論文 - 北村 和雄
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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
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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.
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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
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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）
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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）
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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）
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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）
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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）
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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）
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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.
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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.
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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.
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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.
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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.
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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）
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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）
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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）
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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）
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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.
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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