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