Papers - KITAMURA Kazuo
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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 Reviewed
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
Publishing type：Research paper (scientific journal)
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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 Reviewed
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
Publishing type：Research paper (scientific journal)
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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 Reviewed
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
Publishing type：Research paper (scientific journal)
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循環系の生理活性物質探索法 Reviewed
児島将康、北村和雄、寒川賢治
実験医学 14 ( 12 ) 1708 - 1713 1996
Publishing type：Research paper (scientific journal)
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アドレノメデュリンの役割 Reviewed
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
Publishing type：Research paper (scientific journal)
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新しい降圧ペプチド : アドレノメデュリンとPAMP Reviewed
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
Publishing type：Research paper (scientific journal)
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Ishimitsu T., Nishikimi T., Matsuoka H., Kangawa K., Kitamura K., Minami J.I., Matsuo H., Eto T.
Clinical Science 91 ( 3 ) 293 - 298 1996
Publishing type：Research paper (scientific journal) Publisher：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
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Adrenomedullin: A new modulator of vascular tone Reviewed
Kangawa K., Kitamura K., Minamino N., Matsuo H.
Journal of Cardiac Failure 2 ( SUPPL. 1 ) 1996
Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiac Failure
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Increased plasma adrenomedullin levels in chronic congestive heart failure Reviewed
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
Publishing type：Research paper (scientific journal) Publisher：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.
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Tanaka Miho, Ishizaka Yuko, Ishiyama Yuichiro, Kato Johji, Kida Osamu, Kitamura Kazuo, Kangawa Kenji, Eto Tanenao
Hypertension Research 19 ( 4 ) 239 - 245 1996
Language：English Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Hypertension
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 (<i>p</i><0.05). After treatment 4wk 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. (<i>Hypertens</i> <i>Res</i> 1996; 19: 239-245)
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Adrenomedullin-immunoreactive neurons in the paraventricular and supraoptic nuclei of the rat Reviewed
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 1995.12
Publishing type：Research paper (scientific journal) Publisher：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 Reviewed
H Washimine 1, Y Yamamoto, K Kitamura, M Tanaka, Y Ichiki, K Kangawa, H Matsuo, T Eto
Clin Nephrol 44 ( 6 ) 389 - 393 1995.12
Publishing type：Research paper (scientific journal)
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Increased plasma levels of adrenomedullin in patients with heart failure Reviewed
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 1995.11
Publishing type：Research paper (scientific journal) Publisher：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 1995.11
Publishing type：Research paper (scientific journal) Publisher：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 Reviewed
KATO J.
Am J Hypertens 8 ( 10 ) 997 - 1000 1995.10
Publishing type：Research paper (scientific journal)
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Ichiki Y., Kitamura K., Kangawa K., Kawamoto M., Matsuo H., Eto T.
Journal of Biochemistry 118 ( 4 ) 765 - 770 1995.10
Publishing type：Research paper (scientific journal) Publisher：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 1995.9
Publishing type：Research paper (scientific journal) Publisher：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 1995.9
Publishing type：Research paper (scientific journal) Publisher：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 Reviewed
Ishiyama Y., Kitamura K., Ichiki Y., Sakata J., Kida O., Kangawa K., Eto T.
Clinical and Experimental Pharmacology and Physiology 22 ( 9 ) 614 - 618 1995.9
Publishing type：Research paper (scientific journal) Publisher：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 Reviewed
Kato J., Kitamura K., Kangawa K., Eto T.
European Journal of Pharmacology: Molecular Pharmacology 289 ( 2 ) 383 - 385 1995.4
Publishing type：Research paper (scientific journal) Publisher：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.