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