduced systolic blood pressure equally and activated PRA at day 1. However, augmented LV AM gene expression was suppressed completely by candesartan and quinapril, but remained unaffected by manidipine. In conclusion, POL induces a rapid increase in cardiac AM gene expression and in plasma AM concentrations. Cardiac AM transcription could therefore be partly regulated by RAS in suprarenal aortic banding rats.

DOI： 10.1253/circj.66.397

Recovery process of arthritis induced by 6-sulfanilamidoindazole (6SAI) in rats 査読あり

Y Ohmachi 1, H Fujimura, E Otsuka, T Miyazaki, W Toriumi, K Kitamura, K Doi

Histol Histopathol 17 ( 2 ) 437 - 444 2002年4月

掲載種別：研究論文（学術雑誌）

DOI： 10.14670/HH-17.437

Adrenomedullin and PAMP: Discovery, structures, and cardiovascular functions 査読あり

Kitamura K., Kangawa K., Eto T.

Microscopy Research and Technique 57 ( 1 ) 3 - 13 2002年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：Microscopy Research and Technique

We discovered adrenomedullin (AM) from human pheochromocytoma tissue by monitoring the elevating activity of intracellular cyclic AMP (cAMP) in rat platelets in 1993. Since the discovery of AM, it has attracted intense interest from cardiovascular researchers because AM elicits multiple biological activities, including a potent and powerful hypotensive activity caused by dilatation of resistance vessels. AM is biosynthesized and secreted from tissues, including cardiovascular organs. In addition to AM, "proadrenomedullin N-terminal 20 peptide (PAMP)," another biologically active peptide, was found to be processed from the AM precursor. Plasma AM levels are increased in various cardiovascular and renal diseases. AM, therefore, seems to function as a novel system that controls circulation and body fluid, and may be involved in pathophysiological changes in cardiovascular diseases. Therefore, in this review we will focus on the structure of AM and its gene, distribution, receptor, and the physiological and pathological roles of AM in cardiovascular disease. © 2002 Wiley-Liss, Inc.

DOI： 10.1002/jemt.10052

Adrenomedullin, an endogenous peptide, counteracts cardiovascular damage 査読あり

Shimosawa T., Shibagaki Y., Ishibashi K., Kitamura K., Kangawa K., Kato S., Ando K., Fujita T.

Circulation 105 ( 1 ) 106 - 111 2002年1月

掲載種別：研究論文（学術雑誌）出版者・発行元：Circulation

Background - Adrenomedullin (AM), a potent vasodilator peptide, is produced by posttranslational splicing of proadrenomedullin together with proadrenomedullin N-terminal 20 peptide (PAMP), another hypotensive peptide. Although both AM and PAMP have the potential not only to decrease blood pressure but also to protect organs from damage, there is no direct evidence for their individual physiological roles in vivo. Methods and Results - Using knockout mice with the disruption of AM peptide alone, we investigated the organ-protective effect of AM. Although the AM-/- mutation in mice was embryonic lethal without any apparent phenotypic changes, AM+/- mice were viable and fertile; plasma and organ AM concentrations were almost half of those in AM+/+ mice. With the administration of angiotensin II (Ang II) on a high-salt diet for 12 days, marked perivascular fibrosis and intimal hyperplasia were found in coronary arteries of Ang II/salt-treated AM+/- mice, without the AM upregulation that was observed in Ang II/salt-treated AM+/+ mice. In AM+/- mice, Ang II/salt loading increased both urinary excretion of 8-hydroxydeoxyguanosine and isoprostane, markers of oxidative stress. Consistently, immunostaining of both p67phox and gp91phox, subunits of NAD(P)H oxidase and 3-nitrotyrosine, the metabolites of reactive oxygen species (ROS), and the generation of ROS measured by electron spin resonance spectroscopy apparently increased in the Ang II/salt-treated heart. These data suggested that the overproduction of oxidative stress might be involved in the cardiovascular changes induced by Ang II/salt loading. Conclusions - The evidence presented supports the hypothesis that endogenous AM possesses a protective action against cardiovascular damage, possibly through the inhibition of oxidative stress production.

DOI： 10.1161/hc0102.101399

Cryofixation processing is an excellent method to improve the retention of adrenomedullin antigenicity 査読あり

Yuchi H., Suganuma T., Sawaguchi A., Ide S., Kawano J.I., Aoki T., Kitamura K., Eto T.

Histochemistry and Cell Biology 118 ( 3 ) 259 - 265 2002年

掲載種別：研究論文（学術雑誌）出版者・発行元：Histochemistry and Cell Biology

We reappraised the precise immunohistochemical localization of adrenomedullin (AM) by means of the combined use of the catalyzed signal amplification (CSA) system and plunge freezing (PF)/freeze substitution (FS) for light microscopy or high-pressure freezing (HPF)/FS for electron microscopy, focusing on the rat adrenal gland and heart. In the case of adrenal glands, the PF processing showed that almost all medullary cells were intensively immunoreactive, while the cortical cells showed weak immunoreaction. In the heart, almost all cardiac muscle cells of the atria were also vividly stained with the PF/FS and the CSA enhancement. On the contrary, traces of immunoreactions were seen in most of the ventricular cells. These results are consistent with the previous reports of AM radioimmunoassays and the expression of AM mRNA. However, the chemical fixation processing revealed heterogeneous immunostaining in the atrial and ventricular myocardium as well as the adrenal medulla. Intensity of the immunostaining in the chemically fixed tissues was not likely to correspond with that of AM radioimmunoassays. The HPF/FS processing clearly demonstrated the immunogold labeling on secretory granules of adrenal medullary cells as well as cardiac muscle cells of the right auricles. Immunogold labeling intensity of the cryofixed specimens was 3- to 25-fold higher than that of the chemically fixed ones.

DOI： 10.1007/s00418-002-0431-1

The Seven Amino Acids of Human RAMP2 (86-92) and RAMP3 (59-65) Are Critical for Agonist Binding to Human Adrenomedullin Receptors 査読あり

アドレノメデュリン中枢投与による昇圧反応における交感神経系の関与および心血管反射調節系としての延髄最後野の役割査読あり

斉田光彦、北村和雄、江藤胤尚、河南洋

日本内分泌学会雑誌 78 ( 2 ) 454 - 454 2002年

掲載種別：研究論文（学術雑誌）

培養骨芽細胞, 軟骨細胞におけるアドレノメデュリンの成長因子としての作用査読あり

濱田浩朗、北村和雄、田島直也、帖佐悦男

日本内分泌学会雑誌 78 ( 2 ) 452 - 452 2002年

掲載種別：研究論文（学術雑誌）

CRLR/RAMP1複合体はCGRP-(8-37)に感受性の高いアドレノメデュリン受容体として機能する査読あり

名越康子、桑迫健二、加藤丈司、北村和雄、江藤胤尚

日本内分泌学会雑誌 78 ( 2 ) 452 - 452 2002年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンと心血管病査読あり

北村和雄、北俊弘、加藤丈司、江藤胤尚

日本内分泌学会雑誌 78 ( 2 ) 444 - 444 2002年

掲載種別：研究論文（学術雑誌）

慢性糸球体腎炎患者における血漿・尿中Adrenomedullin(AM),Proadrenomedullin N-temina120peptide(PAMP)の動態査読あり

藤元昭一、木下浩、戸倉健、北村和雄、江藤胤尚

Therapeutic Research 23 ( 5 ) 799 - 804 2002年

掲載種別：研究論文（学術雑誌）

心筋梗塞後リモデリングに対するアドレノメデュリン長期投与の有効性査読あり

中村亮斉、加藤丈司、北村和雄、鬼塚久充、今村卓郎、寒川賢治、江藤胤尚

日本内分泌学会雑誌 78 ( 2 ) 451 - 451 2002年

掲載種別：研究論文（学術雑誌）

高食塩食によるラットアドレノメデュリンとその受容体遺伝子発現の上昇査読あり

曹遠寧、北村和雄、加藤丈司、桑迫健二、江藤胤尚

日本内分泌学会雑誌 78 ( 2 ) 452 - 452 2002年

掲載種別：研究論文（学術雑誌）

Kuwasako K., Kitamura K., Ito K., Uemura T., Yanagita Y., Kato J., Sakata T., Eto T.

Journal of Biological Chemistry 276 ( 52 ) 49459 - 49465 2001年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biological Chemistry

When co-expressed with a receptor activity-modifying protein (RAMP) accessory protein, calcitonin receptor-like receptor (CRLR) can function as a calcitonin gene-related peptide receptor (CRLR-RAMP1) or an adrenomedullin (AM) receptor (CRLR-RAMP2/3). Here we report on the structural domain(s) involved in selective AM binding that were examined using various RAMP chimeras and deletion mutants. Co-expression of chimeric RAMPs and CRLR in HEK293 cells revealed that residues 77-101, situated in the extracellular N-terminal domain of human RAMP2 (hRAMP2), were crucial for selective AM-evoked cAMP production. More detailed analysis showed that deletion of hRAMP2 residues 86-92 significantly attenuated high-affinity 125I-AM binding and AM-evoked cAMP production despite full cell surface expression of the receptor heterodimer and that deletion of hRAMP3 residues 59-65 had a similar effect. There is little sequence identity between hRAMP3 residues 59-65 and hRAMP2 residues 86-92; moreover, substituting alanine for Trp86 (Ala 87), Met88, Ile89, Ser90, Arg 91, or Pro92 of hRAMP2 had no effect on AM-evoked cAMP production. It thus seems unlikely that any one amino acid residue is responsible for determining selective AM binding or that AM binds directly to these peptide segments. Instead these findings suggest that the respective seven-amino acid sequences confer selectivity either by directly contributing to the structure of ligand binding pocket or by allosteric modulation of the conformation of CRLR.

DOI： 10.1074/jbc.M108369200

Action sites of adrenomedullin in the rat brain: Functional mapping by Fos expression 査読あり

Ueta Y., Hara Y., Kitamura K., Kangawa K., Eto T., Hattori Y., Yamashita H.

Peptides 22 ( 11 ) 1817 - 1824 2001年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：Peptides

The effects of intracerebroventricular (icv) administration of adrenomedullin (AM) and proadrenomedullin NH2-terminal 20 peptide (PAMP) on the expression of Fos in the central nervous system (CNS) were examined in conscious rats, using immunohistochemistry. Fos-like immunoreactivity (LI) was detected in various brain areas of the rats, including the supraoptic nucleus, the paraventricular nucleus, the locus coeruleus, the area postrema and the nucleus of the tractus solitarius 90 min after icv administration of AM. Few cells with Fos-LI were found in the CNS 90 min after icv administration of saline. Fos-LI was also detected in the various hypothalamic areas after icv administration of PAMP. These results suggest that centrally administered AM and PAMP may cause physiological responses through the activation of a neural network in the hypothalamus and the brainstem. © 2001 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0196-9781(01)00528-9

Adrenomedullin (11-26): A novel endogenous hypertensive peptide isolated from bovine adrenal medulla 査読あり

Kitamura K., Matsui E., Kato J., Katoh F., Kita T., Tsuji T., Kangawa K., Eto T.

Peptides 22 ( 11 ) 1713 - 1718 2001年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：Peptides

Adrenomedullin (AM) is a potent hypotensive peptide originally isolated from pheochromocytoma tissue. Both the ring structure and the C-terminal amide structure of AM are essential for its hypotensive activity. We have developed an RIA which recognizes the ring structure of human AM. Using this RIA, we have characterized the molecular form of AM in bovine adrenal medulla. Gel filtration chromatography revealed that three major peaks of immunoreactive AM existed in the adrenal medulla. The peptide corresponding to Mr 1500 Da was further purified to homogeneity. The peptide was determined to be AM (11-26) which has one intramolecular disulfide bond. Amino acid sequences of bovine AM and its precursor were deduced from the analyses of cDNA encoding bovine AM precursor. The synthetic AM (11-26) produced dose-dependent strong pressor responses in unanesthetized rats in vivo. The hypertensive activity lasted about one minute, and a dose dependent increase in heart rate was also observed. The present data indicate that AM (11-26) is a major component of immunoreactive AM in bovine adrenal medulla and shows pressor activity. © 2001 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0196-9781(01)00529-0

Biosynthesis and secretion of adrenomedullin and proadrenomedullin N-terminal 20 peptide in a rat model of endotoxin shock 査読あり

Matsui E., Kitamura K., Yoshida M., Kato J., Asada Y., Sumiyoshi A., Eto T.

Hypertension Research 24 ( 5 ) 543 - 549 2001年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

To study the biosyntheses and pathophysiological roles of adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) in septic shock, we compared the time course of plasma concentrations of these peptides and blood pressure in rats injected with either 0.9% saline (control group) or lipopolysaccharide (LPS group). The plasma AM concentration in the LPS group did not increase 30 and 60 min after LPS injection, at which time points the blood pressure remained low. Thereafter, AM rapidly increased, and it amounted to 35 times the basal value 4 h after injection, when the blood pressure returned to the basal level. The increment of plasma PAMP in the LPS group was lower than that of AM. We also examined the tissue concentration of AM and PAMP - as well as the tissue expression of proadrenomedullin (proAM) mRNA - in the LPS and control groups. LPS significantly increased the tissue concentrations of AM and PAMP in the lung, but decreased them in the adrenal gland and cardiac atrium. The LPS injection augmented proAM gene transcription in the lung, adrenal gland and aorta. In an immunohistochemical examination, AM staining was intense in alveolar endothelial cells of the lung in the LPS group. Thus, this septic shock model had high plasma levels of PAMP as well as AM, while the biosynthesis and secretion of the two peptides may have been differentially regulated in various tissues of rats injected with LPS. The present results suggest that these two bioactive peptides may play different roles in the pathophysiology of septic shock.

DOI： 10.1291/hypres.24.543

Adrenomedullin and its role in renal diseases 査読あり

Eto T., Kitamura K.

Nephron 89 ( 2 ) 121 - 134 2001年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：Nephron

DOI： 10.1159/000046059

Effects of endothelin on adrenomedullin secretion and expression of adrenomedullin receptors in rat cardiomyocytes 査読あり

Mishima K., Kato J., Kuwasako K., Ito K., Imamura T., Kitamura K., Eto T.

Biochemical and Biophysical Research Communications 287 ( 1 ) 264 - 269 2001年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

Both endothelin (ET) and adrenomedullin (AM), produced by cardiac myocytes, are thought to be locally-acting hormones in the heart. Recently, calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs) have been shown to function together to serve as AM receptors stimulating cAMP production. In the present study, we examined the effects of ET on AM secretion, intracellular cAMP response to AM, and gene expressions of CRLR and RAMPs in cultured cardiac myocytes. Synthetic ET-1 dose-dependently increased AM secretion from the cardiomyocytes. AM increased the intracellular cAMP level in a dose-dependent manner and the cAMP accumulation by AM was significantly amplified by 24 h preincubation with ET-1. 10 nmol/L ET-1 significantly increased the CRLR mRNA level without any effect on RAMP1 mRNA. 1 μmol/L ET-1 significantly reduced the RAMP2 mRNA level, but ET-1 dose-dependently increased the RAMP3 mRNA level in the cardiac myocytes. These findings suggest that ET-1 not only stimulates AM secretion, but also modulates intracellular cAMP responses to AM probably by altering the expressions of CRLR and RAMPs in rat cardiomyocytes. © 2001 Academic Press.

DOI： 10.1006/bbrc.2001.5572

Plasma mature form of adrenomedullin in diabetic nephropathy 査読あり

Kinoshita H., Fujimoto S., Tokura T., Hisanaga S., Kitamura K., Eto T.

Internal Medicine 40 ( 8 ) 841 - 842 2001年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Internal Medicine

DOI： 10.2169/internalmedicine.40.841

Secretion of proadrenomedullin N-terminal 20 peptide from cultured neonatal rat cardiac cells 査読あり

Tsuruda T., Kato J., Kitamura K., Kuwasako K., Imamura T., Koiwaya Y., Kangawa K., Eto T.

Life Sciences 69 ( 2 ) 239 - 245 2001年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Life Sciences

Proadrenomedullin N-terminal 20 peptide (PAMP) is generated from post-transcriptional enzymatic processing of a 185-amino acid precursor for adrenomedullin (AM), a potent vasodilator peptide. We have reported that AM is secreted from cultured neonatal rat cardiac myocytes and fibroblasts, and that secreted AM modulates the growth of these cells; however, it is unknown whether or not the cardiac cells produce PAMP. In this study, we examined the production of PAMP in cultured neonatal rat cardiac myocytes and fibroblasts. Both the cardiac myocytes and fibroblasts cultured with serum-free media secreted PAMP time-dependently at rates of 5.7±0.9 fmol/105 cells/40 h and 8.4±0.7 fmol/5×104 cells/48 h (mean±SD), respectively. Reverse-phase high performance liquid chromatography showed that immunoreactive PAMP secreted from these cells was identical to PAMP[1-20], a whole active molecule. PAMP and AM secretions were significantly (P<0.01) stimulated by 10-6 mol/L angiotensin II (Ang II) and 10% fetal bovine serum (FBS) in myocytes and fibroblasts, whereas the ratio of PAMP to AM secretion in the myocytes was smaller than that of the fibroblasts. These results suggest that PAMP is secreted along with AM from rat cardiac myocytes and fibroblasts, and the secretion is augmented by the growth-promoting stimuli of Ang II and FBS for these cells. © 2001 Elsevier Science Inc.

DOI： 10.1016/S0024-3205(01)01119-5

Selective inhibition of nicotinic cholinergic receptors by proadrenomedullin N-terminal 12 peptide in bovine adrenal chromaffin cells 査読あり

Kobayashi H., Yamamoto R., Kitamura K., Kuwasako K., Minami S.i., Yanagita T., Shiraishi S., Yokoo H., Eto T., Wada A.

Molecular Brain Research 87 ( 2 ) 175 - 183 2001年3月

掲載種別：研究論文（学術雑誌）出版者・発行元：Molecular Brain Research

We studied whether a novel proadrenomedullin derived peptide was present and what was its physiological function in cultured bovine adrenal chromaffin cells. We found a high level of proadrenomedullin N-terminal 12 peptide (PAMP-12) which consists of a peptide from 9th amino acid to 20th amino acid of proadrenomedullin N-terminal 20 peptide (PAMP-20). PAMP-12 was released from the cells along with catecholamine upon stimulation of nicotinic cholinergic receptors. When PAMP-12 was added in the incubation medium, this peptide inhibited nicotinic receptor-mediated catecholamine release and influx of Na+ and Ca2+ into the cells. PAMP-12 did not affect catecholamine release evoked by histamine or by depolarization by high concentration of potassium. PAMP-12 also inhibited synthesis of catecholamines as well as the activation of tyrosine hydroxylase by nicotinic stimulation. Thus, PAMP-12 is an endogenous peptide that regulates release and synthesis of catecholamines by acting on nicotinic cholinergic receptors in an autocrine manner in adrenal chromaffin cells. © 2001 Elsevier Science B.V.

DOI： 10.1016/S0169-328X(01)00011-0

Roles of protein kinase C and Ca2+-dependent signaling in angiotensin II-induced adrenomedullin production in rat cardiac myocytes 査読あり

Tsuruda T., Kato J., Kitamura K., Mishima K., Imamura T., Koiwaya Y., Kangawa K., Eto T.

Journal of Hypertension 19 ( 4 ) 757 - 763 2001年

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Hypertension

Objectives: We showed that angiotensin II stimulates adrenomedullin production in cultured neonatal rat cardiac myocytes, and that the secreted adrenomedullin inhibits hypertrophy of the myocytes, although the intracellular mechanisms of adrenomedullin production are still unknown. Since protein kinase C (PKC) and the Ca2+ signaling system are involved in cardiac hypertrophy, we examined the roles of these intracellular signaling systems in the production of adrenomedullin by myocytes. Methods: Cultured neonatal rat cardiac myocytes were incubated with agonists or antagonists of PKC and Ca2+ signaling systems for 24 h. Adrenomedullin secreted into the medium and adrenomedullin mRNA expression were measured by radioimmunoassay and quantitative polymerase chain reaction, respectively. Results Both phorbol-12-myristate-13-acetate (PMA), a PKC activator and A23187, a calcium ionophore, significantly increased adrenomedullin mRNA expression and secretion from the myocytes. The induction of adrenomedullin secretion by PMA was abolished by H7, a PKC inhibitor, and by downregulation of PKC induced by pre-incubation with PMA. Similarly, the stimulation of adrenomedullin secretion by 10-6 mol/l angiotensin II was significantly reduced following the inhibition or down-regulation of PKC activity in the myocytes. Blockade of the L-type Ca2+ channel and chelation of intracellular Ca2+ both resulted in a significant reduction of the stimulation of adrenomedullin secretion by angiotensin II. In addition, the secretion was significantly attenuated by inhibitors of calmodulin (W-7) and calmodulin kinase II (KN-62), and slightly attenuated by FK506, a calcineurin inhibitor. Conclusions: These results suggest that PKC and the Ca2+/calmodulin signaling systems are involved in angiotensin II-induced adrenomedullin secretion from rat cardiac myocytes. © 2001 Lippincott Williams & Wilkins.

DOI： 10.1097/00004872-200104000-00013

Distribution and molecular forms of adrenomedullin and proadrenomedullin N-terminal 20 peptide in the porcine gastrointestinal tract 査読あり

Kiyomizu A., Kitamura K., Kawamoto M., Eto T.

Journal of Gastroenterology 36 ( 1 ) 18 - 23 2001年

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Gastroenterology

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are potent hypotensive peptides that are generated from the same precursor and expressed in a variety of mammalian tissues. The purpose of this study was to elucidate the distribution and endogenous molecular forms of AM and PAMP. To this end, we used new radioimmunoassays that recognize the ring structure of AM and the C-terminal region of PAMP to compare the distribution of AM and PAMP in porcine gastrointestinal tissues. Immunoreactive AM was abundant in the duodenum (0.334 ± 0.132fmol/mg) and ileum (0.439 ± 0.235fmol/mg), and ubiquitous in other gastrointestinal tissues. The duodenal and ileal concentrations of AM were about 4 to 14 times higher than those in other gastrointestinal tissues. Similarly, immunoreactive PAMP was abundant in the duodenum (0.577 ± 0.417fmol/mg) and ileum (1.575 ± 1.445fmol/mg) and ubiquitous in other gastrointestinal tissues. The concentrations of immunoreactive AM and PAMP were highest in the ileum. Characterization of these peptides in the ileum, using high-performance liquid chromatography, showed that they were authentic. Furthermore, the concentrations of immunoreactive AM and PAMP in the mucosa and submucosa of the ileum were significantly higher than those in whole ileum. These results suggest that AM and PAMP play physiological roles in the porcine small intestine.

DOI： 10.1007/s005350170149

Adrenomedullin and proadrenomudullin N-terminal 20 peptide (PAMP) are present in human colonic epithelia and exert an antimicrobial effect 査読あり

Marutsuka K., Nawa Y., Asada Y., Hara S., Kitamura K., Eto T., Sumiyoshi A.

Experimental Physiology 86 ( 5 ) 543 - 545 2001年

掲載種別：研究論文（学術雑誌）出版者・発行元：Experimental Physiology

The hypotensive and vasorelaxing peptides adrenomedullin (AM) and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), were found to be distributed on the surface of the colonic mucosa. AM and PAMP showed dose-dependent antimicrobial activity against E. coli. The results suggest that the novel vasoactive peptides AM and PAMP play an important role in mucosal defence.

DOI： 10.1113/eph8602250

Plasma levels of mature form of adrenomedullin in patients with haemodialysis 査読あり

Tokura T., Kinoshita H., Fujimoto S., Hisanaga S., Kitamura K., Eto T.

Nephrology Dialysis Transplantation 16 ( 4 ) 783 - 786 2001年

掲載種別：研究論文（学術雑誌）出版者・発行元：Nephrology Dialysis Transplantation

Background. Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide with hypotensive effects. Immunoreactive AM in human plasma consists of the biologically active mature form, AM (1-52)-CONH2 (mAM) and the intermediate form, AM-gly-COOH (iAM). However, the different effects of mAM and iAM in patients on haemodialysis (HD) have remained unclear. Methods. Thirty-nine patients on HD and 10 controls were included in this study. We determined plasma levels of mAM and iAM using an immunoradiometric assay that recognizes total AM (tAM) and another that is specific for only mAM. Results. The plasma concentrations of mAM and iAM in patients before HD were significantly higher than those in the controls (n = 10) (4.76±0.28 vs 1.28±0.22 fmol/ml, P<0.001, 25.99±1.47 vs 8.52± 0.91 fmol/ml, P<0.001 respectively). The plasma levels of mAM and iAM before HD significantly and negatively correlated with systolic blood pressure (SBP) (r=-0.46, P<0.01, and r=-0.32, P<0.05 respectively) and diastolic blood pressure (DBP) (r=-0.32, P<0.05, and r=-0.35, P<0.05 respectively). After HD, plasma mAM and iAM levels as well as SBP and DBP were significantly lower than before HD. Plasma levels of mAM and iAM correlated significantly (r=0.73, P<0.001). Conclusions. These data suggest that mAM and/or iAM are involved in blood pressure regulation in patients undergoing HD, and further work is needed to understand the precise role of adrenomedullin in this regulation.

DOI： 10.1093/ndt/16.4.783

アドレノメデュリンと高血圧査読あり

江藤胤尚、北村和雄

血圧 8 ( 12 ) 1243 - 1249 2001年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンと循環器・呼吸器疾患査読あり

北村和雄

呼吸 20 ( 4 ) 349 - 355 2001年

掲載種別：研究論文（学術雑誌）

培養ヒト血管平滑筋細胞(VSMC)からのアドレノメデユリン(AM)とPAMPの分泌に及ぼすアルドステロン(Aldo)の作用査読あり

上村智彦、加藤丈司、桑迫健二、北村和雄、江藤胤尚

日本内分泌学会雑誌 77 ( 2 ) 435 - 435 2001年

掲載種別：研究論文（学術雑誌）

中間体アドレノメデュリン(AM-gly)の測定系の確立と生体内分布の検討査読あり

山家純一、北村和雄、青木敏浩、加藤丈司、江藤胤尚、橋田誠一、森下和広、寒川賢治

日本内分泌学会雑誌 77 ( 2 ) 435 - 435 2001年

掲載種別：研究論文（学術雑誌）

Adrenomedullin in patients with cerebral vasospasm after aneurysmal subarachnoid hemorrhage. 査読あり

Fujioka M., Nishio K., Sakaki T., Minamino N., Kitamura K.

Stroke; a journal of cerebral circulation 31 ( 12 ) 3079 - 3083 2000年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：Stroke; a journal of cerebral circulation

DOI： 10.1161/01.STR.31.12.3079-d

Adrenomedullin receptors in rat cerebral microvessels 査読あり

Kobayashi H., Minami S.i., Yamamoto R., Masumoto K., Yanagita T., Uezono Y., Tsuchiya K., Mohri M., Kitamura K., Eto T., Wada A.

Molecular Brain Research 81 ( 1-2 ) 1 - 6 2000年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：Molecular Brain Research

To characterize the sites of action of adrenomedullin (AM) in the cerebral microvasculature, we studied the effect of AM on cyclic AMP (cAMP) level as well as expression of AM and its receptor in the rat cerebral microvessels. The microvessels were prepared from rat cerebral cortex by albumin flotation and glass bead filtration technique. AM and calcitonin gene-related peptide (CGRP) increased cAMP level in the microvessels in a concentration-dependent manner. The effect of AM was more than 100 times more potent than that of CGRP. The accumulation of cAMP by AM was inhibited by AM[22-52], an AM receptor antagonist, but not by CGRP[8-37], a CGRP receptor antagonist, suggesting that AM increased cAMP accumulation by acting on receptors specific to AM. [125I]AM binding to the microvessels was displaced by AM and less potently by AM[22-52]. The displacing potencies of CGRP and CGRP[8-37] were very weak. mRNAs for AM as well as calcitonin- receptor-like receptor and receptor-activity-modifying protein 2 which form a receptor specific to AM, were highly expressed in the microvessels. These results provide biochemical and pharmacological evidence that AM is produced in and acts on the cerebral microvessels in an autocrine/paracrine manner and is involved in regulation of cerebral microcirculation. (C) 2000 Elsevier Science B.V.

DOI： 10.1016/S0169-328X(00)00148-0

Visualization of the calcitonin receptor-like receptor and its receptor activity-modifying proteins during internalization and recycling 査読あり

Kuwasako K., Shimekake Y., Masuda M., Nakahara K., Yoshida T., Kitaura M., Kitamura K., Eto T., Sakata T.

Journal of Biological Chemistry 275 ( 38 ) 29602 - 29609 2000年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biological Chemistry

Expression of the calcitonin receptor-like receptor (CRLR) and its receptor activity modifying proteins (RAMPs) can produce calcitonin gene-related peptide (CGRP) receptors (CRLR/RAMP1) and adrenomedullin (AM) receptors (CRLR/RAMP2 or -3). A chimera of the CRLR and green fluorescent protein (CRLR-GFP) was used to study receptor localization and trafficking in stably transduced HEK 293 cells, with or without co-transfection of RAMPs. CRLR-GFP failed to generate responses to CGRP or AM without RAMPs. Furthermore, CRLR-GFP was not found in the plasma membrane and its localization was unchanged after agonist exposure. When stably coexpressed with RAMPs, CRLR-GFP appeared on the cell surface and was fully active in intracellular cAMP production and calcium mobilization. Agonist-mediated internalization of CRLR-GFP was observed in RAMP1/CGRP or AM, RAMP2/AM, and RAMP3/AM, which occurred with similar kinetics, indicating the existence of ligand-specific regulation of CRLR internalization by RAMPs. This internalization was strongly inhibited by hypertonic medium (0.45 M sucrose) and paralleled localization of rhodamine-labeled transferrin, suggesting that CRLR endocytosis occurred predominantly through a clathrin-dependent pathway. A significant proportion of CRLR was targeted to lysosomes upon binding of the ligands, and recycling of the internalized CRLR was not efficient. In HEK 293 cells stably expressing CRLR-GFP and Myc-RAMPs, these rhodamine-labeled RAMPs were co-localized with CRLR-GFP in the presence and absence of the ligands. Thus, the CRLR is endocytosed together with RAMPs via clathrin-coated vesicles, and both the internalized molecules are targeted to the degradative pathway.

DOI： 10.1074/jbc.M004534200

Enhanced adrenomedullin production by mechanical stretching in cultured rat cardiomyocytes 査読あり

Tsuruda T., Kato J., Kitamura K., Imamura T., Koiwaya Y., Kangawa K., Komuro I., Yazaki Y., Tanenao E.

Hypertension 35 ( 6 ) 1210 - 1214 2000年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension

Adrenomedullin (AM) is secreted from cultured cardiac myocytes. In this study, we examined whether mechanical stretching stimulates AM production in cardiac myocytes, and if so, whether angiotensin II (Ang II) is involved in that mechanism. Neonatal rat cardiac myocytes cultured in serum-free medium were stretched 10% or 20% on flexible silicone rubber culture dishes, and AM mRNA expression was examined by quantitative polymerase chain reaction. The AM mRNA levels in the myocytes stretched 10% and 20% for 24 hours significantly increased by 56% (P<0.05) and 88% (P<0.01), respectively, when compared with the levels in nonstretched cells. AM secretion into the medium after the myocytes were stretched 10% and 20% increased by 22% (P<0.05) and 45% (P<0.01), respectively. In nonstretched myocytes incubated with 10-6 mol/L Ang II for 24 hours, AM mRNA and secretion increased by 86% (P<0.05) and 36% (P<0.01), respectively. These effects of Ang II were abolished by 10-6 mol/L CV-11974, an Ang II type I (AT1) receptor antagonist, but not by 10-6 mol/L PD-123319, an Ang II type II antagonist. Stretch-induced increases of AM gene expression and secretion were significantly inhibited (P<0.05) in the presence of 10-6 mol/L CV-11974 by 46% and 52%, respectively; however, they were not affected by 10-6 mol/L PD-123319. These findings indicate that AM production from cardiac myocytes is augmented by mechanical stretching, partially through the AT1 receptors, which suggests a local interaction between AM and the renin-angiotensin system in stretched cardiac myocytes.

DOI： 10.1161/01.HYP.35.6.1210

Differential responses of circulating and tissue adrenomedullin and gene expression to volume overload 査読あり

Hirano S., Imamura T., Matsuo T., Ishiyama Y., Kato J., Kitamura K., Koiwaya Y., Eto T.

Journal of Cardiac Failure 6 ( 2 ) 120 - 129 2000年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Cardiac Failure

Background: Adrenomedullin (AM), which is produced by various tissues and organs, also circulates in the blood. Circulating AM levels increase during disease states such as essential hypertension, heart failure, and renal failure. However, little is known about how circulating AM or AM production responds to volume overload (VOL). Methods and Results: Progressive VOL was induced in rats by an aortocaval shunt (AC) or by an aortocaval shunt with banding of the abdominal aorta distal to the shunt (AC + B), which created a larger shunt volume. Plasma and tissue AM concentrations, as well as AM gene expression levels, were measured at 1, 5, and 14 days after operation. Plasma concentrations of atrial natriuretic peptide (ANP), aldosterone, and renin activity (PRA) were also examined. Pulmonary congestion, pleural effusion, and ascites rapidly progressed in the AC + B group, suggesting that VOL caused more rapid heart failure under these conditions. Plasma AM concentrations in the AC + B and AC groups at day 1 compared with those in sham-operated rats were increased by 300% and 140%, respectively, and then gradually declined. The time course of plasma AM over 14 days was similar to that of plasma aldosterone and PRA, but not of plasma ANP or intracardiac filling pressure. The increase in plasma AM was accompanied by upregulated AM gene expression in the lung and aorta and by decreased AM concentrations in the atrium, ventricle, and adrenal gland. Cardiac AM gene expression levels were increased in the hypertrophied ventricles of AC and AC + B rats. Conclusions: The major findings of the present study were 1) a rapid increase in plasma AM after the imposition of VOL in association with increased plasma aldosterone and PRA, 2) the contribution of several organs to this increase, and 3) a late increase in the AM messenger RNA (mRNA) level in the ventricles as VOL-induced ventricular hypertrophy developed.

DOI： 10.1054/jcaf.2000.7277

Atypical aortic coarctation with resistant hypertension treated with axilloiliac artery bypass 査読あり

Inagaki H., Kato J., Yamashita A., Uemura T., Kitamura K., Yano Y., Nakamura K., Onitsuka T., Eto T.

Hypertension Research 23 ( 3 ) 247 - 249 2000年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

A 68-year-old woman was found to have atypical coarctation of the aorta, accompanied by systolic hypertension of the upper extremities despite administration of five types of antihypertensive drugs. Since the systolic hypertension was resistant to the conventional antihypertensive therapy, axilioiliac artery bypass grafting with a subcutaneous tunnel was performed to alleviate the pressure gradient. Systolic blood pressure was successfully reduced and hypertension was controlled after surgery.

DOI： 10.1291/hypres.23.247

A physiological role for adrenomedullin in rats; a potent hypotensive peptide in the hypothalamo-neurohypophysial system 査読あり

Ueta Y., Serino R., Shibuya I., Kitamura K., Kangawa K., Russell J.A., Yamashita H.

Experimental Physiology 85 S ( SPEC. ISS. ) 163s - 169s 2000年3月

掲載種別：研究論文（学術雑誌）出版者・発行元：Experimental Physiology

Adrenomedullin, a potent hypotensive peptide, was originally isolated from human phaeochromocytoma. Adrenomedullin immunoreactivity and gene expression are found not only in peripheral organs but also in the central nervous system. Adrenomedullin labelled cells were localised in the hypothalamus, including in the paraventricular and supraoptic nuclei, in rats. Abundant adrenomedullin-immunoreactive fibres and varicosities were found in the hypothalamo-neurohypophysial tract and the internal zone of the median eminence in colchicine-treated and hypophysectomized rats, whereas in control rats few adrenomedullin-labelled fibres were observed. We examined the effects of intracerebroventricular administration of adrenomedullin on neurosecretory cells in the paraventricular and supraoptic nuclei of rats, using immunohistochemistry for Fos protein and in situ hybridisation histochemistry for c-fos mRNA. Intracerebroventricular administration of adrenomedullin caused a marked induction of Fos-like immunoreactivity in the paraventricular nucleus and the dorsal part of the supraoptic nucleus. In the paraventricular and supraoptic nuclei, nuclear Fos-like immunoreactivity was predominantly in oxytocin-immunoreactive cells rather than vasopressin-immunoreactive cells. The induction of c-fos mRNA in the paraventricular and supraoptic nuclei was increased in a dose-related manner 30 min after intracerebroventricular administration of adrenomedullin. This induction was reduced by pre-treatment with the adrenomedullin receptor antagonist, human adrenomedullin- (22-52)-NH2. Intracerebroventricular administration of adrenomedullin also caused a marked increase in the plasma concentration of oxytocin. Extracellular recordings from magnocellular neurosecretory cells in the paraventricular nucleus revealed that putative oxytocin-secreting cells were activated by intracerebroventricular administration of adrenomedullin. These results suggest that central adrenomedullin preferentially stimulates the secretion of oxytocin by activating hypothalamic oxytocin-secreting cells and may have an important role in salt appetite and body fluid homeostasis in rats.

DOI： 10.1111/j.1469-445x.2000.tb00020.x

Diastolic wall stress and ANG II in cardiac hypertrophy and gene expression induced by volume overload 査読あり

Yamakawa H., Imamura T., Matsuo T., Onitsuka H., Tsumori Y., Kato J., Kitamura K., Koiwaya Y., Eto T.

American Journal of Physiology - Heart and Circulatory Physiology 279 ( 6 48-6 ) H2939 - H2946 2000年

掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Physiology - Heart and Circulatory Physiology

We investigated the effects of diastolic wall stress (WS) and angiotensin II (ANG II) on the left ventricular (LV) hypertrophy (LVH) induced by volume overload and on the gene expression of LV adrenomedullin (AM) and atrial natriuretic peptide (ANP) in volume overload. Diastolic WS was pharmacologically manipulated with (candesartan) or without (calcium channel blocker manidipine) inhibition of ANG II type i receptors in aortocaval-shunted rats over 6 wk. Diastolic WS reached a plateau at 2 wk and subsequently declined regardless of further LVH. Although diastolic WS was decreased to a similar extent by both compounds, candesartan blunted LVH over 6 wk, whereas manidipine blunted LVH at 2 wk but not after 4 wk. Levels of AM and ANP gene expression increased as LVH developed but were completely suppressed by candesartan over 6 wk. ANP expression level was also attenuated by manidipine over 6 wk, whereas AM expression level was suppressed at 2 wk but not after 4 wk by manidipine. We concluded that diastolic WS and ANG II might be potent stimuli for the LVH and LV AM and ANP gene expression in volume overload and that diastolic WS could be relatively involved in the early LVH and in the gene expression of ANP rather than of AM.

DOI： 10.1152/ajpheart.2000.279.6.h2939

Increased plasma levels of mature adrenomedullin in chronic glomerulonephritis 査読あり

Kinoshita H., Fujimoto S., Kitamura K., Matsuura Y., Uezono S., Hisanaga S., Eto T.

Nephron 86 ( 3 ) 333 - 338 2000年

掲載種別：研究論文（学術雑誌）出版者・発行元：Nephron

Adrenomedullin (AM) is a potent vasodilative and natriuretic peptide that is processed from its precursor as the intermediate form, AM-glycine-COOH (iAM). Subsequently, iAM is converted to the biologically active mature form, AM(1-52)-CONH2 (mAM), by enzymatic amidation. Using immunoradiometric assays that recognize total AM (tAM) and only mAM, we determined the plasma and urinary levels of mAM and iAM in patients with chronic glomerulonephritis (CGN). The plasma mAM concentration was significantly higher in the patients than in the controls (1.8 ± 0.1 vs. 1.3 ± 0.1 fmol/ml, p < 0.01), whereas the plasma iAM concentration of the CGN patients did not significantly differ from that of the controls (9.4 ± 0.5 vs. 8.9 ± 0.5 fmol/ml). Levels of urinary mAM excretion in the patients did not statistically differ from those of the controls (1.6 ± 0.4 vs. 2.0 ± 0.3 fmol/mg creatinine), whereas urinary iAM excretion was significantly lower in the CGN patients (3.7 ± 0.7 vs. 5.6 ± 0.8 fmol/mg creatinine, p < 0.05). Urinary excretion levels of mAM significantly correlated with those of sodium (r = 0.47, p < 0.05), whereas those of iAM did not. In conclusion, the plasma ratio of mAM to iAM is augmented in CGN patients, and mAM appears to be involved in the regulation of sodium. Therefore, determination of the mAM in addition to the tAM concentration is essential in CGN patients. Copyright (C) 2000 S. Karger AG, Basel.

DOI： 10.1159/000045789

Plasma adrenomedullin levels in patients with diabetes [1] 査読あり

Kinoshita H., Kato K., Kuroki M., Nakamura S., Kitamura K., Hisanaga S., Fujimoto S., Eto T.

Diabetes Care 23 ( 2 ) 253 - 254 2000年

掲載種別：研究論文（学術雑誌）出版者・発行元：Diabetes Care

DOI： 10.2337/diacare.23.2.253

活動性肺結核患者におけるアドレノメデュリンおよび関連ペプチドに関する臨床的検討査読あり

下窪徹、比嘉利信、北村和雄、江藤胤尚、隈本健司

日本胸部臨床 59 ( 8 ) 602 - 607 2000年

掲載種別：研究論文（学術雑誌）

高血圧とアドレノメデュリン査読あり

北村和雄

Geriatric Medicine（老年医学） 38 ( 10 ) 1467 - 1473 2000年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンと関連ペプチド査読あり

北村和雄。江藤胤尚

日本臨牀 58 ( 1 ) 121 - 125 2000年

担当区分：筆頭著者掲載種別：研究論文（学術雑誌）

心筋細胞におけるアドレノメデュリン(AM)分泌機序の検討査読あり

加藤丈司、鶴田敏博、北村和雄、桑迫健二、三嶋和也、江藤胤尚

日本内分泌学会雑誌 76 ( 2 ) 471 - 471 2000年

掲載種別：研究論文（学術雑誌）

培養心筋細胞および非心筋細胞におけるproadrenomedullin N-terminal 20 peptide(PAMP)の産生査読あり

加藤丈司、鶴田敏博、三嶋和也、北村和雄、江藤胤尚

日本内分泌学会雑誌 76 ( 2 ) 471 - 471 2000年

掲載種別：研究論文（学術雑誌）

Marked increase of guanylin secretion in response to salt loading in the rat small intestine 査読あり

Kita T., Kitamura K., Sakata J., Eto T.

American Journal of Physiology - Gastrointestinal and Liver Physiology 277 ( 5 40-5 ) 1999年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Physiology - Gastrointestinal and Liver Physiology

Guanylin and uroguanylin are intestinal peptides that stimulate guanylate cyclase C and cause chloride secretion. These peptides show topological instability due to two disulfide bonds. The disulfide bonds were reduced and S-carboxymethylated to cleave the bonds and obtain stable and sole derivatives. We established a new and reliable RIA system for the stable derivatives from both peptides. With the use of this system, the response of the peptides to salt loading of the rat small intestine was evaluated. The lumen of the small intestines of Sprague-Dawley rats was perfused in vivo with Krebs-Ringer solution containing different concentrations of salt or mannitol. Mature guanylin, proguanylin, and mature uroguanylin were found in the perfusate in the basal state. The highest salt loading (200 mM NaCl for 20 min) increased the guanylin secretion about threefold (1.9 ± 0.2 vs. 5.4 ± 0.5 pmol/min), with the effect lasting for 60 min. The uroguanylin secretion was less affected. Hyperosmolar mannitol also caused a significant but smaller increase of guanylin secretion. Increased guanylin could lead to increased salt and water secretion of the intestine; thus members of the guanylin family have potential roles in the regulation of water and salt metabolism in the small intestine.

DOI： 10.1152/ajpgi.1999.277.5.g960

Novel distribution of adrenomedullin-immunoreactive cells in human tissues 査読あり

Asada Y., Hara S., Marutsuka K., Kitamura K., Tsuji T., Sakata J., Sato Y., Kisanuki A., Eto T., Sumiyoshi A.

Histochemistry and Cell Biology 112 ( 3 ) 185 - 191 1999年10月

掲載種別：研究論文（学術雑誌）出版者・発行元：Histochemistry and Cell Biology

Adrenomedullin (AM) is a novel hypotensive and vasodilator peptide. We previously examined the localization of AM in human, rat, and porcine tissues using a polyclonal antibody against synthetic human AM[40-52]. We demonstrated that AM is widely distributed in the endocrine and neuroendocrine systems, but not in the heart, kidney, or blood vessels, although high levels of AM mRNA were detected in the latter tissues. In this study, we further investigated the distribution of AM by using two newly developed monoclonal antibodies against synthetic human AM peptides, [12-25] and [46-52]. AM immunoreactivity was observed in cardiac myocytes, vascular smooth muscle cells, endothelial cells, and renal distal and collecting tubules. In addition, AM-immunoreactive (IR) cells were found in mucosal and glandular epithelia of the digestive, respiratory, and reproductive systems, as well as the endocrine and neuroendocrine systems. These findings indicate that AM-IR cells are more widely distributed in human tissues and suggest that AM might play multiple biological roles in humans.

DOI： 10.1007/s004180050406

An autocrine or a paracrine role of adrenomedullin in modulating cardiac fibroblast growth 査読あり

Tsuruda T., Kato J., Kitamura K., Kawamoto M., Kuwasako K., Imamura T., Koiwaya Y., Tsuji T., Kangawa K., Eto T.

Cardiovascular Research 43 ( 4 ) 958 - 967 1999年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：Cardiovascular Research

Objective: The aim of the present study was to determine the role of adrenomedullin (AM) in cardiac fibroblasts. Methods: The production and secretion of AM were examined in cultured neonatal rat cardiac fibroblasts, and the effects of AM on proliferation and protein synthesis of these cells were assessed by [3H]thymidine and [3H]phenylalanine incorporation, respectively. Results: Cultured cardiac fibroblasts secreted AM into the medium time-dependently at a rate of 20.3±3.0 fmol/5x104 cells/48 h, mean±S.D. Northern blot analysis showed expression of preproAM mRNA of 1.6 kb in these cells. In addition, 10-6 mol/l of angiotensin II (Ang II) and endothelin-1 (ET-1) significantly increased the AM secretion by 55 and 48%, respectively. Synthetic AM significantly reduced 10-6 mol/l Ang II- or 10-7 mol/l ET-1-stimulated [3H]thymidine and [3H]phenylalanine incorporation in a dose-dependent manner, and these effects were attenuated by a calcitonin gene-related peptide (CGRP) type 1 receptor antagonist, CGRP(8-37). Synthetic AM also had a dose-dependent stimulatory effect on cAMP accumulation in these cells, which was significantly attenuated by CGRP(8-37). A cAMP analogue, 8-bromo-cAMP, mimicked the AM effects, inhibiting the Ang II-stimulated [3H]thymidine and [3H]phenylalanine incorporation. Blockage of the effect of endogenous AM by anti-AM monoclonal antibody not only significantly reduced the basal level of intracellular cAMP, but also enhanced the [3H]thymidine and [3H]phenylalanine incorporation into the cells. Conclusions: Cultured neonatal rat cardiac fibroblasts produce and secrete AM, and the secreted AM may inhibit proliferation and protein synthesis of these cells. AM may exert these inhibitory effects partly by elevating intracellular cAMP. It is suggested that AM has an important role in modulating the growth of cardiac fibroblasts in an autocrine or a paracrine manner. Copyright (C) 1999 Elsevier Science B.V.

DOI： 10.1016/S0008-6363(99)00122-4

A simple immunoradiometric assay for measuring the entire molecules of adrenomedullin in human plasma 査読あり

Ohta H., Tsuji T., Asai S., Tanizaki S., Sasakura K., Teraoka H., Kitamura K., Kangawa K.

Clinica Chimica Acta 287 ( 1-2 ) 131 - 143 1999年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：Clinica Chimica Acta

We developed a one-step two-site immunoradiometric assay (IRMA) using two kinds of monoclonal antibodies, which enables us to directly measure the entire molecules of adrenomedullin (AM) (the sum of mature-type AM (abbreviated, m-AM) amidated at the C-terminus and Gly-extended non-amidated AM) in human plasma using a small amount of sample (100 μl) without prior extraction. The detection limit of this assay was 0.5 pmol/l for a 100-μl sample. Intra- and inter-assay precisions were 3.4-7.3% and 5.8-7.6%, respectively. The dilution curves of plasma samples showed good linearity and analytical recovery was 89-118%. The mean total AM in plasma of healthy subjects was 9.00±2.13 pmol/l, whereas m-AM was 1.05±0.24 pmol/l. This method, together with our previously reported simplified method to specifically measure m-AM (Ohta et al., Clin Chem 1999;45:244-251), allows facile estimation of the plasma concentration of AM-Gly by subtracting m-AM from the total AM measured by the procedure described in this paper. We were able to show that the concentration of total AM in patients with sepsis was markedly higher than that in the healthy controls and that the ratios of m-AM/total AM were significantly different between the controls and patients. Copyright (C) 1999 Elsevier Science B.V.

DOI： 10.1016/S0009-8981(99)00128-X

Cyclic AMP-dependent synthesis and release of adrenomedullin and proadrenomedullin N-terminal 20 peptide in cultured bovine adrenal chromaffin cells 査読あり

Kobayashi H., Yamamoto R., Kitamura K., Niina H., Masumoto K., Minami S.i., Yanagita T., Izumi F., Aunis D., Tanenao E., Wada A.

European Journal of Biochemistry 263 ( 3 ) 702 - 708 1999年8月

掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Biochemistry

Adrenomedullin and proadrenomedullin N-terminal 20 peptide are peptides with multiple physiological functions and are most abundant in adrenal medulla. We studied whether the cAMP-dependent pathway is involved in the regulation of synthesis and release of adrenomedullin and proadrenomedullin N-terminal 20 peptide in cultured bovine adrenal chromaffin cells. Exposure of the cells to dibutyryl cAMP (dbcAMP) increased a progressive accumulation of immunoreactive-adrenomedullin and immunoreactive-proadrenomedullin N- terminal 20 peptide in the extracellular medium, while reciprocally decreasing their cellular content in a time-dependent manner. The decrease of levels of both peptides in the cells was much greater in extent than the increase of the peptides in the medium. H89, an inhibitor of cAMP-dependent protein kinase attenuated these changes, induced by dbcAMP. The resulting changes by dbcAMP and H89 were similar to those of chromogranin B, a marker peptide of chromaffin granule. Northern blot analysis showed that the mRNA encoding these peptides, detected as a band of 1.6 kb, was decreased by the treatment with dbcAMP. The effect of dbcAMP on mRNA was attenuated by H89, and was reversible as the decreased mRNA level caused by dbcAMP could be returned to control levels by culturing cells after removal of dbcAMP. These results suggest that the cAMP-dependent protein kinase pathway stimulates the release of adrenomedullin and proadrenomedullin N-terminal 20 peptide, whereas it lowers synthesis of these peptides via the reduction of their transcript level.

DOI： 10.1046/j.1432-1327.1999.00546.x

Increased plasma levels of mature form of adrenomedullin in patients with chronic renal failure 査読あり

T Ishihara 1, N Yokota, S Hisanaga, S Fujimoto, N Hirayama, J Kato, K Kitamura, T Eto

Clin Nephrol 52 ( 2 ) 119 - 123 1999年8月

掲載種別：研究論文（学術雑誌）

Biological and clinical roles of adrenomedullin in circulation control and cardiovascular diseases 査読あり

Eto T., Kitamura K., Kato J.

Clinical and Experimental Pharmacology and Physiology 26 ( 5-6 ) 371 - 380 1999年7月

掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical and Experimental Pharmacology and Physiology

1. Adrenomedullin (AM) is found ubiquitously in tissues and organs, especially in cardiovascular tissues and in the kidney, lung and endocrine glands. It has multifunctional biological properties, of which, its effects on the control of circulation and body fluid volume regulation seem to be the most outstanding and characteristic. 2. Acute administration of a high dose of AM induces a vasodilator depressor response, cardiac inotropic effects, diuresis and suppression of aldosterone secretion in experimental animals. 3. Long-term continuous administration of a very low dose of AM causes vasodilation in sheep (0.5 μg/kg per h) and hypotension in rats (0.8 μg/kg per h). 4. The plasma concentration of AM increases under pathological conditions such as congestive heart failure, myocardial infarction and hypertensive and renal diseases. Under these disease conditions, AM may be produced in vascular endothelial and smooth muscle cells and in cardiac myocytes in response to volume expansion, hypertension and activated humoral factors, such as catecholamine and the renin-angiotensin system. 5. Increased AM in the circulating blood and cardiovascular tissues may counteract pathological deviation in the system that controls circulation and body fluid volume, acting against cardiovascular damage and disease. 6. Because of these beneficial properties in the cardiovascular system, AM and its pharmaceutical ligands should prove useful in the treatment of cardiovascular diseases.

DOI： 10.1046/j.1440-1681.1999.03047.x

Secretion and clearance of the mature form of adrenomedullin in humans 査読あり

Hirayama N., Kitamura K., Imamura T., Kato J., Koiwaya Y., Eto T.

Life Sciences 64 ( 26 ) 2505 - 2509 1999年5月

掲載種別：研究論文（学術雑誌）出版者・発行元：Life Sciences

In the biosynthesis of adrenomedullin (AM), glycine-extended AM, an intermediate form (iAM) processed from proAM is converted to AM[1-52]-NH2, the bioactive mature form of AM (mAM), by enzymatic amidation. We earlier showed that both molecular forms of AM circulate in human plasma. In the present study, to investigate the secretion and clearance sites of mAM and iAM in humans, we examined the plasma mAM and iAM concentrations in the femoral artery and vein (FA and FV), the aortic root and coronary sinus (AO and CS), and the pulmonary artery and capillary (PA and PC) of patients with ischemic heart disease. Plasma mAM in FV was significantly (p<0.001) higher than in FA. There also was a significant (p<0.001) step-up in the plasma mAM of the CS as compared to the AO. In contrast, plasma mAM was significantly (p<0.001) reduced in the PC as compared to the PA. However, such differences were not observed in plasma iAM levels. These findings suggest that in humans the vasculature of the lower extremities and the heart produce and secrete roAM and that the lung is a clearance site of circulating mAM.

DOI： 10.1016/S0024-3205(99)00208-8

Plasma adrenomedullin and natriuretic peptides in patients with essential or malignant hypertension 査読あり

Kato J., Kitamura K., Matsui E., Tanaka M., Ishizaka Y., Kita T., Kangawa K., Eto T.

Hypertension Research - Clinical and Experimental 22 ( 1 ) 61 - 65 1999年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research - Clinical and Experimental

Adrenomedullin (AM), a potent vasodilator and natriuretic peptide, is found in human blood. To investigate the pathophysiological role of AM in essential and malignant hypertension (EHT and MHT), we measured the plasma concentrations of AM in patients with EHT of WHO stage I or II (n = 42) and in those with MHT (n = 9) by a specific radioimmunoassay, and compared these concentrations with those in normotensive controls (n = 46). The plasma concentrations of atrial and brain natriuretic peptides (ANP and BNP) in these subjects were also measured by immunoradiometric assays, and their relations to plasma AM were examined. The plasma AM level in the EHT patients (7.15 ± 0.21 pmol/l, mean ± SEM) was significantly (p < 0.01) higher than that in the normotensive controls (6.14 ± 0.25 pmol/l), and a further elevation was observed in the MHT patients (14.1 ± 3.8 pmol/l). Similar elevations of plasma ANP and BNP were seen in the two patient groups. The plasma AM level significantly (p < 0.01) correlated with not only the systolic (r = 0.44) and diastolic (r = 0.46) blood pressures, but also with the plasma levels of ANP (r = 0.43) and BNP (r = 0.43). The elevated plasma concentration of AM in the MHT patients decreased significantly (p < 0.05) after antihypertensive treatment, and the plasma ANP and BNP levels similarly declined. These results suggest that AM may participate, along with ANP and BNP, in mechanisms counteracting a further elevation of blood pressure in patients with EHT and MHT.

DOI： 10.1291/hypres.22.61

Cell density of adrenomedullin-immunoreactive cells in the gastric endocrine cells decreases in antral atrophic gastritis 査読あり

Kitani M., Asada Y., Sakata J., Kitamura K., Sumiyoshi A., Eto T.

Histopathology 34 ( 2 ) 134 - 139 1999年2月

掲載種別：研究論文（学術雑誌）出版者・発行元：Histopathology

Aims: Adrenomedullin (AM) is a novel hypotensive and vasorelaxing peptide recently isolated from human phaeochromocytoma tissue, and is widely distributed in various organs. In this study we examined the localization of AM-immunoreactive (IR) cells in the gastric mucosa and AM-IR cell density in antral atrophic gastritis. Methods and results: Gastric mucosal tissues were taken from the gastric body and antral mucosa of 52 patients (27 men, 25 women: mean age 56.0 (range 20-86) years). Immunohistochemical analysis revealed that AM-IR cells were present in the pyloric glands, but not in the fundic glands, and that AM-IR cells were stained positively for chromogranin A and gastrin. The percentage of AM-IR cells vs chromogranin A- and gastrin- IR cells was 42 and 56%, respectively. The number of AM-IR cells decreased with the progression of severity of atrophic changes in the pyloric gland, and also of mononuclear cell infiltration. There was no correlation between the number of AM-IR cells and the degree of neutrophilic infiltration. Similar findings were also obtained for gastrin-IR cells. Conclusion: AM-IR cells are present in the endocrine cells including gastrin-IR cells in the pyloric glands. These results suggest that AM may contribute to gastrin secretion in the pyloric glands.

DOI： 10.1046/j.1365-2559.1999.00573.x

Molecular forms of circulating adrenomeduilin in patients with congestive heart failure 査読あり

Hirayama N., Kitamura K., Imamura T., Kato J., Koiwaya Y., Tsuji T., Kangawa K., Eto T.

Journal of Endocrinology 160 ( 2 ) 297 - 303 1999年2月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Endocrinology

In the biosynthesis of adrenomedullin (AM), an intermediate form, AM(1- 52)-glycine-COOH (iAM), is cleaved from proAM and subsequently processed to a biologically active mature form, AM(1-52)-NH2 (mAM), by enzymatic amidation. We recently reported that immunoreactive AM in human plasma consists of roAM and iAM. To clarify the pathophysiological roles of mAM and iAM in heart failure, we established an assay method to specifically detect mAM, and we determined the plasma concentrations of mAM and iAM in 68 patients with congestive heart failure (CHF). The plasma mAM concentrations of the CHF patients classified as being class I or II of New York Heart Association (NYHA) functional classification were significantly greater than those of the 28 healthy controls, and a further increase was noted in the class III or IV patients. Similar increases in plasma iAM were also observed in these patients compared with controls. The increased plasma mAM and iAM in 12 patients with exacerbated CHF were significantly reduced by treatment of their CHF for 7 days. In addition, the plasma concentrations of both mAM and iAM were significantly correlated with pulmonary capillary wedge pressure, pulmonary artery pressure, fight atrial pressure, cardiothoracic ratio, heart rate, and the plasma concentrations of atrial and brain natriuretic peptides in the CHF patients. Thus the plasma concentrations of both roAM and iAM were increased progressively in proportion to the severity of CHF. These results suggest that, though the role of iAM remains to be clarified, mAM acts against the further deterioration of heart failure in patients with CHF.

DOI： 10.1677/joe.0.1600297

Adrenomedullin-like immunoreactivity in the rat hypothalamo- neurohypophysial tract 査読あり

Ueta Y., Hara Y., Setiadji V.S., Isse T., Shibuya I., Kitamura K., Kangawa K., Matsuo H., Eto T., Hattori Y., Yamashitaa H.

Peptides 20 ( 2 ) 199 - 204 1999年2月

掲載種別：研究論文（学術雑誌）出版者・発行元：Peptides

Adrenomedullin-like immunoreactivity in the hypothalamo- neurohypophysial tract in colchicine-treated and hypophysectomized rats was examined by immunohistochemistry. Adrenomedullin-like immunoreactive (AM-LI) neurons were localized in the hypothalamic areas, including the paraventricular nuclei and the supraoptic nuclei. Abundant AM-LI fibers and varicosities were found in the hypothalamoneurohypophysial tract and the internal zone of the median eminence in the colchicine-treated and hypophysectomized rats, whereas in control rats few AM-LI fibers were observed. These results suggest that the axons of the AM-LI neurons in the hypothalamus may terminate in the neurohypophysis.

DOI： 10.1016/S0196-9781(98)00156-9

Centrally administered adrenomedullin increases plasma oxytocin level with induction of c-fos messenger ribonucleic acid in the paraventricular and supraoptic nuclei of the rat 査読あり

One-step direct assay for mature-type adrenomedullin with monoclonal antibodies 査読あり

H Ohta 1, T Tsuji, S Asai, K Sasakura, H Teraoka, K Kitamura, K Kangawa

Clin Chem 45 ( 2 ) 244 - 251 1999年2月

掲載種別：研究論文（学術雑誌）

Serino R., Ueta Y., Hara Y., Nomura M., Yamamoto Y., Shibuya I., Hattori Y., Kitamura K., Kangawa K., Russell J.A., Yamashita H.

Endocrinology 140 ( 5 ) 2334 - 2342 1999年

掲載種別：研究論文（学術雑誌）出版者・発行元：Endocrinology

The effects of intracerebroventricular (icv) administration of adrenomedullin (AM) on plasma oxytocin (OXT), c-Fos protein (Fos), and c-fos messenger RNA (mRNA) in the paraventricular (PVN) and supraoptic nuclei (SON) of the rat were investigated using RIA for OXT, immunohistochemistry for Fos, and in situ hybridization histochemistry for c-Fos mRNA. Central administration of AM caused a significant increase in the plasma OXT level. Intracerebroventricular administration of AM caused a marked induction of Fos-like immunoreactivity (LI) in the PVN and in the dorsal parts of the SON. In the PVN and SON, OXT-LI cells predominantly exhibited nuclear Fos-LI in comparison with arginine vasopressin-LI cells. In situ hybridization histochemistry revealed that the induction of c-fos mRNA in the PVN and SON was increased in a dose-related manner 30 min after icv administration of AM. This induction was reduced by pretreatment with the AM receptor antagonist, human AM-(22-52)-NH2. These results suggest that central AM is responsible for activating the neurosecretory cells in the PVN and SON via selective AM receptors, and that AM stimulates the secretion of OXT by activating hypothalamic OXT-producing cells.

DOI： 10.1210/endo.140.5.6717

Differential hormonal profiles of adrenomedullin and proadrenomedullin N-terminal 20 peptide in patients with heart failure and effect of treatment on their plasma levels 査読あり

Etoh T., Kato J., Takenaga M., Imamura T., Kitamura K., Koiwaya Y., Eto T.

Clinical Cardiology 22 ( 2 ) 113 - 117 1999年

掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical Cardiology

Background: Adrenomedullin (AM) is a potent vasodilatory peptide discovered in human pheochromocytoma tissue. Proadrenomedullin N-terminal 20 peptide (PAMP) processed from an AM precursor is also a novel hypotensive peptide which inhibits catecholamine secretion from sympathetic nerve endings. Hypothesis: The present study sought to examine the relationships between the two peptides and other clinical parameters by measuring the plasma AM and PAMP concentrations in 98 patients with heart failure. Methods: In all, 98 patients [65 men and 33 women, aged 58.2 ± 11.0 years, mean ± standard deviation (SD)] with heart failure and 26 healthy volunteers (12 men and 14 women, aged 54.1 ± 8.6 years) were examined in this study. Heart failure was secondary to previous myocardial infarction in 58 patients, valvular disease in 28, cardiomyopathy in 9, and congenital heart disease in 3. All patients were classified into two groups of class I or II (Group 1) and class III or IV (Group 2) according to the New York Heart Association (NYHA) functional classification. Results: Both plasma AM and PAMP concentrations in the patients were significantly higher than those in healthy volunteers. In addition, plasma AM and PAMP concentrations in patients in class III or IV of New York Heart Association (NYHA) classification were significantly higher than those in NYHA class I or II. The elevated plasma concentrations of these peptides in patients in NYHA class III or IV significantly decreased in response to the treatment for 7 days. There was a significant correlation between plasma AM and PAMP, though the plasma concentration of PAMP was one-fifth to one-seventh of that of AM in patients and controls. The plasma AM concentration correlated significantly with the plasma concentrations of atrial and brain natriuretic peptides, epinephrine, and right atrial pressure, whereas such a relationship was not noted for the plasma PAMP concentration. Conclusions: Judging from the difference in not only the biological actions but also the hormonal profiles between AM and PAMP, they may differentially modulate the cardiovascular system in patients with heart failure, although they are processed from the same precursor.

DOI： 10.1002/clc.4960220211

Plasma and urine levels of adrenomedullin and proadrenomedullin N- terminal 20 peptide in chronic glomerulonephritis 査読あり

Kinoshita H., Fujimoto S., Kitamura K., Yokota N., Kawamoto M., Tokura T., Hisanaga S., Eto T.

American Journal of Kidney Diseases 34 ( 1 ) 114 - 119 1999年

掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Kidney Diseases

· Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide present in the precursor of adrenomedullin (AM), a vasodilative and natriuretic peptide. We examined the plasma and urinary levels of these peptides in patients with chronic glomerulonephritis (CGN). The mean plasma AM concentration of the patients with CGN did not differ from that of control subjects (4.17 ± 0.17 v 3.87 ± 0.21 fmol/mL, respectively), whereas urinary AM excretion was significantly less in the patients with CGN (5.96 ± 0.95 v control, 8.93 ± 1.02 fmol/mg of creatinine; P < 0.05). Plasma concentrations and urinary excretion of PAMP were significantly less for the patients with CGN compared with control subjects (0.91 ± 0.08 v 1.23 ± 0.20 fmol/mL; P < 0.05 and 25.0 ± 3.0 v 35.0 ± 3.6 fmol/mg of creatinine, respectively; P < 0.05). The plasma AM concentration was negatively correlated with plasma renin activity (r = -0.58; P < 0.01) and aldosterone concentration (r = - 0.40; P < 0.05). Urinary excretions of AM and PAMP showed significant correlations with urine excretion of sodium (r 0.39; P < 0.05 and r = 0.49; P < 0.01, respectively). These findings suggest that AM and PAMP may have roles in the regulation of sodium in patients with CGN.

DOI： 10.1016/S0272-6386(99)70116-2

Increased plasma proadrenomedullin N-terminal 20 peptide in patients with essential hypertension 査読あり

Kuwasako K., Kitamura K., Kangawa K., Ishiyama Y., Kato J., Eto T.

Annals of Clinical Biochemistry 36 ( 5 ) 622 - 628 1999年

掲載種別：研究論文（学術雑誌）出版者・発行元：Annals of Clinical Biochemistry

The novel hypotensive peptide, proadrenomedullin N-terminal 20 peptide (PAMP), is processed from the adrenomedullin precursor. Recently, we identified PAMP-12 [PAMP(9-20)] from the porcine adrenal medulla as a major endogenous and biologically active peptide. Using a new, sensitive radioimmunoassay which recognizes the C-terminal region of PAMP-20 [PAMP(1-20)], we investigated the role of PAMP in patients with essential hypertension who had normal renal function, and whether PAMP-12 is present in humans. The mean PAMP plasma concentration, like that of adrenomedullin. was significantly higher in hypertensive [1.51 fmol/mL, standard error of the mean (SEM) 0.09 fmol/mL] than normotensive participants (1.08 fmol/mL, SEM 0.05). The increase in plasma PAMP concentration in patients with organ damage accompanied by hypertension was significantly higher than that in patients without organ damage. The PAMP concentration had a significant positive correlation with mean blood pressure and adrenomedullin concentration. The immunoreactive PAMP in human tissue and plasma was characterized by reverse-phase high-performance liquid chromatography, PAMP-12, as well as PAMP-20, was abundant in the phaeochromocytoma tissue. These findings suggest that PAMP plays some pathophysiological role against the development of essential hypertension.

DOI： 10.1177/000456329903600510

Autotransplantation and stent implantation for bilateral renal artery fibromuscular dysplasia 査読あり

Kyoraku Y.

Hypertension Research - Clinical and Experimental 22 ( 2 ) 141 - 143 1999年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research - Clinical and Experimental

A 36-yr-old male was found to have renovascular hypertension due to an occluded right renal artery and 70% stenosis in the left renal artery, caused by fibromuscular dysplasia. The right kidney was supplied by collateral blood flow, and secreted more renin than the left kidney. Two differential therapeutic approaches were taken: autotransplantation for the right kidney and percutaneous transluminal renal angioplasty followed by stent implantation for the left. The renovascular hypertension was treated with these therapies, preserving renal function in this patient.

DOI： 10.1291/hypres.22.141

Adrenomedullin in the gastrointestinal tract. Distribution and gene expression in rat and augmented gastric adrenomedullin after fasting 査読あり

アドレノメデュリンの作用と細胞内情報伝達査読あり

桑迫健二、北村和雄

医学のあゆみ 191 ( 5 ) 405 - 411 1999年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンとその役割査読あり

北村和雄

CARDIAC PRACTICE 10 ( 3 ) 307 - 310 1999年

掲載種別：研究論文（学術雑誌）

心肥大および心筋リモデリングにおけるオートクリン・パラクリン囲子としてのアドレノメデュリンの役割査読あり

鶴田敏博、加藤丈司、北村和雄、今村卓郎、小岩屋靖、江藤胤尚

血圧 6 ( 7 ) 661 - 664 1999年

掲載種別：研究論文（学術雑誌）

プロアドレノメデュリン由来ペプチドの心血管系及び交感神経系作用に対する延髄最後野の関与査読あり

斉田光彦、國武孝人、北村和雄、江藤胤尚、河南洋

日本内分泌学会雑誌 75 ( 2 ) 441 - 441 1999年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンの中枢投与による腎交感神経活動の早期抑制反応と脳内オキシトシン受容体の関係査読あり

斉田光彦、加藤和男、國武孝人、北村和雄、江藤胤尚、河南洋

日本内分泌学会雑誌 75 ( 2 ) 332 - 332 1999年

掲載種別：研究論文（学術雑誌）

癌性腹膜炎患者の血中ならびに腹水中におけるアドレノメデュリンの動態査読あり

清水昭彦、北村和雄、江藤胤尚

日本内分泌学会雑誌 75 ( 2 ) 442 - 442 1999年

掲載種別：研究論文（学術雑誌）

新しい脈管作動物質アドレノメデュリンの役割査読あり

江藤胤尚、北村和雄、加藤丈司

最新医学 54 ( 5 ) 1015 - 1021 1999年

掲載種別：研究論文（学術雑誌）

Sakata J., Asada Y., Shimokubo T., Kitani M., Inatsu H., Kitamura K., Kangawa K., Matsuo H., Sumiyoshi A., Eto T.

Journal of Gastroenterology 33 ( 6 ) 828 - 834 1998年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Gastroenterology

The aim of this study was to investigate the regional distribution, molecular forms, and gene expression of adrenomedullin in the rat gastrointestinal tract and to examine physiological changes in gastric adrenomedullin after 24-h fasting. The tissue concentration was measured by radioimmunoassay. The molecular forms were analyzed by high performance liquid chromatography. mRNA levels were quantified by Northern blotting and cells positive for adrenomedullin immunoreactivity were localized by immunohistochemistry. A high concentration of adrenomedullin was found in stomach, cecum, and colon (450-520 fmol/g wet tissue). Adrenomedullin immunoreactivity was also detected in duodenum, jejunum, and ileum (200-250 fmol/g wet tissue). Transcripts of the adrenomedullin gene were widely expressed throughout the gastrointestinal tract. The major form of adrenomedullin immunoreactivity in stomach and colon corresponded precisely with authentic adrenomedullin peptide. Adrenomedullin immunoreactive cells were present in the gastrointestinal endocrine system. The concentration and mRNA level of gastric adrenomedullin after fasting were significantly increased compared with findings in controls. Adrenomedullin is ubiquitous in the gastrointestinal tract, and may be produced by endocrine cells. The results suggest that adrenomedullin, through its potent vasodilating activity, may play some role, in the stomach including the regulation of the mucosal blood flow.

DOI： 10.1007/s005350050183

Dissociation of adrenomedullin concentrations in plasma and cerebrospinal fluid in pregnant and non-pregnant women 査読あり

Nagata N., Kato J., Kitamura K., Kawamoto M., Tanaka N., Eto T., Takasaki M.

European Journal of Endocrinology 139 ( 6 ) 611 - 614 1998年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Endocrinology

Adrenomedullin (AM), a potent vasodilator peptide, has been shown to act within the central nervous system to modulate fluid and electrolyte balance. AM-immunoreactive cells have been found in the anterior pituitary gland and the choroid plexus of humans. In addition, AM activity has been implicated in the regulation of maternal circulation during pregnancy. To determine the relationship between AM concentration in the cerebrospinal fluid (CSF) and plasma, we measured AM levels in CSF and plasma of pregnant (group P, n = 12) and non-pregnant (group NP, n = 10) women scheduled to undergo gynecologic or obstetric surgery. In both groups, the concentration of AM in the plasma exceeded that in the CSF. Plasma AM concentration was significantly higher in pregnant than nonpregnant women (17.3 ± 5.8 vs 5.1 ± 1.4 pmol/l, mean ± S.D.; P < 0.01), whereas CSP AM concentration did not differ between the two groups (1.3 ± 0.9 and 0.9 ± 0.4 pmol/l in groups P and NP respectively). No significant correlation was found between AM concentrations in the CSF and plasma. The present findings suggest that AM is present in the CSF and that its concentration in the CSF is regulated independently from that in the plasma.

DOI： 10.1530/eje.0.1390611

Adrenomedullin regulation by thyroid hormone in the rat 査読あり

Murakami Y., Hattori Y., Taniyama M., Kitamura K., Kasai K.

Life Sciences 63 ( 24 ) PL337 - PL342 1998年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：Life Sciences

To investigate the effect of thyroid hormone on adrenomedullin (AM) changes during hyper- and hypothyroid states, we evaluated plasma AM concentrations and AM mRNA levels in lung tissue from hyper- and hypothyroid rats. AM peptide concentrations were significantly higher in plasma from hyperthyroid rats and lower in plasma from hypothyroid rats compared with control rats. AM mRNA transcripts were significantly increased in lung tissue from hyperthyroid rats and significantly decreased in lung tissue from hypothyroid rats compared with normal rats. These changes are paralleled alterations in AM production in cultured rat vascular smooth muscle cells, in which AM is regulated at the transcriptional level by thyroid hormone. Thus, thyroid hormone positively regulates AM production in vivo.

DOI： 10.1016/s0024-3205(98)00503-7

Cardiovascular and sympathetic effects of proadrenomedullin NH<inf>2</inf>-terminal 20 peptide in conscious rats 査読あり

Saita M., Ishizuka Y., Kato K., Kunitake T., Hanamori T., Kitamura K., Eto T., Kannan H.

Regulatory Peptides 77 ( 1-3 ) 147 - 153 1998年10月

掲載種別：研究論文（学術雑誌）出版者・発行元：Regulatory Peptides

Proadrenomedullin NH2-terminal 20 peptide (PAMP) and adrenomedullin (AM), which are derived from the same gene, are novel vasodilative peptides and have been shown to exhibit hypotensive action in anesthetized animals. To avoid the modification via anesthesia, we investigated the effects of intravenously administered PAMP on mean arterial pressure, heart rate (HR), and renal sympathetic nerve activity (RSNA) relative to those of AM in conscious unrestrained rats. We also examined whether the arterial baroreceptor reflex was altered with the two peptides. Intravenous injection of rat PAMP (rPAMP) (10, 20 and 50 nmol/kg) and rat AM (rAM) (0.3, 1.0 and 3.0 nmol/kg) similarly elicited dose-related hypotension accompanied by increases in HR and RSNA. However, the responses to rPAMP were less potent in magnitude and shorter in duration than those to rAM. Moreover, rAM facilitated baroreflex control, whereas rPAMP attenuated it. These findings indicate that although PAMP, as well as AM, may play an important role as a circulating hormone in the systemic circulation of conscious rats, the two peptides derived from an identical origin might have different mechanisms responsible for their cardiovascular and RSNA actions. Copyright (C) 1998 Elsevier Science B.V.

DOI： 10.1016/S0167-0115(98)00114-1

Increased plasma concentration of adrenomedullin in patients with subarachnoid hemorrhage 査読あり

Kikumoto K., Kubo A., Hayashi Y., Minamino N., Inoue S., Dohi K., Kitamura K., Kangawa K., Matsuo H., Furuya H.

Anesthesia and Analgesia 87 ( 4 ) 859 - 863 1998年10月

掲載種別：研究論文（学術雑誌）出版者・発行元：Anesthesia and Analgesia

Adrenomedullin (AM) is a potent hypotensive peptide originally identified in pheochromocytoma tissues. Impaired cardiovascular conditions, such as hypertension, myocardial infarction, and septic shock, stimulate production of AM. This study was performed to determine whether subarachnoid hemorrhage (SAH) altered plasma AM concentration. Plasma concentrations of AM in 17 patients with SAH were measured for 2 wk after the onset of SAH by AM- specific radioimmunoassay. Plasma concentrations of AM were increased in patients with SAH throughout the study period, compared with those in control subjects. Plasma concentrations of AM in patients classified as Hunt and Kosnik grade III or IV were significantly higher than those classified as Hunt and Kosnik grade I or II on the day of and the day after the onset of SAH. However, plasma concentrations of AM were unaffected by angiographic vasospasm. These findings suggest that plasma concentrations of AM are increased in patients with SAH and may reflect the severity of SAH. Implications: Adrenomedullin has been reported to affect the cerebral circulation. This study was performed to determine whether subarachnoid hemorrhage, a typical cerebrovascular disorder, altered plasma adrenomedullin concentrations. We found that plasma adrenomedullin concentrations increased in patients with Subarachnoid hemorrhage, although no relationship was found between plasma adrenomedullin concentration and angiographic vasospasm. Plasma adrenomedullin concentration may reflect the severity of hemorrhage.

DOI： 10.1097/00000539-199810000-00021

Adrenomedullin and related peptides 査読あり

Kitamura K.

Folia Pharmacologica Japonica 112 ( 3 ) 137 - 146 1998年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Folia Pharmacologica Japonica

'Adrenomedullin (AM)' is a novel hypotensive peptide discovered in human pheochromocytoma by monitoring the elevating activity of platelet cAMP. It has potent and long-lasting vasodilator effects in several vascular systems. In addition, a novel 20-residue hypotensive peptide, termed 'proadrenomedullin N-terminal 20 peptide' (PAMP), is processed from proadrenomedullin. Although initially isolated from human pheochromocytoma tissue and porcine adrenal medullae, AM mRNA is highly expressed in several organs including cardiovascular tissues. Taken together with its widespread distribution and its ability to influence the bioactivity of cells in situ, AM may function as a paracrine or autocrine hormone rather than a classical endocrine system. Furthermore, ubiquitous expression of AM mRNA may indicate its various biological functions as well as the existence of a novel circulation control system. Plasma AM as well as PAMP concentrations significantly increased in various cardiovascular diseases including hypertension, chronic renal failure and congestive heart failure. The present review summarizes the recent advances in AM research and showed that AM and PAMP are important vasoactive peptides, such investigations should enable the elucidation of the basic physiologic mechanisms of novel circulatory homeostasis.

DOI： 10.1254/fpj.112.137

Measurement of plasma and urinary adrenomedullin in patients with IgA nephropathy 査読あり

Kubo A., Iwano M., Minamino N., Sato H., Nishino T., Hirata E., Akai Y., Shiiki H., Kitamura K., Kangawa K., Matsuo H., Dohi K.

Nephron 78 ( 4 ) 389 - 394 1998年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：Nephron

In this study, we measured plasma and urinary adrenomedullin (AM) concentrations in 47 patients with IgA nephropathy. Controls were 39 healthy volunteers. Plasma and urinary AM values were measured by specific radioimmunoassay. The plasma AM concentrations were higher, and the urinary AM levels were lower in patients with IgA nephropathy than in healthy volunteers. Plasma AM concentrations showed a positive correlation with serum creatinine and blood urea nitrogen, whereas urinary AM levels correlated negatively with serum creatinine and blood urea nitrogen. The plasma AM concentrations showed a positive correlation with fractional excretions of sodium and potassium. Renal biopsy specimens of patients without renal failure were scored for activity (percentage of glomeruli demonstrating cellular crescent formation, degree of mesangial proliferation and interstitial infiltration; total score = 9). Urinary AM levels were shown to be lower in the group with a high activity (score 3-9) as compared with the group with a low activity (score 0-2) based on renal biopsy. Thus, urinary levels of AM are affected by the degree of the activity in IgA nephropathy, and AM may participate in the pathophysiology of IgA nephropathy.

DOI： 10.1159/000044966

Central actions of adrenomedullin on cardiovascular parameters and sympathetic outflow in conscious rats 査読あり

Saita M., Shimokawa A., Kunitake T., Kato K., Hanamori T., Kitamura K., Eto T., Kannan H.

American Journal of Physiology - Regulatory Integrative and Comparative Physiology 274 ( 4 43-4 ) R979 - R984 1998年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Physiology - Regulatory Integrative and Comparative Physiology

Adrenomedullin (ADM) is reported to be a peripherally acting hypotensive peptide, but its central actions are unclear. We investigated the effects of centrally administered ADM on blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) in conscious rats and sinoaortic-denervated (SAD) rats. We also investigated the receptors interacting with ADM using two putative antagonists. Intracerebroventricular administration of ADM in doses of 0.1 and 0.5 nmol/kg caused tachycardia and early inhibition of RSNA. Central ADM (1.0 nmol/kg) induced hypertension, tachycardia, and a decrease followed by an increase in RSNA. In SAD rats, increases in BP, HR, and RSNA at the late phase were enhanced by central ADM (1.0 nmol/kg), whereas the early decrease in RSNA remained. Thus the inhibition of RSNA via central ADM may be unrelated to the arterial baroreceptor reflex. Pretreatment with antagonists human calcitonin gene-related peptide-(8-37) and human ADM-(22- 52) significantly suppressed the central actions of ADM. The findings suggest that ADM is involved as a neuropeptide in the receptor-mediated central regulation of the cardiovascular system and RSNA.

DOI： 10.1152/ajpregu.1998.274.4.r979

Plasma adrenomedullin levels in patients with non-insulin dependent diabetes mellitus: Close relationships with diabetic complications 査読あり

Nakamura T., Honda K., Ishikawa S.E., Kitamura K., Eto T., Saito T.

Endocrine Journal 45 ( 2 ) 241 - 246 1998年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Endocrine Journal

The present study was undertaken to determine plasma adrenomedullin levels in patients with non-insulin dependent diabetes mellitus (NIDDM) to elucidate the potential involvement in the pathogenesis of diabetic complications. The patients were 24 males and 21 females with ages of 55 ± 2.1 years (mean ± SEM). Plasma adrenomedullin levels were 5.94 ± 0.44 pmol/l in patients with NIDDM, and were not affected by plasma glucose concentration. The plasma adrenomedullin increased dependent on the severity of diabetic nephropathy and retinopathy. Plasma levels of adrenomedullin positively correlated with various parameters, including serum creatinine levels, urinary excretion of protein, and systolic blood pressure. In contrast, there were negative correlations between the coefficient variation (CV) of RR intervals and plasma adrenomedullin, and between the conduction velocity of ulnar nerves and plasma adrenomedullin levels. These results indicate that the increase in plasma adrenomedullin was closely related to diabetic complications, which may be dependent on the development of microangiopathy.

DOI： 10.1507/endocrj.45.241

The intermediate form of glycine-extended adrenomedullin is the major circulating molecular form in human plasma 査読あり

Kitamura K., Kato J., Kawamoto M., Tanaka M., Chino N., Kangawa K., Eto T.

Biochemical and Biophysical Research Communications 244 ( 2 ) 551 - 555 1998年3月

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

Adrenomedullin (AM), a potent vasodilator peptide, is processed from its AM precursor as glycine extended AM (AM-gly), an intermediate form of AM. Subsequently, mature AM is converted from AM-gly by enzymatic amidation. Using two kinds of radioimmunoassay which recognize the entire AM molecule (E-AM-RIA) and C-terminal amide structure (C-AM-RIA), human plasma AM immunoreactivity was chromatographically characterized. In analyses of gel filtration and reverse phase high-performance liquid chromatography, most of the AM immunoreactivity measured by E-AM-RIA was eluted at a position identical to where mature AM and AM-gly emerged and was not recognized by C-AM-RIA. These data show that immunoreactive AM measured by E-AM-RIA is not amidated. When amidated by peptidylglycine α-amidating enzyme, the immunoreactive AM was converted to a form that can be detected by C-AM-RIA. These results indicate that most of the total AM immunoreactivity measured by E-AM-RIA represents immunoreactivity of AM-gly and that the concentration of immunoreactive mature AM in plasma is much lower than that of AM-gly. In practice, plasma concentration of AM-gly and mature AM in healthy volunteers was 2.7 ± 0.18 fmol/ml and 0.48 ± 0.05 fmol/ml, respectively. Furthermore, plasma concentration of AM-gly and total AM was significantly elevated in patients with hypertension compared to normotensive control. The present data indicate that most of circulating plasma AM immunoreactivity is occupied by AM-gly, an intermediate form of AM, which may reflect the process of production of AM in tissues.

DOI： 10.1006/bbrc.1998.8310

Decrease in circulating and urine adrenomedullin concentrations in stroke-prone spontaneously hypertensive rats 査読あり

Hirano S., Ishiyama Y., Matsuo T., Imamura T., Sakata J., Kitamura K., Koiwaya Y., Eto T.

Hypertension Research 21 ( 1 ) 23 - 28 1998年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

Adrenomedullin (AM) is a peptide with potent vasodilatory and hypotensive properties. Plasma AM levels in rats with experimentally induced hypertension, such as Dahl salt-sensitive rats and two-kidney, one-clip hypertensive rats, are higher than those in normotensive rats. We previously noted, however, that plasma AM levels in spontaneously hypertensive rats (SHR) are similar to those in Wistar-Kyoto rats. To define the role of AM in rats with severe hypertension, we investigated changes in circulating and tissue AM levels in stroke-prone spontaneously hypertensive rats (SHRSP/Izm). The immunoreactive rat AM levels in plasma, urine, and tissue measured with a sensitive radioimmunoassay, and the AM inRNA levels in various tissues in 15-wk-old SHRSP/Izm were compared with those in age-matched Wistar-Kyoto rats (WKY/Izm). The plasma and urinary AM levels in SHRSP/Izm were significantly lower than those in WKY/Izm [plasma AM, 2.14±0.06 (SE) vs. 3.24±0.16 fmol/ml, p< 0.001; urinary AM, 16.36±3.21 vs. 36.12±6.09 fmol/ml, p<0.01]. A negative correlation was found between the plasma AM level and the systolic blood pressure in both SHRSP/Izm and WKY/Izm. Reverse-phase high-performance liquid chromatography showed that the molecular components of plasma immunoreactive AM in SHRSP/Izm were similar to those in WKY/Izm. Furthermore, tissue AM levels in various organs in SHRSP/Izm were not lower than those in WKY/Izm. In conclusion, low levels of circulating AM may contribute to the maintenance of high blood pressure in 15-wk-old SHRSP/Izm. These low plasma AM levels may be caused by accelerated metabolism of circulating AM in SHRSP/Izm.

DOI： 10.1291/hypres.21.23

Adrenomedullin: A Possible Autocrine or Paracrine Inhibitor of Hypertrophy of Cardiomyocytes 査読あり

Tsuruda T., Kato J., Kitamura K., Kuwasako K., Imamura T., Koiwaya Y., Tsuji T., Kangawa K., Eto T.

Hypertension 31 ( 1 ) 505 - 510 1998年1月

掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension

Adrenomedullin (AM), a potent vasodilator peptide, exists in the cardiac ventricle; however, the role of AM in the ventricular tissue remains unknown. In the present study, we investigated the production and secretion of AM in cultured neonatal rat cardiomyocytes, and we examined the effect of AM on de novo protein synthesis in these cells by measuring [() C]phenylalanine incorporation. The cardiomyocytes cultured with serum-free media secreted AM into the media in a time-dependent manner at the rate of 12.2 +/- 0.5 fmol/10 cells/48 hours (mean +/- SEM). Angiotensin II (1 micro mol/L) or 10% fetal bovine serum significantly (P <.01) increased the AM secretion by 115% and 305%, respectively. In addition, Northern blot analysis of total RNA extracted from the myocytes disclosed the expression of prepro-AM mRNA of 1.6 kb. Synthetic AM at 1 micro mol/L significantly reduced the 10-6 mol/L angiotensin II- and 10% fetal bovine serum-stimulated [() C]phenylalanine incorporation into the cells, by 16% (P <.05) and 20% (P <.01), respectively. The inhibitory effect of AM on the angiotensin II-stimulated [() C]phenylalanine incorporation was abolished dose-dependently by a calcitonin gene-related peptide receptor antagonist, CGRP(8-37). Furthermore, blockade of the action of endogenous AM by either 10-6 mol/L CGRP(8-37) or anti-AM monoclonal antibody significantly enhanced the basal and 10-6 mol/L angiotensin II-stimulated [() C]phenylalanine incorporation. In summary, cultured neonatal rat cardiomyocytes produce and secrete AM, and the secreted AM inhibits the protein synthesis of these cells. Thus, AM may act on cardiomyocytes as an autocrine or a paracrine factor modulating the cardiac growth. (Hypertension. 1998;31[part 2]:505-510.). © 1998 Lippincott Williams & Wilkins, Inc.

DOI： 10.1161/01.HYP.31.1.505

Distribution and expression of adrenomedullin in human gastrointestinal tissue 査読あり

Kitani M., Sakata J., Asada Y., Kitamura K., Eto T.

Annals of Clinical Biochemistry 35 ( 5 ) 643 - 648 1998年

掲載種別：研究論文（学術雑誌）出版者・発行元：Annals of Clinical Biochemistry

Adrenomedullin (AM) is a biologically active peptide recently isolated from phaeochromocytoma. We report here the distribution and characterization of immunoreactive AM and gene expression of AM in human gastrointestinal tissue. Using a sensitive radioimmunoassay system for the peptide, immunoreactive human AM was detected in the stomach, duodenum, jejunum, ileum and colon. The AM concentration of these tissues was about 0.4-0.8 pmol/g wet tissue. Reverse phase and gel filtration high-performance liquid chromatographies showed that most of the immunoreactive AM in stomach and jejunum was identical to authentic human AM. By northern blot analysis, human AM mRNA was found to be expressed ubiquitously in the human gastrointestinal tissues. Furthermore, an immunohistochemical study revealed that immunoreactive AM cells were present in the gastrointestinal glands. These results suggest that AM may play some role as a gastrointestinal hormone.

DOI： 10.1177/000456329803500508

Short-term modulation of the renin-angiotensin system does not alter plasma adrenomedullin concentration in humans 査読あり

Kita T., Kitamura K., Kuwasako K., Kawamoto M., Eto T.

Journal of Hypertension 16 ( 12 SUPPL. ) 2057 - 2062 1998年

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Hypertension

Objective. Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are novel hypotensive peptides produced from the same precursor. A relationship between AM and the renin-angiotensin-aldosterone (RAA) axis was reported in several studies, but the response of the above two peptides to short-term modulation of the RAA axis in humans is not yet clear. Here, we assessed the responses of AM and PAMP in patients with varying RAA system status, including renovascular hypertension (RVH) and primary aldosteronism (PA). Design and methods. Essential hypertension (EHT), RVH and PA patients were hospitalized and maintained on a standard diet (NaCl 10 g/day). The patients underwent a captopril (25 mg) loading test. A renin-secretion stimulating test (furosemide 1 mg/kg, i.v. + 2 h of walking) and an ACTH loading test were performed for the PA patients. The plasma renin activity (PRA), plasma aldosterone concentration (PAC), and plasma AM and PAMP levels were monitored before and after the loadings. Results. In the basal state, significantly higher concentrations of AM and PAMP were shown in the RVH patients compared to the other groups. AM and PAMP were significantly correlated with PRA but not PAC in all patients. The AM and PAMP levels were not affected by the captopril loading with or without a hypotensive reaction. The AM and PAMP levels were increased only slightly despite the large increase in PAC induced in the PA patients by the renin-secretion stimulating and ACTH loading tests. Conclusion. The responses of plasma AM and PAMP to a short-term modulation of the RAA system were relatively small, despite the correlations observed between PRA and AM or PAMP.

DOI： 10.1097/00004872-199816121-00030

Purification and characterization of PAMP-12 (PAMP[9-20]) in porcine adrenal medulla as a major endogenous biologically active peptide 査読あり

アドレノメデュリンとPAMPの発見の経緯とその構造査読あり

寒川賢治、北村和雄

医学のあゆみ 184 ( 1 ) 3 - 9 1998年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンと関連ペプチド査読あり

北村和雄

日本薬理学雑誌 112 ( 3 ) 137 - 146 1998年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンとPAMP 査読あり

北村和雄

医学のあゆみ 185 ( 1 ) 71 - 74 1998年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンおよび関連ペプチドの測定と問題点査読あり

北村和雄

医学のあゆみ 184 ( 1 ) 21 - 25 1998年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンおよび関連ペプチド査読あり

北村和雄

循環科学 18 ( 12 ) 1132 - 1135 1998年

掲載種別：研究論文（学術雑誌）

循環器系疾患における血中成熟型および中間型アドレノメデュリンの動態と意義査読あり

平山直輝、北村和雄、江藤胤尚

日本内分泌学会雑誌 74 ( 2 ) 621 - 621 1998年

掲載種別：研究論文（学術雑誌）

心血管系への生理作用査読あり

石山雄一郎、北村和雄

医学のあゆみ 184 ( 1 ) 44 - 48 1998年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンの心血管系及び交感神経系に対する作用への延髄最後野の関与査読あり

斉田光彦、加藤和男、國武孝人、花森隆充、北村和雄、江藤胤尚、河南洋

日本内分泌学会雑誌 74 ( 2 ) 619 - 619 1998年

掲載種別：研究論文（学術雑誌）

バルーン頚動脈内皮傷害後の内膜肥厚に及ぼすアドレノメデュリン持続静注の効果の検討査読あり

松井英三郎、加藤丈司、北村和雄、江藤胤尚、浅田祐士郎、住吉昭信

日本内分泌学会雑誌 74 ( 2 ) 619 - 619 1998年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンによる循環調節査読あり

江藤胤尚、北村和雄、加藤丈司

臨床高血圧 4 ( 3 ) 155 - 168 1998年

掲載種別：研究論文（学術雑誌）

Plasma adrenomedullin in cerebrovascular disease: a possible indicator of endothelial injury 査読あり

K Kuwasako 1, O Kida, K Kitamura, J Kato, T Eto

Int Angiol 16 ( 4 ) 272 - 279 1997年12月

掲載種別：研究論文（学術雑誌）

Kuwasako K., Kitamura K., Ishiyama Y., Washimine H., Kato J., Kangawa K., Eto T.

FEBS Letters 414 ( 1 ) 105 - 110 1997年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：FEBS Letters

Proadrenomedullin N-terminal 20 peptide (PAMP-20) is a potent hypotensive peptide processed from the adrenomedullin (AM) precursor. We developed a specific radioimmunoassay which recognizes the C-terminal region of PAMP-20. Using this radioimmunoassay, the distribution of immunoreactive (ir-) PAMP was determined in porcine tissues. High concentrations of ir-PAMP were observed in the adrenal medulla and in the atrium, and these values were comparable to the corresponding; concentrations of ir-AM. The concentration of ir-PAMP was almost the same as that of ir-AM in the kidney, while ir-PAMP was significantly lower than ir-AM in the ventricle, lung, and aorta. Reversed-phase high performance liquid chromatography in each porcine tissue sample revealed that two major peaks of ir-PAMP existed: one emerged at a position identical to that of authentic porcine PAMP-20; the other unknown peak was eluted earlier. The unknown peptide was purified to homogeneity from porcine adrenal medulla, and its complete amino acid sequence was determined. This peptide was found to be PAMP[9-20] with a C-terminal amide structure, and was named PAMP-12. Intravenous injections of PAMP-12 in anesthetized rats showed a significant hypotensive effect in a dose-dependent fashion, and the effect was comparable to that of PAMP-20. These data indicate that PAMP-12, a major component of ir-PAMP, is processed from the AM precursor, as is PAMP-20, and may participate in cardiovascular control.

DOI： 10.1016/S0014-5793(97)00971-X

Effect of chronically infused adrenomedullin in two-kidney, one-clip hypertensive rats 査読あり

Khan A.I., Kato J., Ishiyama Y., Kitamura K., Kangawa K., Eto T.

European Journal of Pharmacology 333 ( 2-3 ) 187 - 190 1997年8月

掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Pharmacology

The hypotensive effect of chronically infused adrenomedullin, a potent vasodilator peptide, was examined in conscious two-kidney, one-clip (2K-1C) hypertensive and sham-operated rats. They were infused with 1.0 μg/h of synthetic human adrenomedullin for 14 days by means of osmotic minipumps. Control groups were infused on the same schedule with 0.9% saline. Systolic blood pressure was measured before and during the infusion. Plasma renin activity, aldosterone and human adrenomedullin concentrations were determined at day 14 of the infusion. A significant reduction of systolic blood pressure was observed in the adrenomedullin-infused 2K-1C rats at day 4, and systolic blood pressure remained significantly lower throughout the experiment compared to that of the control 2K-1C. A similar hypotensive effect was seen in the adrenomedullin-infused sham-operated rats. Both the plasma renin activity and aldosterone concentrations of the adrenomedullin-infused 2K-1C and sham groups were significantly reduced compared to those of the respective control, whereas, the plasma human adrenomedullin concentration in the adrenomedullin-infused groups was found to be within the physiological range. These findings demonstrated that chronically infused adrenomedullin had a hypotensive effect accompanied by significant reductions of plasma renin activity and plasma aldosterone concentration in 2K-1C hypertensive and sham-operated rats.

DOI： 10.1016/S0014-2999(97)01136-9

The effect of hypothermic cardiopulmonary bypass on plasma adrenomedullin in adult cardiac surgical patients 査読あり

Nagata N., Kitamura K., Kato J., Naruo H., Eto T., Takasaki M.

Anesthesia and Analgesia 84 ( 6 ) 1193 - 1197 1997年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Anesthesia and Analgesia

Cardiopulmonary bypass (CPB) can evoke a systemic inflammatory response, which is accompanied by an increase in plasma cytokines that may stimulate the production of adrenomedullin (AM), a potent vasodilator peptide. This study was undertaken to investigate whether CPB influenced plasma AM concentration in 10 patients undergoing cardiac surgical procedures. We found that the plasma AM concentration increased significantly after the commencement of CPB, with the greatest increase observed at weaning from bypass(P < 0.01). After CPB, plasma AM concentration declined but still exceeded baseline significantly 24 h postoperatively. The increase in the plasma AM concentration at weaning from CPB correlated significantly with aortic cross-clamp time (r = 0.74, P < 0.05). The authors conclude that the secretion of AM into circulation is augmented by CPB in patients undergoing cardiac surgery, which suggests a possible role of AM in cardiovascular regulation during and after surgery with CPB.

DOI： 10.1097/00000539-199706000-00004

Plasma levels of adrenomedullin in primary and secondary pulmonary hypertension in patients <20 years of age 査読あり

Yoshibayashi M., Kamiya T., Kitamura K., Saito Y., Kangawa K., Nishikimi T., Matsuoka H., Eto T., Matsuo H.

American Journal of Cardiology 79 ( 11 ) 1556 - 1558 1997年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Cardiology

To elucidate the pathophysiologic significance of adrenomedullin in pulmonary hypertension, we measured plasma adrenomedullin-like immunoreactivity (AM-LI) concentrations in blood samples obtained from various sites during cardiac catheterization by using radioimmunoassay in patients with pulmonary hypertension in comparison with patients without pulmonary hypertension. In patients with pulmonary hypertension, plasma AM- LI concentrations were significantly elevated and there was a significant uptake of AM-LI in pulmonary circulation, indicating the involvement of adrenomedullin in the cardiovascular regulation of pulmonary circulation in pulmonary hypertension.

DOI： 10.1016/S0002-9149(97)00195-1

Increased plasma concentrations of adrenomedullin correlate with relaxation of vascular tone in patients with septic shock 査読あり

Nishio K., Akai Y., Murao Y., Doi N., Ueda S., Tabuse H., Miyamoto S., Dohi K., Minamino N., Shoji H., Kitamura K., Kangawa K., Matsuo H.

Critical Care Medicine 25 ( 6 ) 953 - 957 1997年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Critical Care Medicine

Objective: To investigate plasma concentrations of adrenomedullin in patients with septic shock and the potential association of these concentrations with relaxation of vascular tone. Design: Prospective, case series. Setting: Department of Emergency and Critical Care Medicine, Nara Medical University. Patients: Twelve patients who fulfilled the clinical criteria for severe sepals or septic shock (as defined by the Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee) and 13 healthy volunteers. Interventions: Arterial blood samples were obtained via a 20-gauge cannula inserted into each patient's radial artery. Measurements and Main Results: After extraction and purification, plasma adrenomedullin was measured by radioimmunoassay. Systemic vascular resistance index, pulmonary vascular resistance, cardiac index, and stroke volume index were determined with a thermodilution catheter. The mean plasma concentration of adrenomedullin was markedly higher in patients than in controls (226.1 ± 66.4 [SEM] va. 5.05 ± 0.21 fmol/mL, p < .01). Moreover, these concentrations correlated significantly with cardiac index, stroke volume index, and heart rate values, and correlated significantly with decreases in diastolic blood pressure, systemic vascular resistance index, and pulmonary vascular resistance index values. Conclusions: Enhanced production of adrenomedullin in patients with septic shock may contribute to reduced vascular tone, hypotension, or both. More data are needed to clarify the role of adrenomedullin in the regulation of vascular tone in this patient population.

DOI： 10.1097/00003246-199706000-00010

Changes in cardiac adrenomedullin concentration in renovascular hypertensive rats 査読あり

Ishiyama Y., Kitamura K., Kato J., Sakata J., Kangawa K., Eto T.

Hypertension Research 20 ( 2 ) 113 - 117 1997年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

We assessed changes in tissue and plasma adrenomedullin levels in two-kidney, one-clip renovascular hypertensive rats. Four weeks after clipping, adrenomedullin concentrations were significantly higher in the cardiac ventricles and lower in the left atrium than the respective values in sham-operated rats. The left ventricular adrenomedullin concentration significantly correlated with systolic blood pressure and the degree of cardiac hypertrophy. No difference was noted in the adrenomedullin concentrations of the adrenal gland, aorta, lung, kidneys, or plasma between the two groups. These findings indicate possible involvement of cardiac adrenomedullin in this model of hypertension.

DOI： 10.1291/hypres.20.113

Different secretion patterns of adrenomedullin, brain natriuretic peptide, and atrial natriuretic peptide during exercise in hypertensive and normotensive subjects 査読あり

Nishikimi T., Morimoto A., Ishikawa K., Saito Y., Kangawa K., Matsuo H., Kitamura K., Takishita S., Matsuoka H.

Clinical and Experimental Hypertension 19 ( 4 ) 503 - 518 1997年5月

掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical and Experimental Hypertension

The purpose of this study was to investigate the effect of exercise on plasma concentrations of adrenomedullin, brain natriuretic peptide (BNP), and atrial natriuretic peptide (ANP) in patients with essential hypertension (n = 15) and in normotensive controls (n = 10). Exercise consisted of two fixed workloads, 40 and 80 watts of work load using a supine bicycle ergometer. Plasma levels of all three peptides at rest were significantly higher in hypertensives than in controls. Plasma concentrations of ANP increased with exercise in both groups and had greater increments in hypertensive patients than in normotensives. Plasma concentrations of BNP increased only in patients with hypertension and the levels of increase correlated with basal plasma BNP levels (r = 0.94, p < 0.001) and with left ventricular mass (r = 0.62, p < 0.01) determined by echocardiography. In contrast, plasma adrenomedullin did not change with exercise in either group. These results suggest that secretion patterns of these peptides are regulated by different mechanisms and that the amount and kind of peptides mobilized by exercise may depend on the underlying diseases or pathophysiologic condition.

DOI： 10.3109/10641969709084511

Production of adrenomedullin in human vascular endothelial cells 査読あり

Ishihara T., Kato J., Kitamura K., Katoh F., Fujimoto S., Kangawa K., Tanenao E.

Life Sciences 60 ( 20 ) 1763 - 1769 1997年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：Life Sciences

To examine the production of adrenomedullin (AM) in human vascular endothelial cells, AM concentration in cultured endothelial cells derived from the human umbilical vein and the conditioned media of the cells were measured in the present study. The cultured endothelial cells secreted immunoreactive AM (ir-AM) into the medium at a rate of 14.7 ± 3.0 fmol/106 cells/24 h with an intracellular ir-AM of 5.2 ± 0.8 fmol/106 cells. Analysis by reverse phase high performance-liquid chromatography (HPLC) showed that ir-AM in both the cells and the conditioned medium eluted at the position identical to that of human AM(1-52). Treatment with dexamethasone significantly augmented the secretion of ir-AM from the cells without any effect on the intracellular ir-AM concentration. Northern blot analysis showed not only the presence of the 1.6 kb human AM precursor mRNA in the endothelial cells, but also its increased expression in the dexamethasone-treated cells. Thus, AM was synthesized and secreted by the human endothelial cells of the umbilical vein, and glucocorticoid augmented the AM production. These findings suggest not only the role of AM as a local modulator of the vascular tone but also the possibility that endothelial cells contribute to circulating AM in the human blood.

DOI： 10.1016/S0024-3205(97)00136-7

Plasma concentrations of adrenomedullin correlate with the extent of pulmonary hypertension in patients with mitral stenosis 査読あり

Nishikimi T., Nagata S., Sasaki T., Tomimoto S., Matsuoka H., Takishita S., Kitamura K., Miyata A., Matsuo H., Kangawa K.

Heart 78 ( 4 ) 390 - 395 1997年

掲載種別：研究論文（学術雑誌）出版者・発行元：Heart

Objective - To examine the pathophysiological significance of adrenomedullin in the pulmonary circulation by investigating the relation between plasma concentrations of adrenomedullin and central haemodynamics in patients with mitral stenosis. Methods - Plasma concentrations of adrenomedullin in blood samples obtained from the femoral veins pulmonary artery, left atrium, and aorta were measured by a newly developed specific radio-immunoassay in 23 consecutive patients with mitral stenosis (16 females and seven males, aged 55 (10) years (mean (SD)) who were undergoing percutaneous mitral commissurotomy. Results - Patients with mitral stenosis had higher concentrations of adrenomedullin than age matched normal controls (3.9 (0.3) v 2.5 (0.3) pmol/l, p < 0.001). There was a reduction in adrenomedullin concentrations between the pulmonary artery and the left atrium (3.8 (0.2) v 3.2 (0.4) pmol/l, p < 0.001). The venous concentrations of adrenomedullin correlated with mean pulmonary artery pressure (r = 0.65, p < 0.001), total pulmonary vascular resistance (r = 0.83, p < 0.0001), and pulmonary vascular resistance (r = 0.65, p < 0.001). Plasma concentrations of adrenomedullin did not change immediately after percutaneous mitral commissurotomy; however, they decreased significantly one week later. Conclusions - Plasma concentrations of adrenomedullin are increased in patients with mitral stenosis. This may help to attenuate the increased pulmonary arterial resistance in secondary pulmonary hypertension due to mitral stenosis.

DOI： 10.1136/hrt.78.4.390

アドレノメデュリン(AM)の多彩な作用査読あり

北村和雄

医学のあゆみ 182 ( 2 ) 136 - 137 1997年

掲載種別：研究論文（学術雑誌）

Adrenomedullin動態と脳血管障害査読あり

竹下啓、高本俊介、小松本悟、奈良昌治、北村和雄

脳卒中 19 ( 6 ) 548 - 548 1997年

掲載種別：研究論文（学術雑誌）

心血管系でのアドレノメデュリンとPAMP 査読あり

北村和雄、加藤丈司、鶴田敏博、寒川賢治、江藤胤尚

日本内分泌学会雑誌 73 ( 5 ) 330 - 330 1997年

掲載種別：研究論文（学術雑誌）

新しい循環調節ペプチド"アドレノメデュリン"と"PAMP"の発見とその基礎的・臨床的研究査読あり

北村和雄

日本内分泌学会雑誌 73 ( 2 ) 63 - 63 1997年

担当区分：筆頭著者掲載種別：研究論文（学術雑誌）

アドレノメデュリン査読あり

北村和雄

心臓 29 ( 4 ) 281 - 289 1997年

担当区分：筆頭著者掲載種別：研究論文（学術雑誌）

アドレノメデュリンとPAMP 査読あり

北村和雄、江藤胤尚

日本臨牀 55 ( 8 ) 1963 - 1970 1997年

担当区分：筆頭著者掲載種別：研究論文（学術雑誌）

起立性低血圧を認める糖尿病性神経障害患者と健常者におけるティルティング負荷に対する血中アドレノメデュリン(AM)動態査読あり

中村

日本内分泌学会雑誌 73 ( 2 ) 280 - 280 1997年

掲載種別：研究論文（学術雑誌）

覚醒ラットにおけるアドレノメデュンの末梢および中枢作用について査読あり

斉田光彦、下川歩、國武孝人、加藤和男、白阪哲朗、北村和雄、江藤胤尚、河南洋

日本内分泌学会雑誌 73 ( 5 ) 355 - 355 1997年

掲載種別：研究論文（学術雑誌）

アドレノメデュリン査読あり

杉田江里、谷山松雄、伴良雄、北村和雄

病理と臨床 15 ( 3 ) 253 - 258 1997年

掲載種別：研究論文（学術雑誌）

本態性高血圧症に対する塩酸ベニジピン(コニール(R))長期投与の検討-宮崎コニール研究会- 査読あり

江藤胤尚、木田修、北村和雄、児玉健二、近藤宏一、比嘉利信、熊谷治士、田口利文、市来能成、石山雄一郎

臨牀と研究 78 ( 8 ) 2079 - 2086 1997年

掲載種別：研究論文（学術雑誌）

長期持続静注アドレノメデュリン(AM)の降圧効果-無麻酔無拘束の高血圧自然発症ラット(SHR)およびWistar-Kyotoラット(WKY)を用いた検討- 査読あり

加藤丈司、カーンIアズハルル、北村和雄、寒川賢治、江藤胤尚

Therapeutic Research 18 ( 7 ) 2201 - 2204 1997年

掲載種別：研究論文（学術雑誌）

呼吸器疾患における血漿アドレノメデュリンおよびPAMP濃度に関する検討査読あり

下窪徹、比嘉利信、田中雅之、石畠英昭、鬼塚黎子

臨牀と研究 74 ( 10 ) 2507 - 2510 1997年

掲載種別：研究論文（学術雑誌）

悪性褐色細胞腫多発性肝転移例に対する, 経肝動脈塞栓療法におけるアドレノメデユリンの動態査読あり

芦澤直人、高橋和宏、馬場是明、鈴木伸、北村和雄、江藤胤尚、矢野捷介

日本内分泌学会雑誌 73 ( 5 ) 355 - 355 1997年

掲載種別：研究論文（学術雑誌）

Cardiac secretion of adrenomedullin by percutaneous transluminal coronary angioplasty 査読あり

Etoh T., Doi H., Hanada Y., Kato J., Imamura T., Kitamura K., Koiwaya Y., Eto T.

Hormone and Metabolic Research 29 ( 10 ) 530 - 531 1997年

掲載種別：研究論文（学術雑誌）出版者・発行元：Hormone and Metabolic Research

DOI： 10.1055/s-2007-979095

Plasma proadrenomedullin N-terminal 20 peptide (PAMP) in patients with congestive heart failure 査読あり

Etoh T., Kato J., Washimine H., Imamura T., Kitamura K., Koiwaya Y., Kangawa K., Eto T.

Hormone and Metabolic Research 29 ( 1 ) 46 - 47 1997年

掲載種別：研究論文（学術雑誌）出版者・発行元：Hormone and Metabolic Research

DOI： 10.1055/s-2007-978980

Hypotensive effectof chronically infused adrenomedullin in conscious Wistar-Kyoto and spontaneously hypertensive rats 査読あり

Khan A.I., Kato J., Kitamura K., Kangawa K., Eto T.

Clinical and Experimental Pharmacology and Physiology 24 ( 2 ) 139 - 142 1997年

掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical and Experimental Pharmacology and Physiology

1. The hypotensive effect of chronically infused human adrenomedullin (hAM), a potent vasodilator peptide that has been reported to have a natriuretic action, was examined In normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. Conscious WKY rats and SHR were infused with 200 ng/h synthetic hAM for 14 days by means of osmotic minipumps, Control groups were infused at the same schedule with 0.9% saline. Systolic blood pressure (SBP) and daily urinary excretion of Na+ and K+ were measured before and during the infusion period. In addition, plasma renin activity (PRA), aldosterone and hAM concentrations were measured on day 14 of infusion, 3. A significant reduction in SBP was observed in hAM treated SHR at day 2 and SBP remained significantly lower throughout the experiment compared with control SHR. Similarly, SBP in the hAM-treated WKY rats was found to be significantly lower than in control WKY rats during infusion, However, the hypotensive effect was not accompanied by any significant increase in urinary volume or Na+ excretion in hAM-treated rats of either strain. Chronic infusion with hAM significantly suppressed PRA and lowered the concentration of plasma aldosterone in WKY rats but not in SHR. The plasma hAM levels in treated WKY rats and SHR were 0.9 ± 0.4 and 0.6 ± 0.2 fmol/ml, respectively. 4. These findings demonstrate that chronically infused hAM has a hypotensive effect in both WKY rats and SHR without an increase in urinary volume or Na+ excretion at a plasma AM concentration within the physiological limit.

DOI： 10.1111/j.1440-1681.1997.tb01796.x

Effect of exercise on plasma adrenomedullin and natriuretic peptide levels in myocardial infarction 査読あり

Morimoto A., Nishikimi T., Takaki H., Okano Y., Matsuoka H., Takishita S., Kitamura K., Miyata A., Kangawa K., Matsuo H.

Clinical and Experimental Pharmacology and Physiology 24 ( 5 ) 315 - 320 1997年

掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical and Experimental Pharmacology and Physiology

1. We investigated the effect of exercise on plasma adrenomedullin, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations and studied the relationship between these peptides and haemodynamic parameters in nine patients with old myocardial infarction (MI) and in eight normal subjects. 2. The exercise protocol consisted of two fixed work loads (40 and 80 W) for 4 min each and venous blood samples were taken at rest, during each exercise stage and after exercise while monitoring the mean arterial pressure (MAP) and heart rate (HR). In MI, pulmonary arterial pressure (PAP), pulmonary capillary wedge pressure (PCWP), left ventricular end-diastolic pressure (LVEDP) and cardiac output (CO) were measured throughout exercise. 3. Adrenomedullin levels did not significantly increase with exercise. Adrenomedullin levels correlated with PAP and PCWP at rest (P < 0.05). Atrial natriuretic peptide levels correlated with PAP, PCWP and LVEDP throughout exercise (P < 0.05) but, on multiple regression analysis, PCWP correlated only with ANP (P<0.01). Brain natriuretic peptide levels correlated with LVEDP throughout exercise (P < 0.01) and its increment correlated closely with basal BNP levels at rest (P < 0.01). 4. These results suggest that adrenomedullin does not respond to the acute haemodynamic changes of exercise, whereas ANP responds to it and PCWP is the major stimulus factor. Brain natriuretic peptide responds to exercise in proportion to the basal synthesis of BNP in patients with left ventricular dysfunction and LVEDP may play a role in increasing BNP during exercise.

DOI： 10.1111/j.1440-1681.1997.tb01194.x

Adrenomedullin: a new hypotensive peptide 査読あり

K Kangawa 1, K Kitamura, N Minamino, T Eto, H Matsuo

J Hypertens Suppl 14 ( 5 ) s105 - s110 1996年12月

掲載種別：研究論文（学術雑誌）

Adrenomedullin-sensitive receptors are preferentially expressed in cultured rat mesangial cells 査読あり

Osajima A., Uezono Y., Tamura M., Kitamura K., Mutoh Y., Ueta Y., Kangawa K., Kawamura M., Eto T., Yamashita H., Izumi F., Takasugi M., Kuroiwa A.

European Journal of Pharmacology 315 ( 3 ) 319 - 325 1996年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Pharmacology

By using cultured rat mesangial cells, we compared the effects on cyclic nucleotide levels of adrenomedullin with those of the structurally related peptides, calcitonin gene-related peptide (CGRP) and amylin. Adrenomedullin potently increased cAMP levels 7-foId in a time- and concentration-dependent manner. Its EC50 was 3 x 10-9 M. CGRP was less potent (2-fold) with an EC50 of 10-7 M, and amylin had no effect on cAMP levels. All three peptides failed to increase cGMP levels. Treatment of cells with near maximal concentrations of adrenomedullin (10-7 M) and CGRP (10-6 M) had no additive effect on cAMP levels. Human adrenomedullin-(22-52)-NH2, a putative adrenomedullin receptor antagonist, inhibited the production of cAMP elicited by adrenomedullin (IC50: 7 x 10-8 M) and CGRP (IC50: 5 x 10-8 M). Human CGRP-(8-37), a CGRP receptor antagonist, conversely, reduced the cAMP elevation caused by these peptides with a lower potency (IC50: 10-6 M for both peptides). This demonstrated that human adrenomedullin-(22-52)-NH2 was a more effective antagonist for adrenomedullin- and CGRP-specific receptors than human CGRP-(8-37). Results suggest that receptors sensitive to adrenomedullin are preferentially expressed in cultured rat mesangial cells. Immunohistochemical study showed almost no immunoreactive adrenomedullin and CGRP, if any, in the cells. Adrenomedullin may regulate mesangial function as either a paracrine or circulating hormone via a cAMP- but not a cGMP-dependent mechanism.

DOI： 10.1016/S0014-2999(96)00557-2

Adrenomedullin: Changes in circulating and cardiac tissue concentration in Dahl salt-sensitive rats on a high-salt diet 査読あり

Shimokubo T., Sakata J., Kitamura K., Kangawa K., Matsuo H., Eto T.

Clinical and Experimental Hypertension 18 ( 7 ) 949 - 961 1996年10月

掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical and Experimental Hypertension

Adrenomedullin (AM), a novel hypotensive peptide, is suggested to be involved in defense mechanisms against hypertension, however, the detail mechanisms have not been clarified. To elucidate whether AM synthesis would be altered in a salt-dependent hypertension, we have investigated the AM concentration and AM messenger RNA (mRNA) level in tissues of Dahl salt-sensitive rats on either low- or high-salt intake. The AM concentration in cardiac ventricle of the high-salt group was significantly higher than that of the low-salt group. The plasma AM concentration was also significantly higher in the high-salt group than in the low-salt group. Furthermore, the plasma AM concentration correlated well with the weight of left ventricle. RNA blot analysis revealed that the AM mRNA level in cardiac ventricle of the high-salt group was higher than that of the low salt group. These results suggest that AM participates in the pathophysiology of salt-dependent hypertension and plays a role in cardiac hypertrophy.

DOI： 10.3109/10641969609097910

Inhibition of aldosterone production by adrenomedullin, a hypotensive peptide, in the rat 査読あり

Yamaguchi T., Baba K., Doi Y., Yano K., Kitamura K., Eto T.

Hypertension 28 ( 2 ) 308 - 314 1996年8月

掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension

Recently, we conducted in vitro studies and reported that adrenomedullin, a novel hypotensive peptide, inhibits aldosterone secretion by dispersed rat adrenal zona glomerulosa cells. To assess the physiological role of this inhibitory effect, we investigated the effect of adrenomedullin on aldosterone production in vivo. Male Sprague-Dawley rats were fed a normal sodium diet before the experiments. To begin the experimental procedure, we stimulated aldosterone production with a sodium-deficient diet or bilateral nephrectomy. After 3 days of sodium depletion or immediately after nephrectomy, we injected synthetic human adrenomedullin (2.5 nmol/kg SC) and repeated the injection three times at 6-hour intervals. Two hours after the last injection, the rats were decapitated and adrenal capsular tissue was collected. Adrenomedullin had no effect on plasma and adrenal aldosterone concentrations in the rats fed a normal sodium diet. Rats fed a sodium-deficient diet had significantly increased aldosterone concentrations in both plasma (4770.1±364.3 pmol/L) and adrenal gland (57.34±3.27 pmol per adrenal). Subsequently, injection of adrenomedullin significantly inhibited increases in concentrations (plasma, 2648.9±313.2 pmol/L; adrenal, 44.28±4.94 pmol per adrenal). In nephrectomized rats, increased aldosterone concentrations in plasma and adrenal gland were also significantly inhibited by adrenomedullin. In the second part of the study, plasma renin concentration, adrenal renin activity, plasma corticosterone concentration, serum potassium concentration, and plasma immunoreactive adrenomedullin concentration were examined for adrenomedullin effects. The first four were unaffected, and the last, plasma immunoreactive adrenomedullin, was elevated 15% to 30%. These in vivo results, together with our in vitro data, suggest that adrenomedullin may indeed play a physiological role in the control of blood pressure and electrolyte balance.

DOI： 10.1161/01.HYP.28.2.308

Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway. 査読あり

H Yoshida 1, K Kitamura, K Tanaka, S Omura, T Miyazaki, T Hachiya, R Ohno, T Naoe

Cancer Res 1;56 ( 13 ) 2945 - 2948 1996年7月

掲載種別：研究論文（学術雑誌）

Proadrenomedullin N-terminal 20 peptide is rapidly cleaved by neutral endopeptidase 査読あり

Nagatomo Y., Kitamura K., Kangawa K., Fujimoto Y., Eto T.

Biochemical and Biophysical Research Communications 223 ( 3 ) 539 - 543 1996年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide which is processed from an adrenomedullin precursor. PAMP is rapidly cleaved by human neutral endopeptidase (NEP), a protease which plays a key role in the degradation of human atrial natriuretic peptide (ANP). A double reciprocal plot indicated that Km of NEP as a substrate of PAMP was 6.1 μM and Vmax was 3.1 mmol/min/mg of NEP. EDTA, phosphoramidon and thiorphan inhibit the proteolysis of PAMP by NEP. NEP cleaves at least 6 peptide bonds in human PAMP; Arg2-Leu3, Glu8-Phe9, Lys12-Trp13, Lys15-Trp16, Trp16-Ala17 and Ala17-Leu18. The present data suggest that NEP may be involved in the circulation control by degrading PAMP as well as ANP.

DOI： 10.1006/bbrc.1996.0930

Antihypertensive therapy reduces increased plasma levels of adrenomedullin and brain natriuretic peptide concomitant with regression of left ventricular hypertrophy in a patient with malignant hypertension 査読あり

Nishikimi T., Matsuoka H., Ishikawa K., Yoshihara F., Kawano Y., Kitamura K., Saito Y., Kangawa K., Matsuo H., Omae T.

Hypertension Research 19 ( 2 ) 97 - 101 1996年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research

We investigated the potential role of increased plasma adrenomedullin and brain natriuretic peptide (BNP) levels in a patient with malignant hypertension. A 51-year-old man was admitted to our hospital with a chief complaint of visual disturbance. His blood pressure was 270/160 mmHg on admission. Papillary edema associated with retinal bleeding was observed. Echocardiography revealed marked concentric left ventricular hypertrophy with mild systolic dysfunction. Plasma levels of adrenomedullin and BNP were markedly elevated. Antihypertensive therapy reduced the plasma levels of adrenomedullin in association with a concomitant decrease in blood pressure. The plasma level of BNP also decreased and regression of left ventricular hypertrophy and normalization of left ventricular systolic function were observed. Our findings suggest that adrenomedullin may be involved in the defense mechanism against further elevations in blood pressure in patients with hypertension and that the plasma level of BNP may reflect left ventricular systolic dysfunction, left ventricular hypertrophy, or both, in patients with severe hypertension.

DOI： 10.1291/hypres.19.97

Adrenomedullin and proadrenomedullin N-terminal 20 peptide in impaired renal function 査読あり

T Eto 1, H Washimine, J Kato, K Kitamura, Y Yamamoto

Kidney Int Suppl 55 s148 - s149 1996年6月

掲載種別：研究論文（学術雑誌）

Distribution and characterization of rat immunoreactive proadrenomedullin N-terminal 20 peptide (PAMP) and the augmented cardiac PAMP in spontaneously hypertensive rat 査読あり

H Inatsu 1, J Sakata, T Shimokubo, M Kitani, M Nishizono, H Washimine, K Kitamura, K Kangawa, H Matsuo, T Eto

Biochem Mol Biol Int 38 ( 2 ) 365 - 372 1996年2月

掲載種別：研究論文（学術雑誌）

Nitric oxide-dependent hypotensive effects of adrenomedullin in rats 査読あり

Kazuki Matsunaga, Takanori Iwasaki, Yukio Yonetani, Kazuo Kitamura, Tanenao Eto, Kenji Kangawa, Hisayuki Matsuo

Drug Development Research 37 ( 1 ) 55 - 60 1996年1月

掲載種別：研究論文（学術雑誌）

Plasma adrenomedullin concentration in patients with heart failure 査読あり

J Kato 1, K Kobayashi, T Etoh, M Tanaka, K Kitamura, T Imamura, Y Koiwaya, K Kangawa, T Eto

J Clin Endocrinol Metab 81 ( 1 ) 180 - 183 1996年1月

掲載種別：研究論文（学術雑誌）

Increased plasma adrenomedullin in acute myocardial infarction 査読あり

Kobayashi K., Kitamura K., Hirayama N., Date H., Kashiwagi T., Ikushima I., Hanada Y., Nagatomo Y., Takenaga M., Ishikawa T., Imamura T., Koiwaya Y., Eto T.

American Heart Journal 131 ( 4 ) 676 - 680 1996年

掲載種別：研究論文（学術雑誌）出版者・発行元：American Heart Journal

Adrenomedullin has a potent vasodilating effect comparable to that of calcitonin gene-related peptide. To investigate the pathophysiologic role of endogenous adrenomedullin, we determined sequentially the plasma adrenomedullin level in 16 consecutive patients with acute myocardial infarction (AMI). Plasma adrenomedullin was higher immediately after the onset of AMI and decreased gradually; plasma levels during the 3-week period after the AMI were higher than plasma levels in 15 healthy control subjects (p < 0.001), with higher levels in patients with congestive heart failure than in patients without congestive heart failure throughout the period of the study (p < 0.05). plasma adrenomedullin was positively correlated with pulmonary capillary wedge pressure, pulmonary arterial pressure, right atrial pressure, and heart rate in the early stage of AMI. These findings suggest that the elevation of plasma adrenomedullin is related to the retention of body fluid volume, the enhancement of sympathetic activity, and/or the elevation of pressure in pulmonary vascular beds. Adrenomedullin may act against excessive vasoconstrictors increased in AMI.

DOI： 10.1016/S0002-8703(96)90270-7

Elevated plasma adrenomedullin level in hyperthryoidism 査読あり

Taniyama M., Kitamura K., Ban Y., Eto T., Katagiri T.

European Journal of Clinical Investigation 26 ( 6 ) 454 - 456 1996年

掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Clinical Investigation

Adrenomedullin is a recently discovered peptide that was first purified from phaeochromocytoma tissue and has marked vasodilatory activity, causing hypotension. In thyrotoxicosis, various haemodynamic changes are observed, including an increase in cardiac output and heart rate with a concomitant decrease in peripheral vascular resistance. To evaluate the mechanism underlying these haemodynamic changes in thyrotoxicosis, we measured the plasma adrenomedullin concentration in thyrotoxic patients with Graves' disease. The plasma concentration of adrenomedullin was elevated in hyperthyroid patients (147 ± 5.7 pmol L-1) compared with euthyroid control subjects (56 ± 1.3 pmol L-1) (P < 0.001). The correlation between the plasma adrenomedullin concentration and serum free thyroid hormone levels was marginally significant. The mean blood pressure was relatively low in the face of an elevated plasma adrenomedullin level. Adrenomedullin may therefore be responsible for the vasodilatation observed in thyrotoxicosis.

DOI： 10.1046/j.1365-2362.1996.155307.x

新規降圧ペプチドPAMPのNEPによる代謝・分解の可能性査読あり

北村和雄

治療学 30 ( 8 ) 927 - 927 1996年

担当区分：筆頭著者掲載種別：研究論文（学術雑誌）

ヒト血中アドレノメデュリン免疫活性の本態査読あり

北村和雄、加藤丈司、田中美帆、江藤胤尚、寒川賢治、松尾壽之

日本内分泌学会雑誌 72 ( 2 ) 276 - 276 1996年

掲載種別：研究論文（学術雑誌）

新しい降圧ペプチド“アドレノメデュリン”と“PAMP” 査読あり

北村和雄

心臓 28 ( 5 ) 452 - 460 1996年

掲載種別：研究論文（学術雑誌）

ヒト培養血管平滑筋細胞, 内皮細胞におけるアドレノメデュリン(AM)の産生調節査読あり

南野直人、井角能隆、栃本智子、北村和雄、寒川賢治、松尾壽之

日本内分泌学会雑誌 72 ( 2 ) 322 - 322 1996年

掲載種別：研究論文（学術雑誌）

糖尿病患者における血中アドレノメデュリン分泌動態査読あり

中村友厚、本多和文、岡田耕治、石川三衛、齋藤寿一、北村和雄

日本内分泌学会雑誌 72 ( 2 ) 277 - 277 1996年

掲載種別：研究論文（学術雑誌）

甲状腺機能亢進症における血中アドレノメデュリンおよびPAMP 査読あり

谷山松雄、北村和雄、杉田江里、長倉穂積、原秀雄、伊藤國彦、江藤胤尚、片桐敬、伴良雄

日本内分泌学会雑誌 72 ( 2 ) 277 - 277 1996年

掲載種別：研究論文（学術雑誌）

甲状腺髄様癌におけるadrenomedullin(AM), PAMPの免疫組織学的検討査読あり

杉田江里、山王なほ子、谷山松雄、北村和雄、伴良雄、片桐敬、伊藤國彦、長村義之

日本内分泌学会雑誌 72 ( 2 ) 370 - 370 1996年

掲載種別：研究論文（学術雑誌）

循環系の生理活性物質探索法査読あり

児島将康、北村和雄、寒川賢治

実験医学 14 ( 12 ) 1708 - 1713 1996年

掲載種別：研究論文（学術雑誌）

アドレノメデュリンの役割査読あり

寒川賢治、北村和雄、南野直人、松尾壽之

日本内分泌学会雑誌 72 ( 5 ) 752 - 752 1996年

掲載種別：研究論文（学術雑誌）

新しい降圧ペプチド : アドレノメデュリンとPAMP 査読あり

寒川賢治、北村和雄、南野直人、松尾壽之

最新医学 51(4月臨時増刊) 51 ( 4 ) 880 - 891 1996年

掲載種別：研究論文（学術雑誌）

Behaviour of adrenomedullin during acute and chronic salt loading in normotensive and hypertensive subjects 査読あり

Ishimitsu T., Nishikimi T., Matsuoka H., Kangawa K., Kitamura K., Minami J.I., Matsuo H., Eto T.

Clinical Science 91 ( 3 ) 293 - 298 1996年

掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical Science

1. Responses of adrenomedullin to acute and chromic salt loading were examined in normotensive and hypertensive subjects. 2. In the acute salt load study, isotonic saline (50 ml/kg for 1 h) was intravenously infused into nine normotensive subjects and 11 patients with essential hypertension. Plasma adrenomedullin was higher in hypertensive than in normotensive subjects but was unchanged by saline infusion in either the normotensive (before infusion, 2.4 ± 0.2 fmol/ml; after infusion, 2.4 ± 0.1 fmol/ml) or hypertensive (before infusion, 3.0 ± 0.1 fmol/ml; after infusion, 2.9 ± 0.2 fmol/ml) group, while renin was suppressed and atrial natriuretic peptide was markedly increased. Plasma endothelin was not affected either. 3. In the chronic salt load study, seven normotensive subjects and 23 patients with essential hypertension underwent two 7-day periods of 30 and 260 mmol/day sodium intake. Depending on the blood pressure change, 13 hypertensive subjects were classified as salt-resistant and 10 as salt-sensitive. Salt-sensitive hypertensive subjects had suppressed plasma renin activity even during low salt intake. Plasma adrenomedullin or endothelin were not affected by the salt intake changes in any group; however, the high salt intake increased atrial natriuretic peptide in all groups. 4. These data indicate that the circulating level of adrenomedullin is not changed by either acute or chronic salt loading in normotensive subjects and patients with essential hypertension.

DOI： 10.1042/cs0910293

Adrenomedullin: A new modulator of vascular tone 査読あり

Kangawa K., Kitamura K., Minamino N., Matsuo H.

Journal of Cardiac Failure 2 ( SUPPL. 1 ) 1996年

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Cardiac Failure

DOI： 10.1016/S1071-9164(96)80069-8

Increased plasma adrenomedullin levels in chronic congestive heart failure 査読あり

Kobayashi K., Kitamura K., Etoh T., Nagatomo Y., Takenaga M., Ishikawa T., Imamura T., Koiwaya Y., Eto T.

American Heart Journal 131 ( 5 ) 994 - 998 1996年

掲載種別：研究論文（学術雑誌）出版者・発行元：American Heart Journal

Adrenomedullin is a potent vasodilator peptide and occurs in circulating blood of human beings and experimental animals. Because it is produced in intact aorta of rats and in cultured vascular endothelial cells, adrenomedullin seems to participate in regulation of local vascular tone. To determine the pathophysiological roles of adrenomedullin, we investigated its plasma concentrations in 49 patients with heart failure. Plasma adrenomedullin levels increased significantly with advancing severity of the disease (New York Heart Association functional class I, 4.1 ± 1.0; II, 5.6 ± 1.6; III, 6.4 ± 0.8; IV, 13.2 ± 6.8 (fmol/l)). Plasma adrenomedullin was correlated with pulmonary artery pressure (r= 0.44, p=0.0114) and pulmonary capillary wedge pressure (r = 0.83, p = 0.0002). These findings indicate that adrenomedullin may play some important role in the pathophysiologic makeup of heart failure by its vasodilating effects against the concomitant exaggeration of humor pressor agents such as catecholamine and the renin- angiotensin system. Hemodynamic changes in pulmonary circulation may have some influence on the increased synthesis and secretion of plasma adrenomedullin in chronic congestive heart failure.

DOI： 10.1016/S0002-8703(96)90185-4

Chronic effect of β-adrenoceptor blockade on plasma levels of brain natriuretic peptide during exercise in essential hypertension 査読あり

Tanaka M., Ishizaka Y., Ishiyama Y., Kato J., Kida O., Kitamura K., Kangawa K., Eto T.

Hypertension Research - Clinical and Experimental 19 ( 4 ) 239 - 245 1996年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research - Clinical and Experimental

Many factors have been reported to stimulate the release of brain natriuretic peptide (BNP) as well as atrial natriuretic peptide (ANP). In hypertensive patients, however, little is known about whether these factors differ from those in normotensive subjects or if they are influenced by antihypertensive treatment. We measured the plasma concentrations of BNP and ANP in 12 hypertensive patients and examined the chronic effects of β-adrenoceptor blockade on BNP secretion during exercise with a bicycle ergometer. The exercise raised both plasma BNP and ANP with concomitant increases in systolic blood pressure, heart rate (HR) and plasma norepinephrine (NE) and epinephrine (Epi) before and after treatment. Before treatment, the changes in ANP and BNP correlated with that in HR (p < 0.05). After treatment 4 wk of treatment, the change in ANP correlated with those in NE and Epi as well as HR. Multivariate regression analysis indicated that only NE was a significant stimulus for ANP secretion during the treatment period. As for BNP, HR was the only significant stimulant for its secretion both before and after treatment. In essential hypertension, β-adrenergic receptor blockade affected the factors stimulating exercise-induced ANP release but not those stimulating BNP release. BNP release, therefore, seems to be stimulated by similar but distinct factors from those that stimulate ANP release.

DOI： 10.1291/hypres.19.239

Adrenomedullin-immunoreactive neurons in the paraventricular and supraoptic nuclei of the rat 査読あり

Ueta Y., Kitamura K., Isse T., Shibuya I., Kabashima N., Yamamoto S., Kangawa K., Matsuo H., Eto T., Yamashita H.

Neuroscience Letters 202 ( 1-2 ) 37 - 40 1995年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：Neuroscience Letters

The existence of adrenomedullin (AM) in the rat hypothalamus was examined by immunohistochemistry. AM-immunoreactive neurons were found in the supraoptic nucleus (SON) and in the magnocellular parts of the paraventricular nucleus (PVN). The co-existence of AM-, oxytocin- and/or vasopressin-immunoreactivity was identified in the same neurons in the hypothalamus. The results suggest that the AM may play a role in neurotransmission or in cardiovascular control with neurohypophyseal hormones. © 1995.

DOI： 10.1016/0304-3940(95)12204-4

Plasma concentration of human adrenomedullin in patients on hemodialysis 査読あり

H Washimine 1, Y Yamamoto, K Kitamura, M Tanaka, Y Ichiki, K Kangawa, H Matsuo, T Eto

Clin Nephrol 44 ( 6 ) 389 - 393 1995年12月

掲載種別：研究論文（学術雑誌）

Increased plasma levels of adrenomedullin in patients with heart failure 査読あり

Nishikimi T., Saito Y., Kitamura K., Ishimitsu T., Eto T., Kangawa K., Matsuo H., Omae T., Matsuoka H.

Journal of the American College of Cardiology 26 ( 6 ) 1424 - 1431 1995年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of the American College of Cardiology

Objectives.: To investigate the role of adrenomedullin in the pathophysiology of heart failure, we measured plasma levels of adrenomedullin in patients with heart failure. Background.: Adrenomedullin is a potent hypotensive peptide newly discovered in pheochromocytoma tissue by monitoring its elevating activity on platelet adenosine 3′, 5′-cyclic monophosphate (cAMP). A significant level of adrenomedullin has been identified in human plasma. These findings suggest the possibility of adrenomedullin as a new circulating hormone that participates in the regulation of the cardiovascular system. Methods.: Venous blood samples at rest were obtained from patients with heart failure in New York Heart Association functional classes I (n = 15), II (n = 25), III (n = 16) and IV (n = 10) and from normal subjects (n = 27). Plasma adrenomedullin levels were determined by our newly developed radioimmunoassay. Other humoral factor levels measured simultaneously included norepinephrine, atrial natriuretic peptide, brain natriuretic peptide, plasma renin activity, aldosterone and cAMP. Left ventricular ejection fraction was measured by echocardiography. In eight patients with severe heart failure, plasma adrenomedullin levels were measured before and after treatment. Results.: The mean (± SD) plasma level of adrenomedullin in control subjects was 2.52 ± 0.75 pmollliter. Plasma levels of adrenomedullin in patients with heart failure were unaffected in those in functional class I (2.85 ± 0.62 pmol/liter) but tended to be increased in those in class II (3.54 ± 0.82 pmol/liter) and were significantly increased in those in classes III and IV (4.78 ± 1.218 and 8.74 ± 3.42 pmollliter, respectively). There was a significant correlation between plasma levels of adrenomedullin and norepinephrine (r = 0.618, p < 0.001), atrial natriuretic peptide (r = 0.696, p < 0.001) and brain natriuretic peptide (r = 0.692, p < 0.001). Left ventricular ejection fraction inversely correlated with plasma adrenomedullin levels (r = 0.485, p < 0.001). Plasma adrenomedullin levels significantly decreased after treatment (from 7.40 ± 3.40 to 3.98 ± 1.00 pmol/liter, p < 0.05). Conclusions.: These results suggest that plasma levels of adrenomedullin are elevated in heart failure and that an increased plasma volume and an activated sympathetic nervous system in this condition may be related to its synthesis or secretion. Given that adrenomedullin exerts potent cardiovascular effects, increased adrenomedullin may be involved in the defense mechanism against further peripheral vascular resistance elevation in heart failure. © 1995 American College of Cardiology.

DOI： 10.1016/0735-1097(95)00338-X

Inhibition of catecholamine synthesis by proadrenomedullin N-terminal 20 peptide in cultured bovine adrenal medullary cells 査読あり

Niina H., Kobayashi H., Kitamura K., Katoh F., Eto T., Wada A.

European Journal of Pharmacology 286 ( 1 ) 95 - 97 1995年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Pharmacology

In cultured bovine adrenal medullary cells, proadrenomedullin N-terminal 20 peptide (PAMP), at concentrations ≥ 3 μM, inhibited carbachol-induced [14C]catecholamine synthesis from [14C]tyrosine. Carbachol-induced activation of tyrosine hydroxylase was also attenuated by PAMP. These results suggest that PAMP is a novel endogenous peptide that regulates catecholamine synthesis via the suppression of its rate-limiting enzyme in adrenal medullary cells. © 1995.

DOI： 10.1016/0014-2999(95)00528-S

Plasma adrenomedullin in patients with primary aldosteronism 査読あり

Kato J., Kitamura K., Kuwasako K., Tanaka M., Ishiyama Y., Shimokubo T., Ichiki Y., Nakamura S., Kangawa K., Eto T.

American Journal of Hypertension 8 ( 10 ) 997 - 1000 1995年10月

掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Hypertension

Adrenomedullin (AM) is a novel hypotensive peptide originally isolated from the pheochromocytoma tissue of humans. To examine the pathophysiological role of AM in primary aldosteronism (PA), the plasma concentration of AM in patients with PA was measured with a specific radioimmunoassay and compared to that in age- and sex-matched healthy normotensive subjects. In addition, the concentrations of AM as well as catecholamines in the plasma from both the adrenal vein and the inferior vena cava (IVC) were measured to determine whether or not the circulating AM in these PA patients is supplied from the adrenal medulla, which contains a much higher concentration of AM than any other human tissue does. The plasma concentration of AM in the PA patients (4.57 ± 0.32 fmol/mL, n = 6) was significantly (P < .01) higher than that in the healthy subjects (3.06 ± 0.20 fmol/mL, n = 12). A significant positive correlation (r = 0.62, P < .01) was observed between the mean blood pressure and the plasma AM level. The AM concentration in plasma from the adrenal vein was almost the same level as that from the IVC although the concentrations of both epinephrine and norepinephrine in the adrenal vein were much higher than those in the IVC. Therefore, it seems unlikely that the plasma AM in the PA patients is mainly supplied from the adrenal medulla. Judging from the potent hypotensive activity of AM, the present findings suggest that AM participates in defense mechanisms acting against the elevation of blood pressure in the patients with PA. © 1995 American Journal of Hypertension Ltd.

DOI： 10.1016/0895-7061(95)00217-0

Distribution and characterization of immunoreactive adrenomedullin in porcine tissue, and isolation of adrenomedullin [26-52] and adrenomedullin [34-52] from porcine duodenum 査読あり

Ichiki Y., Kitamura K., Kangawa K., Kawamoto M., Matsuo H., Eto T.

Journal of Biochemistry 118 ( 4 ) 765 - 770 1995年10月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biochemistry

Using a sensitive radioimmunoassay which recognizes the carboxy-terminal region of porcine adrenomedullin, the distribution of immunoreactive adrenomedullin was investigated in the porcine central nervous system and in peripheral tissue. Adrenomedullin was widely distributed in porcine tissue, and its concentration was highest in adrenal medulla (126±32 fmol/mg wet tissue, mean±SD). Relatively high concentrations of immunoreactive adrenomedullin were found in the right atrium, lung, duodenum, and pituitary gland. The molecular form of immunoreactive adrenomedullin in all porcine tissues was found to be almost wholly porcine adrenomedullin itself by analysis with reverse-phase high-performance liquid chromatography coupled with radioimmunoassay. Minor molecular forms of immunoreactive adrenomedullin were found in the porcine duodenum. These were isolated and identified as adrenomedullin [26-52] and adrenomedullin [34-52]. © 1995 Oxford University Press.

DOI： 10.1093/oxfordjournals.jbchem.a124978

Augmented adrenomedullin concentrations in right ventricle and plasma of experimental pulmonary hypertension 査読あり

Shimokubo T., Sakata J., Kitamura K., Kangawa K., Matsuo H., Eto T.

Life Sciences 57 ( 19 ) 1771 - 1779 1995年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：Life Sciences

Adrenomedullin is a strong vasorelaxing peptide discovered in pheochromocytoma tissue. Monocrotaline, a pyrrolizidine alkaloid derived from Crotalaria spectabilis, is known to cause pulmonary hypertension. To test the hypothesis that adrenomedullin plays a role similar to that of atrial natriuretic peptide or brain natriuretic peptide in modulating right ventricular responses to pulmonary hypertension, we have compared concentrations of immunoreactive rat adrenomedullin and adrenomedullin messenger RNA levels in tissues of monocrotaline treated rats with those of control rats. We also measured the effect of pulmonary hypertension on plasma level of the peptide. The concentrations of adrenomedullin immunoreactivity in right ventricle and plasma were significantly higher in monocrotaline treated rats than in control rats. The messenger RNA level of adrenomedullin in right ventricle was also higher in monocrotaline treated rats than in control rats. These results suggest that adrenomedullin participates in the mechanism to counteract the high blood pressure in pulmonary circulation. © 1995.

DOI： 10.1016/0024-3205(95)02155-C

Proadrenomedullin NH<inf>2</inf>-terminal 20 peptide, a new product of the adrenomedullin gene, inhibits norepinephrine overflow from nerve endings 査読あり

Shimosawa T., Ito Y., Ando K., Kitamura K., Kangawa K., Fujita T.

Journal of Clinical Investigation 96 ( 3 ) 1672 - 1676 1995年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Clinical Investigation

Proadrenomedullin NH2-terminal 20 peptide (PAMP) and adrenomedullin, which are derived from proadrenomedullin, exhibit remarkable hypotensive action. We investigated the effect of PAMP and adrenomedullin on peripheral sympathetic neural transmission. Using perfused rat mesenteric arteries, PAMP (0, 1, 5, and 10 pmol/ml) decreased norepinephrine overflow by periarterial electrical nerve stimulation in a dose-dependent fashion (0.244 ± 0,043, 0,231 ± 0.048, 0.195 ± 0.061, and 0.168 ± 0.051 ng/gram tissue weight: NS, P < 0.05, and P < 0.02, respectively). In contrast to PAMP, adrenomedullin (1, 5, and 10 pmol/ml) did not change it. In contrast, vasoconstrictive response of mesenteric arteries to exogenous norepinephrine was significantly attenuated by 10 pmol/ml of adrenomedullin but not by the same dose of PAMP. Calcitonin gene-related peptide (8-37) [CGRP(8-37)], a CGRP receptor antagonist, inhibited the vasodilatory effect of adrenomedullin but could not suppress the sympathoinhibitory effect of PAMP. Neither a nicotinic antagonist, hexamethonium, nor a presynaptic α2 antagonist, yohimbine, blocked the sympathoinhibitory effect of PAMP. Thus, it suggests that PAMP and adrenomedullin, which are derived from the same gene, exhibit different hypotensive mechanisms: PAMP inhibits neural transmission at peripheral sympathetic nerve ending, although adrenomedullin directly dilates vascular smooth muscle, possibly through CGRP-like receptor.

DOI： 10.1172/JCI118208

HAEMODYNAMIC RESPONSES TO RAT ADRENOMEDULLIN IN ANAESTHETIZED SPONTANEOUSLY HYPERTENSIVE RATS 査読あり

Ishiyama Y., Kitamura K., Ichiki Y., Sakata J., Kida O., Kangawa K., Eto T.

Clinical and Experimental Pharmacology and Physiology 22 ( 9 ) 614 - 618 1995年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical and Experimental Pharmacology and Physiology

1. The haemodynamic effects of rat adrenomedullin (AM), a novel hypotensive peptide, were examined in anaesthetized 16–18 week old spontaneously hypertensive rats (SHR) and Wistar‐Kyoto rats (WKY). 2. An intravenous injection of rat AM dose‐dependently reduced the mean blood pressure (MBP) with a concomitant fall in total peripheral resistance index (TPRI) and an increase in cardiac index (CI) in both strains of rats. Per cent changes in MBP, TPRI and CI were not different between SHR and WKY. 3. The plasma half‐life of rat AM in SHR was similar to that in WKY when it was administered at the dose of 1.0 nmol/kg. 4. These findings indicate that AM has a potent vasorelaxant activity in both SHR and WKY. The haemodynamic responsiveness to exogenous AM and its pharmaeokinetics in SHR were comparable with those in WKY. Copyright © 1995, Wiley Blackwell. All rights reserved

DOI： 10.1111/j.1440-1681.1995.tb02075.x

Receptors for adrenomedullin in human vascular endothelial cells 査読あり

Kato J., Kitamura K., Kangawa K., Eto T.

European Journal of Pharmacology: Molecular Pharmacology 289 ( 2 ) 383 - 385 1995年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Pharmacology: Molecular Pharmacology

Accumulation of the intracellular cyclic AMP (cAMP) was measured in cultured endothelial cells of the human umbilical vein following the incubation with adrenomedullin, a newly discovered hypotensive peptide, to determine the presence of specific receptors for adrenomedullin. Adrenomedullin increased the intracellular cAMP in a dose-dependent fashion in the endothelial cells, and the EC50 value was as low as 10-9 M. Calcitonin gene-related peptide (CGRP) that has a homology to adrenomedullin in its amino-acid sequence also increased the intracellular cAMP with an EC50 value greater than 10-7 M. The effect of CGRP was attenuated in the presence of CGRP-(8-37) had no effect on the cAMP accumulation by adrenomedullin. These findings indicate that the cultured endothelial cells of human umbilical vein possess specific adrenomedullin receptors coupled with the adenylate cyclase activity that may have little affinity with CGRP. © 1995.

DOI： 10.1016/0922-4106(95)90117-5

Immunohistochemical identification of adrenomedullin in human, rat, and porcine tissue 査読あり

Washimine H., Asada Y., Kitamura K., Ichiki Y., Hara S., Yamamoto Y., Kangawa K., Sumiyoshi A., Eto T.

Histochemistry and Cell Biology 103 ( 4 ) 251 - 254 1995年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：Histochemistry and Cell Biology

The histological localization was investigated of adrenomedullin (AM), a novel vasorelaxant peptide originally isolated from human pheochromocytoma. The immunohistological distribution was examined of AM in human, rat, and procine tissues using a polyclonal antibody to a fragment comprising C-terminal amino acids 40-52 of human adrenomedullin [AM(40-52)NH2]. Almost all of the human pheochromocytoma and normal adrenal medullary cells of all three species were immunostained and found to be intensely positive for AM. Furthermore, AM-immunoreactive cells were present in the pancreatic islets, gastrointestinal neuroendocrine system, anterior pituitary, and choroid plexus with some degree of interspecies heterogeneity. These findings indicate that AM-immunoreactive cells are widely distributed in the endocrine and neuroendocrine system, suggesting that AM plays some important role in the control of systemic and local circulation and also of humoral secretion. © 1995 Springer-Verlag.

DOI： 10.1007/BF01457408

Mechanisms of adrenomedullin-induced vasodilation in the rat kidney 査読あり

Hirata Y., Hayakawa H., Suzuki Y., Suzuki E., Ikenouchi H., Kohmoto O., Kimura K., Kitamura K., Eto T., Kangawa K., Matsuo H., Omata M.

Hypertension 25 ( 4 II ) 790 - 795 1995年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension

To explore the mechanism of adrenomedullin-induced vasorelaxation, we tested the effects of adrenomedullin on renal function in rats in vivo and measured the release of endothelium-derived nitric oxide from isolated perfused rat kidney (using a chemiluminescence assay) and the diameters of the glomerular arterioles in the hydronephrotic kidney. Adrenomedullin decreased blood pressure in a dose-dependent manner (3 nmol/kg: -29±2% [SEM]; P<.01) and slightly increased the glomerular filtration rate and urinary sodium excretion (+108%; P<.05). These changes were associated with significant increases in urinary excretion of cyclic AMP (+54%; P<.05). Adrenomedullin decreased renal vascular resistance (10-7 mol/L adrenomedullin: -41 ± 2%; P<.001) and increased release of nitric oxide (+5.1±0.7 fmol/min per gram kidney weight; P<.001) in the isolated kidney. This increase in nitric oxide release was abolished by the inhibitor N(G)- monomethyl-L-arginine, and it also reversed the decrease in renal vascular resistance seen with adrenomedullin. Renal responses of deoxycorticosterone acetate-salt hypertensive rats to adrenomedullin were significantly smaller than those of control rats for both release of nitric oxide (10-7 mol/L adrenomedullin: +0.8±0.2 fmol/min per gram kidney weight; P<.01 versus control) and renal vasodilation (-28±6%; P<.05). Videomicroscopic analysis revealed that adrenomedullin increased the diameters of both afferent and efferent arterioles (3 nmol/kg: +11%; P<.05). Thus, adrenomedullin-induced renal vasodilation is partially endothelium dependent and is attenuated in deoxycorticosterone acetate-salt hypertension, probably due to endothelial damage.

DOI： 10.1161/01.hyp.25.4.790

Molecular forms of human brain natriuretic peptide (BNP) in plasma of patients on hemodialysis (HD) 査読あり

Y Ishizaka 1, Y Yamamoto, M Tanaka, F Kato, Y Ishizaka, N Yokota, J Kato, K Kitamura, T Eto, K Kangawa, et al.

Clin Nephrol . 1995 Apr;43(4):237-42. 43 ( 4 ) 237 - 242 1995年4月

掲載種別：研究論文（学術雑誌）

Adrenomedullin: Implications for Hypertension Research 査読あり

Kitamura K., Kangawa K., Matsuo H., Eto T.

Drugs 49 ( 4 ) 485 - 495 1995年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：Drugs

DOI： 10.2165/00003495-199549040-00001

Adrenomedullin stimulates two signal transduction pathways, cAMP accumulation and Ca2+ mobilization, in bovine aortic endothelial cells 査読あり

Shimekake Y., Nagata K., Ohta S., Kambayashi Y., Teraoka H., Kitamura K., Eto T., Kangawa K., Matsuo H.

Journal of Biological Chemistry 270 ( 9 ) 4412 - 4417 1995年3月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biological Chemistry

The biological action of adrenomedullin, a novel hypotensive peptide, on bovine aortic endothelial cells, was examined. The specific binding of adrenomedullin to these cells was observed, and adrenomedullin was found to induce intracellular cAMP accumulation in a dose-dependent manner. EC50 for the cAMP accumulation was about 100 times lower than the apparent IC50 for the binding assay. Adrenomedullin also induced increase of intracellular free Ca2+ in endothelial cells in a dose-dependent manner. The Ca2+ response to adrenomedullin was biphasic with an initial transient increase due to the release from thapsigargin-sensitive intracellular Ca2+ storage and a prolonged increase by influx through the ion channel on the plasma membrane. This intracellular free Ca2+ increase resulted from phospholipase C activation and inositol 1,4,5-trisphosphate formation, and seemed to cause nitric oxide synthase activation by monitoring intracellular cGMP accumulation. Both cAMP accumulation and Ca2+ increased responses to adrenomedullin were mediated by cholera toxin-sensitive G protein, but the two signal transduction pathways were independent. Thus, the results suggest that adrenomedullin elicits the hypotensive effect through at least two mechanisms, a direct action on vascular smooth muscle cells to increase intracellular cAMP and an action on endothelial cells to stimulate nitric oxide release, with both leading to vascular relaxation.

DOI： 10.1074/jbc.270.9.4412

Proadrenomedullin N‐Terminal 20 Peptide (PAMP), an Endogenous Anticholinergic Peptide: Its Exocytotic Secretion and Inhibition of Catecholamine Secretion in Adrenal Medulla 査読あり

Katoh F., Kitamura K., Niina H., Yamamoto R., Washimine H., Kangawa K., Yamamoto Y., Kobayashi H., Eto T., Wada A.

Journal of Neurochemistry 64 ( 1 ) 459 - 461 1995年1月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Neurochemistry

Abstract: In cultured bovine adrenal medullary cells, stimulation of nicotinic receptors by carbachol evoked the Ca2+‐dependent exocytotic cosecretion of proadrenomedullin N‐terminal 20 peptide (PAMP) (EC50 = 50.1 µM) and catecholamines (EC50 = 63.0 µM), with the molar ratio of PAMP/catecholamines secreted being equal to the ratio in the cells. Addition of PAMP[1–20]NH2 inhibited carbachol‐induced 22Na+ influx via nicotinic receptors (IC50 = 2.5 µM) in a noncompetitive manner and thereby reduced carbachol‐induced 45Ca2+ influx via voltage‐dependent Ca2+ channels (IC50 = 1.0 µM) and catecholamine secretion (IC50 = 1.6 µM). It did not alter high K+‐induced 45Ca2+ influx via voltage‐dependent Ca2+ channels or veratridine‐induced 22Na+ influx via voltage‐dependent Na+ channels. PAMP seems to be a novel antinicotinic peptide cosecreted with catecholamines by a Ca2+‐dependent exocytosis in response to nicotinic receptor stimulation. Copyright © 1995, Wiley Blackwell. All rights reserved

DOI： 10.1046/j.1471-4159.1995.64010459.x

アドレノメデュリン含有細胞がラット視床下部室傍核および視索上核に存在する査読あり

上田陽一、西野枝子、椛島成利、澁谷泉、北村和雄、寒川賢治、山下博

日本内分泌学会雑誌 71 ( 6 ) 929 - 929 1995年

掲載種別：研究論文（学術雑誌）

培養血管内皮細胞におけるアドレノメデュリン(AM)の産生・分泌とその調節機構査読あり

庄司浩気、南野直人、諏合伸、北村和雄、江藤胤尚、寒川賢治、松尾壽之

日本内分泌学会雑誌 71 ( 3 ) 361 - 361 1995年

掲載種別：研究論文（学術雑誌）

ブタ各組織におけるアドレノメヂュリン免疫活性の分子型の同定査読あり

市来能成、北村和雄、寒川賢治、江藤胤尚

日本内分泌学会雑誌 71 ( 3 ) 424 - 424 1995年

掲載種別：研究論文（学術雑誌）

起立負荷時における血中アドレノメデュリン分泌動態査読あり

井手野順一、本多一文、中村友厚、六角久美子、斎藤孝子、北村和雄

日本 71 ( 3 ) 500 - 500 1995年

掲載種別：研究論文（学術雑誌）

視索上核神経内分泌細胞におけるアドレノメデュリンの作用：スライスパッチ法による検討査読あり

椛島成利,nurhadiibrahim,澁谷泉、野口淳、上田陽一、北村和雄、寒川賢治、山下博

日本内分泌学会雑誌 71 ( 6 ) 930 - 930 1995年

掲載種別：研究論文（学術雑誌）

新しい循環調節因子の発見査読あり

寒川賢治、南野直人、松尾壽之、北村和雄、江藤胤尚

日本内分泌学会雑誌 71 ( 3 ) 260 - 260 1995年

掲載種別：研究論文（学術雑誌）

Plasma Adrenomedullin in Various Diseases and Exercise-Induced Change in Adrenomedullin in Healthy Subjects 査読あり

Tanaka M., Kitamura K., Ishizaka Y., Ishiyama Y., Kato J., Eto T., Kangawa K.

Internal Medicine 34 ( 8 ) 728 - 733 1995年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Internal Medicine

Adrenomedullin is a novel hypotensive peptide recently discovered in human pheochromocytoma. In the present study, we measured the plasma immunoreactive adrenomedullin of healthy subjects and patients with various diseases. Immunoreactive adrenomedullin was found to circulate in blood of the healthy subjects at a considerable concentration (3.3±0.3 fmol/ml). Plasma adrenomedullin was significantly increased in the patients with congestive heart failure (5.4±0.3 fmol/ml), essential hypertension (5.3±0.4 fmol/ml) and renal disease (4.9±0.4 fniol/ml). In healthy volunteers physical exercise significantly increased the plasma adrenomedullin concentration. The increase of adrenomedullin was inversely related to systolic blood pressure. These findings indicate that adrenomedullin participates in the circulation control in both physiological and diseased conditions. Although the exact origin of circulating adrenomedullin is still unknown, it is thought to be released rapidly by acute exercise, thereby regulating the cardiovascular system by its vasodilating activity. (Internal Medicine 34: 728-733, 1995). © 1995, The Japanese Society of Internal Medicine. All rights reserved.

DOI： 10.2169/internalmedicine.34.728

視索上核神経内分泌細胞におけるアドレノメデュリンの作用：Ca2+画像解析法による検討査読あり

椛島成利、nurtiadiIbrahim、澁谷泉、野口淳、上田陽一、北村和雄、寒川賢治、山下博

日本内分泌学会雑誌 71 ( 6 ) 930 - 930 1995年

掲載種別：研究論文（学術雑誌）

新しい降圧ペプチド"proadrenomedullin N-terminal 20 peptide(PAMP)"の研究:単離・構造決定, 生体内分布と生物学的活性の検討査読あり

北村和雄、鷲峯久紀、市来能成、加藤ふみ、江藤胤尚、和田明彦、寒川賢治、松尾壽之

日本内分泌学会雑誌 71 ( 3 ) 412 - 412 1995年

担当区分：筆頭著者掲載種別：研究論文（学術雑誌）

新しい降圧ペプチド“アドレノメデュリン” 査読あり

北村和雄

医学のあゆみ 173 ( 11 ) 910 - 911 1995年

担当区分：筆頭著者掲載種別：研究論文（学術雑誌）

培養血管平滑筋細胞におけるアドレノメデュリン(AM)の産生調節--血菅作動性物質を中心として査読あり

諏合伸、南野直人、庄司浩気、北村和雄、江藤胤尚、寒川賢治、松尾壽之

日本内分泌学会 71 ( 3 ) 413 - 413 1995年

掲載種別：研究論文（学術雑誌）

Human proadrenomedullin N-terminal 20 peptide in pheochromocytoma and normal adrenal medulla 査読あり

Kuwasako K., Kitamura K., Ichiki Y., Kato J., Kangawa K., Matsuo H., Eto T.

Biochemical and Biophysical Research Communications 211 ( 2 ) 694 - 699 1995年

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide found in adrenomedullin precursor. Using a radioimmunoassay for human PAMP, we purified immunoreactive PAMP (ir-PAMP) from human pheochromocytoma and determined its complete amino acid sequence. The major component of PAMP-like immunoreactivity was found to be PAMP [1-20] NH2 with an amino acid sequence identical to that of the deduced amino acid sequence by cDNA analysis. Both ir-PAMP and ir-adrenomedullin were found to be abundant in normal adrenal medulla as well as pheochromocytoma tissue arising from adrenal medulla, and there was a significantly (p < 0.05) positive correlation between ir-adrenomedullin and ir-PAMP concentrations in these tissues. However, the PAMP/adrenomedullin ratio in pheochromocytoma tissues (0.197 ± 0.013) was significantly (p < 0.005) lower than that in adrenal medullae (0.384 ± 0.041). The present data indicate that PAMP is biosynthesized from adrenomedullin precursor, but the biosynthesis or metabolism of PAMP in pheochromocytoma may be different from that of normal adrenal medulla. © 1995 Academic Press, Inc.

DOI： 10.1006/bbrc.1995.1867

Endothelin-1 and big endothelin-1 increase in human endometrium during menstruation 査読あり

Ohbuchi H., Nagai K., Yamaguchi M., Ikenoue T., Mori N., Kitamura K., Araki S., Toshimori K.

American Journal of Obstetrics and Gynecology 173 ( 5 ) 1483 - 1490 1995年

掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Obstetrics and Gynecology

OBJECTIVES: Although the physiologic and pathologic roles of endothelin-1 in reproduction have been investigated, little is known about human uterine tissue levels. We studied the levels of immunoreactive endothelin-1 and immunoreactive big endothelin-1 in human endometrium and myometrium during each menstrual phase. STUDY DESIGN: Materials were obtained at hysterectomy (endometrium, n = 33; myometrium, n = 27). We measured immunoreactive endothelin-1 and immunoreactive big endothelin-1 by radioimmunoassay and performed an immunohistochemical study of the tissue. Data were analyzed by the Mann-Whitney U test. RESULTS: We detected larger amounts of immunoreactive endothelin-1 and immunoreactive big endothelin-1 in the endometrium than in the myometrium throughout the menstrual, proliferative, and secretory phases. Endometrial immunoreactive endothelin-1 and immunoreactive endothelin-1 were significantly increased in the menstrual phase (endothelin-1 68.8 ± 23.3 pg/mg protein, n = 5, p < 0.005; big endothelin-1 45.2 ± 5.7 pg/mg protein, n = 5, p < 0.003) compared with the other phases (endothelin-1 30.7 ± 9.5 and 30.5 ± 14.0 pg/mg protein; big endothelin-1 19.9 ± 6.7 and 24.1 ± 7.4 pg/mg protein). Immunohistochemistry demonstrated that the endometrial stromal cells were positive for antiendothelin monoclonal antibody only in the premenstrual and menstrual phases. CONCLUSION: Levels of immunoreactive endothelin-1 and immunoreactive big endothelin-1 are different in each type of uterine tissue and in each phase of the menstrual cycle. These changes may indicate some role of endothelin-1 in menstruation. © 1995, All rights reserved.

DOI： 10.1016/0002-9378(95)90637-1

Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells 査読あり

Sugo S., Minamino N., Shoji H., Kangawa K., Kitamura K., Eto T., Matsuo H.

Biochemical and Biophysical Research Communications 207 ( 1 ) 25 - 32 1995年

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

To elucidate physiological functions of adrenomedullin (AM) secreted from vascular smooth muscle cells (VSMCs), we examined the effect of cytokines, growth factors and related substances on AM production in cultured rat VSMC. Among them, interleukin-1α (IL-1α), IL-1β, tumor necrosis factor-α (TNF-α) and TNF-β, as well as lipopolysaccharide (LPS), markedly augmented production and gene expression of AM. Although maximal stimulation levels of these substances were not greatly different, ED50 values of IL-1s (0.3 ng/ml) were about 1/10 that of TNFs and LPS. AM mRNA levels maximized at 3-6 h after stimulation with IL-1β and LPS, while TNF-α increased the AM mRNA level up to 48 h. Furthermore, IL-1α, TNF-α and LPS additively increased AM production in VSMC. AM production was slightly augmented by fibroblast, epidermal and platelet derived growth factors. These results suggest that AM secreted from VSMC actually exerts a vasorelaxant effect under physiological conditions such as endotoxin shock, atherosclerosis and inflammation. © 1995 Academic Press, Inc.

DOI： 10.1006/bbrc.1995.1148

Exercise-Induced Secretion of Brain Natriuretic Peptide in Essential Hypertension and Normal Subjects 査読あり

Tanaka M., Ishizaka Y., Ishiyama Y., Kato J., Kida O., Kitamura K., Eto T., Kangawa K., Matsuo H.

Hypertension Research - Clinical and Experimental 18 ( 2 ) 159 - 166 1995年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension Research - Clinical and Experimental

To determine the major stimuli for the release of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP), we measured their plasma concentrations in 14 normal subjects and 19 patients with essential hypertension during exercise with a bicycle ergometer. The plasma levels of both hormones at baseline were significantly higher in the hypertensive group than in the controls (p<0.05). The exercise raised both the plasma BNP and ANP, with concomitant increases in systolic blood pressure (SBP), heart rate (HR) and plasma norepinephrine (NE) or epinephrine (Epi) in each group. In the controls the change in ANP correlated with those in SBP, HR and NE (p<0.05), and similarly the change in BNP with those in SBP, HR, NE and Epi (p<0.05). In multivariate regression analysis only NE was found to be a significant stimulus for ANP secretion, whereas SBP or Epi was related to BNP release. In the hypertensives the change in ANP correlated with those in HR and NE, but on multivariate regression analysis the change in ANP correlated only with that in HR. The change in BNP in the hypertensives correlated only with that in HR. These findings indicate that in normal subjects the exercise-induced release of BNP and ANP is more sensitive to a similar but slightly different sympathetic stimulus, whereas in hypertensives the major stimulus for the release of both hormones is heart rate, indicating that the mediators for BNP or ANP release are altered by some factors involved in hypertension. (Hypertens Res 1995; 18: 159-166). © 1995, The Japanese Society of Hypertension. All rights reserved.

DOI： 10.1291/hypres.18.159

Clinical studies on the sites of production and clearance of circulating adrenomedullin in human subjects 査読あり

Nishikimi T., Kitamura K., Saito Y., Shimada K.E., Ishimitsu T., Takamiya M., Kangawa K., Matsuo H., Eto T., Omae T., Matsuoka H.

Hypertension 24 ( 5 ) 600 - 604 1994年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：Hypertension

Adrenomedullin is a novel hypotensive peptide, newly discovered in pheochromocytoma. Because immunoreactive adrenomedullin is present in human plasma, adrenomedullin may play a role in regulating blood pressure. A recent report showed that human adrenomedullin mRNA is expressed not only in pheochromocytoma but also in the normal adrenal medulla, kidney, lung, and ventricle. However, whether or not these organs actually release adrenomedullin into the circulation remains unknown. To investigate the sites of production and degradation of adrenomedullin in human subjects, we obtained blood samples from various sites and measured immunoreactive adrenomedullin concentrations. In study 1, blood samples were obtained from the infrarenal inferior vena cava, suprarenal inferior vena cava, superior vena cava, right atrium, right ventricle, pulmonary artery, pulmonary capillary, left ventricle, and aorta during cardiac catheterization in 15 patients with ischemic heart disease (67±10 years). In study 2, blood samples were taken from the infrarenal inferior vena cava, suprarenal inferior vena cava, right and left renal veins, and left adrenal vein in 5 hypertensive patients (42±14 years) suspected of having renovascular hypertension. In study 3, peripheral venous blood samples were obtained in 2 patients (males, 45 and 36 years old) with pheochromocytoma at rest and during hypertensive attacks. Plasma adrenomedullin concentrations were measured by a newly developed radioimmunoassay. In study 1, there were no significant differences in plasma adrenomedullin concentrations in various sites of the right-side circulation. There was no step-up of plasma adrenomedullin levels in the coronary sinus. However, the plasma concentration of adrenomedullin in aorta was slightly but significantly lower than in pulmonary artery. In study 2, there was no difference of plasma adrenomedullin levels between right and left renal veins and aorta. The plasma concentration of adrenomedullin in left adrenal vein tended to be higher than in aorta, but not significantly. In study 3, the plasma adrenomedullin concentration did not increase at rest or even during a hypertensive attack in patients with pheochromocytoma, even though epinephrine and norepinephrine rose markedly. These results suggest that the adrenal glands, lungs, kidneys, and heart may not be the main sources of circulating adrenomedullin, despite the fact that these organs express adrenomedullin mRNA. The pulmonary circulation, however, may be one of the sites of adrenomedullin clearance.

DOI： 10.1161/01.HYP.24.5.600

Plasma levels of adrenomedullin, a newly identified hypotensive peptide, in patients with hypertension and renal failure 査読あり

Ishimitsu T., Nishikimi T., Saito Y., Kitamura K., Eto T., Kangawa K., Matsuo H., Omae T., Matsuoka H.

Journal of Clinical Investigation 94 ( 5 ) 2158 - 2161 1994年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Clinical Investigation

Adrenomedullin is a potent hypotensive peptide newly discovered in pheochromocytoma tissue by monitoring its elevating activity on platelet cAMP. We measured plasma concentration of adrenomedullin in patients with essential hypertension and chronic renal failure. As compared with normal subjects, plasma adrenomedullin was increased by 26% (P < 0.05) in hypertensives without organ damage and by 45% (P < 0.005) in those with organ damage. The increase in plasma adrenomedullin was more prominent in renal failure than in hypertension. Renal failure patients with plasma creatinine of 1.5-3, 3-6, and > 6 mg/dl had higher plasma adrenomedullin levels than healthy subjects by 78% (P < 0.05), 131% (P < 0.001), and 214% (P < 0.001), respectively. Moreover, adrenomedullin showed intimate correlations with norepinephrine, atrial natriuretic peptide, and cAMP in plasma (r = 0.625, P < 0.001; r = 0.656, P < 0.001; and r = 0.462, P < 0.001; respectively). Thus, plasma adrenomedullin is supposed to increase in association with changes in sympathetic nervous activity and body fluid volume in hypertension and renal failure. Considering its potent vasodilator effect, adrenomedullin may be involved in the defense mechanism preserving the integrity of the cardiovascular system in these disorders.

DOI： 10.1172/JCI117573

Distribution and characterization of immunoreactive rat adrenomedullin in tissue and plasma 査読あり

Sakata J., Shimokubo T., Kitamura K., Nishizono M., Iehiki Y., Kangawa K., Matsuo H., Eto T.

FEBS Letters 352 ( 2 ) 105 - 108 1994年9月

掲載種別：研究論文（学術雑誌）出版者・発行元：FEBS Letters

Adrenomedullin is a new bioactive peptide recently isolated from pheochromocytoma. We report on the rat adrenomedullin distribution and molecular forms in various tissues and plasma. Using a sensitive radioimmunoassay system for rat adrenomedullin, high concentrations of immunoreactive rat adrenomedullin were detected in adrenal gland, lung and cardiac atrium. In lung and atrium, the immunoreactivity concentration in rat was about 6-10 times higher than that in human. The mean plasma concentration of immunoreactive rat adrenomedullin was 3.60 ±0.34 fmol/ml (mean ± S.D.). Analysis in adrenal gland, lung and atrium with reverse-phase and gel-filtration high-performance liquid chromatography showed that most immunoreactive rat adrenomedullin emerged as a single peak at a position exactly identical to that of the authentic rat adrenomedullin peptide, synthesized according to the sequence predicted from the cDNA. © 1994.

DOI： 10.1016/0014-5793(94)00928-7

Production and secretion of adrenomedullin from vascular smooth muscle cells: Augmented production by tumor necrosis factor-α 査読あり

Sugo S., Minamino N., Shoji H., Kangawa K., Kitamura K., Eto T., Matsuo H.

Biochemical and Biophysical Research Communications 203 ( 1 ) 719 - 726 1994年8月

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

In this study, we demonstrate production and secretion of adrenomedullin (AM) from cultured vascular smooth muscle cells (VSMCs). In addition to endothelial cells (ECs), we found immunoreactive (ir-) AM in culture media of rat and bovine VSMCs in the survey for AM-producing cells. Although the secretion level of ir-AM was at most 1/6 that of rat ECs, all the examined VSMCs were shown to produce AM. By gel filtration, reverse phase high-performance liquid chromatography, and biological characterization, ir-AM in the culture medium was identified to be rat AM of 50 residues. By RNA blot analysis, a positive band of AM mRNA was detected in cultured VSMC at an intensity 3-4 fold higher than that in adrenal gland. Gene expression and production of AM were markedly augmented by tumor necrosis factor-α. Based on these data as well as the presence of AM specific receptors on VSMCs, AM secreted from VSMC is deduced to function as an autocrine or paracrine regulatory in vascular cell communication. © 1994 by Academic Press, Inc.

DOI： 10.1006/bbrc.1994.2241

Genomic structure of human adrenomedullin gene 査読あり

Ishimitsu T., Kojima M., Kangawa K., Hino J., Matsuoka H., Kitamura K., Eto T., Matsuo H.

Biochemical and Biophysical Research Communications 203 ( 1 ) 631 - 639 1994年8月

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

Adrenomedullin (AM) is a potent hypotensive peptide recently discovered from human pheochromocytoma tissue by its stimulating activity of platelet cAMP production. In this study, we have isolated the gene for human AM from a human genomic library and determined its structure. The genomic DNA of human AM consists of 4 exons and 3 introns, and the 5′ flanking region contains TATA, CAAT and GC boxes. There are also multiple binding sites for activator protein-2 (AP-2) and a cAMP-regulated enhancer element. Southern blot analyses revealed that the AM gene is situated in a single locus of chromosome 11. These indicate that the human AM gene has components for its functional expression and that the expression may be subject to the activity of protein kinase C and the feedback from cAMP level. © 1994 by Academic Press, Inc.

DOI： 10.1006/bbrc.1994.2229

Identification and hypotensive activity of proadrenomedullin N-terminal 20 peptide (PAMP) 査読あり

Kitamura K., Kangawa K., Ishiyama Y., Washimine H., Ichiki Y., Kawamoto M., Minamino N., Matsuo H., Eto T.

FEBS Letters 351 ( 1 ) 35 - 37 1994年8月

掲載種別：研究論文（学術雑誌）出版者・発行元：FEBS Letters

Proadrenomedullin N-terminal 20 peptide (PAMP) is a candidate for a novel biologically active peptide processed from an adrenomedullin precursor. Using a radioimmunoassay for human PAMP, major and minor immunoreactive PAMPs were purified from porcine adrenal medulla and complete amino acid sequences were determined. The major immunoreactive peptide was PAMP itself with an amidated carboxy terminus. The minor one was determined to be PAMP[5-20]. An intravenous bolus injection of human PAMP in anesthetized rats caused a rapid and strong hypotensive effect in a dose dependent manner. The present data indicate that PAMP is an endogenous biologically active peptide which is processed from adrenomedullin precursor. © 1994.

DOI： 10.1016/0014-5793(94)00810-8

Immunoreactive proadrenomedullin N-terminal 20 peptide in human tissue, plasma and urine 査読あり

Washimine H., Kitamura K., Ichiki Y., Yamamoto Y., Kangawa K., Matsuo H., Eto T.

Biochemical and Biophysical Research Communications 202 ( 2 ) 1081 - 1087 1994年7月

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

Proadrenomedullin N-terminal 20 peptide (PAMP) is a candidate for a novel biologically active peptide processed from proadrenomedullin. This study clearly demonstrates the existence of PAMP in vivo that had been deduced from analysis of cDNA. To identify PAMP in vivo, we established a radioimmunoassay for PAMP and characterized immunoreactivities in human tissue, plasma and urine. Half maximal inhibition of the assay was observed at 10 fmol/tube. A high concentration of immunoreactive PAMP was found in adrenal medulla (18.4 ± 8.95 fmol/mg, mean ± S.D.) and pheochromocytoma tissue (12.3 ± 9.82 fmol/mg) where the concentrations are comparable to that of adrenomedullin. As determined by three different kinds of chromatography, most of the immunoreactive peptide in pheochromocytoma was eluted at a position exactly identical to that of synthetic PAMP. Further, considerable concentration of immunoreactive PAMP was found in human plasma and urine. The present data indicate that PAMP as well as adrenomedullin is processed from an adrenomedullin precursor. © 1994 Academic Press, Inc.

DOI： 10.1006/bbrc.1994.2039

Ca(2+)-dependent cosecretion of adrenomedullin and catecholamines mediated by nicotinic receptors in bovine cultured adrenal medullary cells 査読あり

Katoha F., Niina H., Kitamura K., Ichiki Y., Yamamoto Y., Kangawa K., Eto T., Wada A.

FEBS Letters 348 ( 1 ) 61 - 64 1994年7月

掲載種別：研究論文（学術雑誌）出版者・発行元：FEBS Letters

Bovine cultured adrenal medullary cells (4 × 106) contained 4266.5 ± 370.0 fmol of immunoreactive adrenomedullin and 373.4 ± 32.6 mnol of catecholamines. Nicotinic (but not muscarinic) receptors mediated the Ca2+-dependent co-secretion of adrenomedullin and catecholamines, with the molar ratio of adrenomedullin/catecholamines secreted into the medium being equal to the ratio stored in the cells. The concentration-response curve of carbachol for adrenomedullin secretion (EC50 42 μM) was similar to that for catecholamine secretion (EC50 63 μM). Reverse phase HPLC analysis showed that immunoreactive adrenomedullins in the cells and secreted into the medium were both eluted exclusively at the position almost identical to synthetic human adrenomedullin[1-52]NH2. © 1994.

DOI： 10.1016/0014-5793(94)00566-4

Endothelial Cells Actively Synthesize and Secrete Adrenomedullin 査読あり

Sugo S., Minamino N., Kangawa K., Miyamoto K., Kitamura K., Sakata J., Eto T., Matsuo H.

Biochemical and Biophysical Research Communications 201 ( 3 ) 1160 - 1166 1994年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

This study demonstrates active production of adrenomedullin (AM) in cultured vascular endothelial cells (ECs). To identify the origin of plasma AM and its functional relationship to vascular smooth muscle cells (VSMCs), we checked production of AM in a series of tissues and cell lines and found immunoreactive (ir-) AM in culture media of rat, porcine, human and bovine ECs. Ir-AM was accumulated linearly for up to 48 hours in the culture medium of rat ECs, and the secretion rate of AM was almost comparable to that of endothelin-1. By gel filtration and reverse phase high performance liquid chromatography, ir-AM in the culture medium was shown to have chromatographic behavior indistinguishable from that of synthetic rat AM. By RNA blot analysis of rat tissue, the most highly positive band was detected in cultured ECs, at an intensity 20 to 40 fold higher than that in adrenal gland. Based on these data as well as the presence of AM specific receptor on VSMCs, AM secreted from ECs is deduced to act directly on VSMCs, regulating vascular tone. © 1994 Academic Press. All rights reserved.

DOI： 10.1006/bbrc.1994.1827

Adrenomedullin stimulates cyclic amp formation in rat vascular smooth muscle cells 査読あり

Ishizaka Y., Ishizaka Y., Tanaka M., Kitamura K., Kangawa K., Minamino N., Matsuo H., Eto T.

Biochemical and Biophysical Research Communications 200 ( 1 ) 642 - 646 1994年4月

掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

A newly identified human peptide, adrenomedullin (AM) increased cAMP levels with dose and time dependencies in a manner similar to that of human calcitonin gene-related peptide (CGRP) in rat vascular smooth muscle cells (VSMC). The EC50 value of human AM is 2 x 10−8 M which is slightly higher than that of CGRP (8.5 x 10−9 M). In a receptor binding assay for AM in rat VSMC, the binding of [125I] AM was competitively inhibited by human AM, but not by human CGRP. Thus, AM is thought to increase intracellular cAMP in rat VSMC via its specific receptor to evoke vasodilation. © 1994 Academic Press, Inc.

DOI： 10.1006/bbrc.1994.1496

Immunoreactive adrenomedullin in human plasma 査読あり

Kitamura K., Ichiki Y., Tanaka M., Kawamoto M., Emura J., Sakakibara S., Kangawa K., Matsuo H., Eto T.

FEBS Letters 341 ( 2-3 ) 288 - 290 1994年3月

掲載種別：研究論文（学術雑誌）出版者・発行元：FEBS Letters

A specific and sensitive radioimmunoassay for adrenomedullin has been developed. Half-maximal inhibition of binding of radioiodinated adrenomedullin was observed at 4 tool/tube. The radioimmunoassay recognized the entire adrenomedullin molecule and has little crossreactivity with adrenomedullin fragment peptides. Adrenomedullin-like immunoreactivity was found to circulate in human plasma at considerable concentration (3.3 ± 0.39 fmol ml). The immunoreactivity of adrenomedullin was eluted at almost the same position as synthetic adrenomedullin on gel-filtration chromatography and reverse-phase high-performance liquid chromatography, suggesting that circulating adrenomedullin recognized by the present radioimmunoassay is identical or very similar to authentic adrenomedullin. Plasma immunoreactive adrenomedullin significantly increased in patients with hypertension, with a progressive rise proportionate to disease severity. © 1994.

DOI： 10.1016/0014-5793(94)80474-5

Complete amino acid sequence of porcine adrenomedullin and cloning of cDNA encoding its precursor 査読あり

Kitamura K., Kangawa K., Kojima M., Ichiki Y., Matsuo H., Eto T.

FEBS Letters 338 ( 3 ) 306 - 310 1994年2月

掲載種別：研究論文（学術雑誌）出版者・発行元：FEBS Letters

Porcine adrenomedullin was isolated from adrenal medulla extract and its amino acid sequence was determined. The peptide is identical to human adrenomedullin with a single replacement of Gly for Asn at position 40. The cDNA clone encoding the porcine adrenomedullin precursor was isolated and sequenced. The precursor for adrenomedullin (preproadrenomedullin) is 188 amino adds in length, including the adrenomedullin sequence, followed by a glycine (the amide donor). In addition to adrenomedullin, proadrenomedullin (proAM) contains a candidate for a unique 20-residue peptide, proAM-N20, whose carboxy-terminus may be amidated. By RNA blot analysis, porcine adrenomedullin mRNA was found to be highly expressed in several porcine tissues including lung and kidney as well as adrenal medulla. © 1994.

DOI： 10.1016/0014-5793(94)80289-0

Distribution and characterization of immunoreactive adrenomedullin in human tissue and plasma 査読あり

Ichiki Y., Kitamura K., Kangawa K., Kawamoto M., Matsuo H., Eto T.

FEBS Letters 338 ( 1 ) 6 - 10 1994年1月

掲載種別：研究論文（学術雑誌）出版者・発行元：FEBS Letters

A specific and sensitive radioimmunoassay for human adrenomedullin has been developed and distribution and characterization of immunoreactive adrenomedullin in human tissue were investigated. The radioimmunoassay specifically recognizes its carboxyterminal region and half maximal inhibition of binding of radioiodinated adrenomedullin(40-52)NH2 was observed at 11 fmol tube. Immunoreactive adrenomedullin was abundant in adrenal medulla (47.7 ± 26.1 fmol mg, mean ± S.D.) and was ubiquitously found in all tissue examined. The mean plasma concentration of adrenomedullin in three normal individuals was 17.2 ± 6.4 pg ml (mean ± S.D.). By analysis with reverse-phase high-performance liquid chromatography coupled with the radioimmunoassay, most immunoreactive adrenomedullin in the adrenal medulla, atrium and lung was found to be adrenomedullin(1-52)NH2. © 1994.

DOI： 10.1016/0014-5793(94)80106-1

ヒトproadrenomedullin N-terminal 20 peptide (proAM-N20) の生体内分布と分子型の検討査読あり

鷲峯久紀、北村和雄、市来能成、山本良髙、寒川賢治、江藤胤尚

日本内分泌学会雑誌 70 ( 3 ) 264 - 264 1994年

掲載種別：研究論文（学術雑誌）

培養ウシ副腎髄質細胞におけるadrenomedullin(AM)分泌に関する検討査読あり

加藤ふみ、北村和雄、市来能成、山本良髙、江藤胤尚、寒川賢治、和田明彦

日本内分泌学会雑誌 70 ( 3 ) 264 - 264 1994年

掲載種別：研究論文（学術雑誌）

褐色細胞腫由来血管拡張ペプチドadrenomedullin(AM)の腎作用に関する検討査読あり

平田恭信、北村和雄、江藤胤尚、寒川賢治、松尾壽之

日本内分泌学会雑誌 70 ( 3 ) 264 - 264 1994年

掲載種別：研究論文（学術雑誌）

降圧ペプチドアドレノメデュリン査読あり

北村和雄

産科と婦人科 61 ( 12 ) 1701 - 1705 1994年

掲載種別：研究論文（学術雑誌）

新しい降圧ペプチド“adrenomedullin”(AM)の研究：発見およびその臨床的意義査読あり

北村和雄、寒川賢治、市来能成、松尾壽之、江藤胤尚

日本内分泌学会雑誌 70 ( 3 ) 264 - 264 1994年

掲載種別：研究論文（学術雑誌）

Plasma Concentration of Human Brain Natriuretic Peptide in Patients on Hemodialysis 査読あり

Ishizaka Y., Yamamoto Y., Fukunaga T., Yokota N., Kida O., Kitamura K., Kangawa K., Minamino N., Matsuo H., Eto T.

American Journal of Kidney Diseases 24 ( 3 ) 461 - 472 1994年

掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Kidney Diseases

The plasma concentration of immunoreactive human brain natriuretic peptide (ir-BNP) was measured in 40 patients on hemodialysis (HD) and in 12 healthy subjects. Immunoreactive human atrial natriuretic peptide (ir-ANP) was also measured. The mean (+SE) plasma it-BNP concentration in the patients before HD (18.4 + 3.4 fmol/mL) was markedly higher than that in the control group (0.39 ± 0.08 fmol/mL). The plasma it-BNP level was significantly decreased by HD from 18.4 ± 3.4 fmol/mL to 10.5 ± 2.2 fmol/mL (P < 0.001), but the latter value was still higher than the upper limit of the normal range for our laboratory. There were significant correlations between the plasma it-ANP level and the mean blood pressure before HD (P < 0.05) and between the HD-induced changes in plasma it-ANP level and mean blood pressure (P < 0.001). These correlations were not observed between the plasma it-BNP level and mean blood pressure. The plasma it-BNP level correlated with the cardiothoracic ratio and this correlation was closer to that between the plasma ir-ANP level and cardiothoracic ratio. Ultrasound echocardiographic studies in 13 patients revealed that the pre-HD state of high cardiac output was corrected by HD in association with decreases in plasma ir-BNP and ir-ANP levels. Correlations were observed between the pre-HD it-ANP level and the interventricular septal thickness index (r = 0.68, P < 0.05) and between the change in it-BNP level and that in left atria) diameter (r = 0.806, P < 0.001). In conclusion, BNP levels were high in HD patients compared with the control subjects and were decreased during HD. In addition, BNP and ANP levels correlated with several parameters of volume change and cardiac status. © 1994, National Kidney Foundation. All rights reserved. All rights reserved.

DOI： 10.1016/S0272-6386(12)80903-6

Cardiac Content and Plasma Concentration of Atrial Natriuretic Polypeptide (ANP) in Spontaneously Hypertensive Rats (SHR) 査読あり

Pheochromocytoma associated with nocturnal hypertension 査読あり

Y Ishiyama 1, T Ohgi, T Kita, A Sasaki, K Kitamura, O Kida, T Kawasaki, T Eto

Intern Med . 32 ( 10 ) 781 - 783 1993年10月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.2169/internalmedicine.32.781.

Vasodilator effect of adrenomedullin and calcitonin gene-related peptide receptors in rat mesenteric vascular beds 査読あり

C Nuki 1, H Kawasaki, K Kitamura, M Takenaga, K Kangawa, T Eto, A Wada

Biochem Biophys Res Commun . 15 ( 196（1） ) 245 - 251 1993年10月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1006/bbrc.1993.2241.

Hemodynamic effects of a novel hypotensive peptide, human adrenomedullin, in rats 査読あり

Y Ishiyama 1, K Kitamura, Y Ichiki, S Nakamura, O Kida, K Kangawa, T Eto

Eur J Pharmacol . 14 ( 241（2-3） ) 271 - 273 1993年9月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/0014-2999(93)90214-3.

Molecular cloning and biological activities of rat adrenomedullin, a hypotensive peptide 査読あり

J Sakata 1, T Shimokubo, K Kitamura, S Nakamura, K Kangawa, H Matsuo, T Eto

Biochem Biophys Res Commun . 15 ( 195（2） ) 245 - 251 1993年9月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1006/bbrc.1993.2132.

Alterations in circulating and cardiac tissue concentrations of brain natriuretic peptide in spontaneously hypertensive rats 査読あり

N Yokota 1, Y Yamamoto, K Kitamura, K Kangawa, N Minamino, H Matsuo, T Eto

Cardiovasc Res . 27 ( 7 ) 1312 - 1315 1993年7月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1093/cvr/27.7.1312.

Dimeric form of calcitonin gene-related peptide in the porcine thyroid gland 査読あり

Y Ichiki 1, K Kitamura, K Kangawa, T Eto

Biochem Biophys Res Commun . 31 ( 191（3） ) 961 - 967 1993年3月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1006/bbrc.1993.1311.

Platelet neuropeptide Y in spontaneously hypertensive rats 査読あり

T Ogawa 1, K Kitamura, K Kangawa, H Matsuo, T Eto

J Hypertens . 10 ( 8 ) 765 - 771 1992年8月

掲載種別：研究論文（学術雑誌）

Organ distribution and characterization of porcine peptides (VIP, CGRP and PHI) that increase cAMP in rat platelets 査読あり

Y Ichiki 1, K Kitamura, K Kangawa, M Kawamoto, H Matsuo, T Eto

Biochem Biophys Res Commun 30 ( 187（3） ) 1587 - 1593 1992年7月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/0006-291x(92)90484-3.

Isolation and characterization of peptides which act on rat platelets, from a pheochromocytoma 査読あり

K Kitamura 1, K Kangawa, M Kawamoto, Y Ichiki, H Matsuo, T Eto

Biochem Biophys Res Commun 29 ( 185（1） ) 134 - 141 1992年5月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/s0006-291x(05)80966-0.

Immunoreactive endothelin in human kidney 査読あり

S Morita 1, K Kitamura, Y Yamamoto, T Eto, Y Osada, A Sumiyoshi, M Koono, K Tanaka

Ann Clin Biochem 28 ( Pt 3 ) 267 - 271 1991年5月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1177/000456329102800312.

Increased secretion of brain natriuretic peptide and atrial natriuretic peptide, but not sufficient to induce natriuresis in rats with nephrotic syndrome 査読あり

N Yokota 1, Y Yamamoto, M Aburaya, K Kitamura, T Eto, K Kangawa, N Minamino, H Matsuo, K Tanaka

Biochem Biophys Res Commun 15 ( 174（1） ) 128 - 135 1991年1月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/0006-291x(91)90495-s.

Renal tubular lesions induced by human Bence Jones protein in the rat N-acetyl-beta-D-glucosaminidase as a sensitive marker 査読あり

N Yokota 1, Y Yamamoto, K Kitamura, N Kuroki, S Hisanaga, S Fujimoto, T Eto, K Tanaka

Int J Exp Pathol 72 ( 3 ) 255 - 262 1991年1月

掲載種別：研究論文（学術雑誌）

ネフローゼラットの心臓におけるneuropeptide Y(ir-NPY)およびir-ANP含量の検討査読あり

家村文夫、横田直人、北村和雄、山本良髙、江藤胤尚

日本内分泌学会雑誌 67 ( 4 ) 375 - 375 1991年

掲載種別：研究論文（学術雑誌）

Cardiac content of brain natriuretic peptide in DOCA salt-hypertensive rats 査読あり

N Yokota 1, M Aburaya, Y Yamamoto, J Kato, K Kitamura, O Kida, T Eto, N Minamino, K Kangawa, H Matsuo

Life Sci 48 ( 5 ) 397 - 402 1991年

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/0024-3205(91)90494-v.

Preferential increase in the free form of atrial natriuretic peptide in adriamycin-induced nephrotic rats 査読あり

N Yokota 1, J Kato, Y Yamamoto, K Kitamura, O Kida, T Eto, K Tanaka

Nephron 59 ( 1 ) 61 - 65 1991年

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1159/000186519.

Increased plasma brain natriuretic peptide levels in DOCA-salt hypertensive rats relation to blood pressure and cardiac concentration 査読あり

Biochem Biophys Res Commun

N Yokota 1, M Aburaya, Y Yamamoto, J Kato, K Kitamura, O Kida, T Eto, N Minamino, K Kangawa, H Matsuo, 14 ( 173（2） ) 632 - 638 1990年10月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/s0006-291x(05)80082-8.

Distribution and molecular form of immunoreactive big endothelin-1 in porcine tissue 査読あり

K Kitamura 1, T Yukawa, S Morita, Y Ichiki, T Eto, K Tanaka

Biochem Biophys Res Commun 31 ( 170（2） ) 497 - 503 1990年7月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/0006-291x(90)92119-k.

Isolation of NPY-25 (neuropeptide Y[12-36]), a potent inhibitor of calmodulin, from porcine brain 査読あり

K Kitamura 1, K Kangawa, K Tanaka, H Matsuo

Biochem Biophys Res Commun . 29 ( 169（3） ) 497 - 503 1990年6月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/0006-291x(90)92018-u.

Chromatographic characterization of immunoreactive endothelin in rat lung 査読あり

K Kitamura , T Tanaka, J Kato, T Eto, K Tanaka

Life Sci 46 ( 6 ) 405 - 409 1990年

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/0024-3205(90)90083-4.

Increased immunoreactive neuropeptide Y in platelets of spontaneously hypertensive rats (SHR) 査読あり

T Ogawa 1, K Kitamura, M Kawamoto, T Eto, K Tanaka

Biochem Biophys Res Commun 29 ( 165（3） ) 1399 - 1405 1989年12月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/0006-291x(89)92759-9.

Immunoreactive endothelin in rat kidney inner medulla marked decrease in spontaneously hypertensive rats 査読あり

K Kitamura 1, T Tanaka, J Kato, T Ogawa, T Eto, K Tanaka

Biochem Biophys Res Commun 14 ( 162（1） ) 38 - 44 1989年7月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/0006-291x(89)91958-x.

Regional distribution of immunoreactive endothelin in porcine tissue abundance in inner medulla of kidney 査読あり

K Kitamura 1, T Tanaka, J Kato, T Eto, K Tanaka

Biochem Biophys Res Commun 30 ( 161（1） ) 348 - 352 1989年5月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/0006-291x(89)91603-3.

Catalytic site of rat liver and bovine heart fructose-6-phosphate,2-kinasefructose-2,6-bisphosphatase 査読あり

K Kitamura , K Uyeda, F C Hartman, K Kangawa, H Matsuo

J Biol Chem 15 ( 264（11） ) 6344 - 6348 1989年4月

掲載種別：研究論文（学術雑誌）

Phosphorylation of myocardial fructose-6-phosphate,2-kinase: fructose-2,6-bisphosphatase by cAMP-dependent protein kinase and protein kinase C. Activation by phosphorylation and amino acid sequences of the phosphorylation sites 査読あり

K Kitamura , K Kangawa, H Matsuo, K Uyeda

J Biol Chem 15 ( 263（32） ) 16796 - 16801 1988年11月

掲載種別：研究論文（学術雑誌）

Isozymes of fructose 6-phosphate,2-kinasefructose-2,6-bisphosphatase in rat and bovine heart, liver, and skeletal muscle 査読あり

M Taniyama , K Kitamura, H Thomas, J W Lawson, K Uyeda

Biochem Biophys Res Commun 30 ( 157（3） ) 949 - 954 1988年10月

掲載種別：研究論文（学術雑誌）

DOI： doi: 10.1016/s0006-291x(88)80966-5.

Immunoreactive neuromedin B and neuromedin C distribution and molecular heterogeneity in rat and human tissue extracts 査読あり

A Sakamoto , K Kitamura, Y Haraguchi, T Yoshida, K Tanaka

Am J Gastroenterol 82 ( 10 ) 1035 - 1041 1987年10月

掲載種別：研究論文（学術雑誌）

Plasma concentration of human atrial natriuretic polypeptide in patients with impaired renal function 査読あり

Y Yamamoto, T Higa, K Kitamura, K Tanaka, K Kangawa, H Matsuo

Clin Nephrol 27 ( 2 ) 84 - 86 1987年2月

掲載種別：研究論文（学術雑誌）

The mechanism of activation of heart fructose 6-phosphate,2-kinasefructose-2,6-bisphosphatase 査読あり

K Kitamura, K Uyeda

J Biol Chem 15 ( 262（2） ) 679 - 681 1987年1月

掲載種別：研究論文（学術雑誌）

Plasma concentration of atrial natriuretic polypeptide in chronic hemodialysis patients 査読あり

Y Yamamoto, T Higa, K Kitamura, K Tanaka, K Kangawa, H Matsuo

Clin Nephrol 27 ( 2 ) 84 - 6 1987年

掲載種別：研究論文（学術雑誌）

Higa T., Kitamura K., Tanaka K., Miyata A., Kangawa K., Matsuo H.

Japanese Circulation Journal 49 ( 9 ) 973 - 979 1985年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Circulation Journal

The cardiac content and plasma concentration of atrial natriuretic polypeptide (ANP) in hypertensive rats were measured by using radioimmunoassay for ANP. The animals used in this study were young (5-week-old) and adult (12- to 14-week-old) spontaneously hypertensive rats (SHR), stroke- prone SHR (SHR-SP) and normotensive control Wistar-Kyoto rats (WKY). Most immunoreactive ANP in the cardiac extract of the hypertensive rats (both SHR and SHR-SP) was found to be predominantly γ-form as well as that of WKY. Cardiac ANP content in adult SHR and SHR-SP was significantly lower than in adult WKY (p < 0.01), although there were no differences among three groups in young rats. Similar tendencies were also observed for plasma ANP concentration. The level of plasma in adult hypertensive rats was significantly lower or tended to be lower than in adult normotensive rats. Furthermore, a high negative correlation was present between blood pressure and cardiac ANP content (r = -0.748, p < 0.01) and between blood pressure and plasma ANP concentration (r = -0.608, p < 0.01) in all adult rats but there were no such relationships in young rats. The present study suggests that atrial natriuretic polypeptide may contribute to the pathogenesis or maintenance of high blood pressure in the genetic hypertensive rats. © 1985, The Japanese Circulation Society. All rights reserved.

DOI： 10.1253/jcj.49.973

Plasma concentration of atrial natriuretic polypeptide in chronic hemodialysis patients 査読あり

Y Yamamoto, T Higa, K Kitamura, K Tanaka, K Kangawa, H Matsuo

Regul Pept Suppl 4 110 - 112 1985年

掲載種別：研究論文（学術雑誌）

Regional distribution of β-neo-endorphin in rat brain and pituitary 査読あり

Kitamura K., Minamino N., Hayashi Y., Kangawa K., Matsuo H.

Biochemical and Biophysical Research Communications 109 ( 3 ) 966 - 974 1982年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

A highly specific and sensitive radioimmunoassay for β-neo-endorphin was developed, by using an antiserum against β-neo-endorphin. With this assay, the regional distribution of β-neo-endorphin was determined in rat brain and pituitary, and compared with that of α-neo-endorphin, which was assayed in the same samples. β-Neo-endorphin was found to be concentrated in the pituitary, especially in the posterior lobe, like α-neo-endorphin. β-Neo-endorphin was also widely distributed in brain, but in a different manner than α-neo-endorphin. Remarkable differences were observed in hippocampus, striatum and cortex, where α-neo-endorphin was found to predominate over β-neo-endorphin. The fact suggests that both peptides, although they are structurally related, possess different physiological functions. © 1982.

DOI： 10.1016/0006-291X(82)92034-4

腸管に存在するエンケフアリン関連ペプチド査読あり

北村和雄、松尾寿之

日本内分泌学会雑誌　秋季大会抄録号　 58 ( suppl-1 ) 1180 - 1180 1982年

掲載種別：研究論文（学術雑誌）

Regional distribution of α-neo-endorphin in rat brain and pituitary 査読あり

Minamino N., Kitamura K., Hayashi Y., Kangawa K., Matsuo H.

Biochemical and Biophysical Research Communications 102 ( 1 ) 226 - 234 1981年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

α-Neo-endorphin was isolated as the first form of "big" Leu-enkephalin and its complete amino acid sequence has recently been established. Using an antiserum raised against synthetic α-neo-endorphin, a highly sentitive and specific radioimmunoassay was developed. The antiserum practically possesses no cross-reactivity to Leu-enkephalin, dynorphin[1-13] and PH-8P, and very little to β-neo-endorphin. Distribution of α-neo-endorphin has been determined in rat brain and pituitary by the use of the highly specific antiserum. The highest concentration was observed at posterior lobe of pituitary. Furthermore, immunoreactive α-neo-endorphin was characterized by gel-filtration and high performance liquid chromatography, and shown to be identical with authentic α-neo-endorphin. © 1981.

DOI： 10.1016/0006-291X(81)91511-4