Papers - KITAMURA Kazuo
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Plasma Proadrenomedullin N-Terminal 20 Peptide (PAMP) in Patients with Congestive Heart Failure. Reviewed
Etoh T.
Horm.Metab.Res. 29 ( 1 ) 46 - 47 1997
Publishing type：Research paper (scientific journal)
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Khan A.I., Kato J., Kitamura K., Kangawa K., Eto T.
Clinical and Experimental Pharmacology and Physiology 24 ( 2 ) 139 - 142 1997
Publishing type：Research paper (scientific journal) Publisher：Clinical and Experimental Pharmacology and Physiology
1. The hypotensive effect of chronically infused human adrenomedullin (hAM), a potent vasodilator peptide that has been reported to have a natriuretic action, was examined In normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. Conscious WKY rats and SHR were infused with 200 ng/h synthetic hAM for 14 days by means of osmotic minipumps, Control groups were infused at the same schedule with 0.9% saline. Systolic blood pressure (SBP) and daily urinary excretion of Na+ and K+ were measured before and during the infusion period. In addition, plasma renin activity (PRA), aldosterone and hAM concentrations were measured on day 14 of infusion, 3. A significant reduction in SBP was observed in hAM treated SHR at day 2 and SBP remained significantly lower throughout the experiment compared with control SHR. Similarly, SBP in the hAM-treated WKY rats was found to be significantly lower than in control WKY rats during infusion, However, the hypotensive effect was not accompanied by any significant increase in urinary volume or Na+ excretion in hAM-treated rats of either strain. Chronic infusion with hAM significantly suppressed PRA and lowered the concentration of plasma aldosterone in WKY rats but not in SHR. The plasma hAM levels in treated WKY rats and SHR were 0.9 ± 0.4 and 0.6 ± 0.2 fmol/ml, respectively. 4. These findings demonstrate that chronically infused hAM has a hypotensive effect in both WKY rats and SHR without an increase in urinary volume or Na+ excretion at a plasma AM concentration within the physiological limit.
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Effect of exercise on plasma adrenomedullin and natriuretic peptide levels in myocardial infarction Reviewed
Morimoto A., Nishikimi T., Takaki H., Okano Y., Matsuoka H., Takishita S., Kitamura K., Miyata A., Kangawa K., Matsuo H.
Clinical and Experimental Pharmacology and Physiology 24 ( 5 ) 315 - 320 1997
Publishing type：Research paper (scientific journal) Publisher：Clinical and Experimental Pharmacology and Physiology
1. We investigated the effect of exercise on plasma adrenomedullin, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations and studied the relationship between these peptides and haemodynamic parameters in nine patients with old myocardial infarction (MI) and in eight normal subjects. 2. The exercise protocol consisted of two fixed work loads (40 and 80 W) for 4 min each and venous blood samples were taken at rest, during each exercise stage and after exercise while monitoring the mean arterial pressure (MAP) and heart rate (HR). In MI, pulmonary arterial pressure (PAP), pulmonary capillary wedge pressure (PCWP), left ventricular end-diastolic pressure (LVEDP) and cardiac output (CO) were measured throughout exercise. 3. Adrenomedullin levels did not significantly increase with exercise. Adrenomedullin levels correlated with PAP and PCWP at rest (P < 0.05). Atrial natriuretic peptide levels correlated with PAP, PCWP and LVEDP throughout exercise (P < 0.05) but, on multiple regression analysis, PCWP correlated only with ANP (P<0.01). Brain natriuretic peptide levels correlated with LVEDP throughout exercise (P < 0.01) and its increment correlated closely with basal BNP levels at rest (P < 0.01). 4. These results suggest that adrenomedullin does not respond to the acute haemodynamic changes of exercise, whereas ANP responds to it and PCWP is the major stimulus factor. Brain natriuretic peptide responds to exercise in proportion to the basal synthesis of BNP in patients with left ventricular dysfunction and LVEDP may play a role in increasing BNP during exercise.
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Adrenomedullin: a new hypotensive peptide Reviewed
K Kangawa 1, K Kitamura, N Minamino, T Eto, H Matsuo
J Hypertens Suppl 14 ( 5 ) s105 - s110 1996.12
Publishing type：Research paper (scientific journal)
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Adrenomedullin-sensitive receptors are preferentially expressed in cultured rat mesangial cells Reviewed
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 1996.11
Publishing type：Research paper (scientific journal) Publisher：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 1996.10
Publishing type：Research paper (scientific journal) Publisher：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 Reviewed
Yamaguchi T., Baba K., Doi Y., Yano K., Kitamura K., Eto T.
Hypertension 28 ( 2 ) 308 - 314 1996.8
Publishing type：Research paper (scientific journal) Publisher：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. Reviewed
H Yoshida 1, K Kitamura, K Tanaka, S Omura, T Miyazaki, T Hachiya, R Ohno, T Naoe
Cancer Res 1;56 ( 13 ) 2945 - 2948 1996.7
Publishing type：Research paper (scientific journal)
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Proadrenomedullin N-terminal 20 peptide is rapidly cleaved by neutral endopeptidase Reviewed
Nagatomo Y., Kitamura K., Kangawa K., Fujimoto Y., Eto T.
Biochemical and Biophysical Research Communications 223 ( 3 ) 539 - 543 1996.6
Publishing type：Research paper (scientific journal) Publisher：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 Toshio, Matsuoka Hiroaki, Ishikawa Kazuhiko, Yoshihara Fumiki, Kawano Yuhei, Kitamura Kazuo, Saito Yoshihiko, Kangawa Kenji, Matsuo Hisayuki, Omae Teruo
Hypertension Research 19 ( 2 ) 97 - 101 1996.6
Language：English Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Hypertension
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 270/160mmHg 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. (<i>Hypertens Res</i> 1996; 19: 97-101)
DOI： 10.1291/hypres.19.97
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Adrenomedullin and proadrenomedullin N-terminal 20 peptide in impaired renal function Reviewed
T Eto 1, H Washimine, J Kato, K Kitamura, Y Yamamoto
Kidney Int Suppl 55 s148 - s149 1996.6
Publishing type：Research paper (scientific journal)
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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 Reviewed
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 1996.2
Publishing type：Research paper (scientific journal)
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Nitric oxide-dependent hypotensive effects of adrenomedullin in rats Reviewed
Kazuki Matsunaga, Takanori Iwasaki, Yukio Yonetani, Kazuo Kitamura, Tanenao Eto, Kenji Kangawa, Hisayuki Matsuo
Drug Development Research 37 ( 1 ) 55 - 60 1996.1
Publishing type：Research paper (scientific journal)
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Plasma adrenomedullin concentration in patients with heart failure Reviewed
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 1996.1
Publishing type：Research paper (scientific journal)
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Increased plasma adrenomedullin in acute myocardial infarction Reviewed
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
Publishing type：Research paper (scientific journal) Publisher：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 Reviewed
Taniyama M., Kitamura K., Ban Y., Eto T., Katagiri T.
European Journal of Clinical Investigation 26 ( 6 ) 454 - 456 1996
Publishing type：Research paper (scientific journal) Publisher：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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新規降圧ペプチドPAMPのNEPによる代謝・分解の可能性 Reviewed
北村和雄
治療学 30 ( 8 ) 927 - 927 1996
Authorship：Lead author Publishing type：Research paper (scientific journal)
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ヒト血中アドレノメデュリン免疫活性の本態 Reviewed
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
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
北村和雄
心臓 28 ( 5 ) 452 - 460 1996
Publishing type：Research paper (scientific journal)
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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 Reviewed
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
Publishing type：Research paper (scientific journal)