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