Papers - KITAMURA Kazuo
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NAKAMURA TOMOATSU, HONDA KAZUFUMI, ISHIKAWA SAN-E, KITAMURA KAZUO, ETO TANENAO, SAITO TOSHIKAZU
Endocrine Journal 45 ( 2 ) 241 - 246 1998.4
Language：English Publishing type：Research paper (scientific journal) Publisher：The Japan Endocrine Society
The present study was undertaken to determine plasma adrenomedullin levels in patients with non-insulin dependent diabetes mellitus (NIDDM) to elucidate the potential involvement in the pathogenesis of diabetic complications. The patients were 24 males and 21 females with ages of 55±2.1 years (mean±SEM). Plasma adrenomedullin levels were 5.94±0.44pmol/<i>l</i> in patients with NIDDM, and were not affected by plasma glucose concentration. The plasma adrenomedullin increased dependent on the severity of diabetic nephropathy and retinopathy. Plasma levels of adrenomedullin positively correlated with various parameters, including serum creatinine levels, urinary excretion of protein, and systolic blood pressure. In contrast, there were negative correlations between the coefficient variation (CV) of RR intervals and plasma adrenomedullin, and between the conduction velocity of ulnar nerves and plasma adrenomedullin levels. These results indicate that the increase in plasma adrenomedullin was closely related to diabetic complications, which may be dependent on the development of microangiopathy.
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Kitamura K., Kato J., Kawamoto M., Tanaka M., Chino N., Kangawa K., Eto T.
Biochemical and Biophysical Research Communications 244 ( 2 ) 551 - 555 1998.3
Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
Adrenomedullin (AM), a potent vasodilator peptide, is processed from its AM precursor as glycine extended AM (AM-gly), an intermediate form of AM. Subsequently, mature AM is converted from AM-gly by enzymatic amidation. Using two kinds of radioimmunoassay which recognize the entire AM molecule (E-AM-RIA) and C-terminal amide structure (C-AM-RIA), human plasma AM immunoreactivity was chromatographically characterized. In analyses of gel filtration and reverse phase high-performance liquid chromatography, most of the AM immunoreactivity measured by E-AM-RIA was eluted at a position identical to where mature AM and AM-gly emerged and was not recognized by C-AM-RIA. These data show that immunoreactive AM measured by E-AM-RIA is not amidated. When amidated by peptidylglycine α-amidating enzyme, the immunoreactive AM was converted to a form that can be detected by C-AM-RIA. These results indicate that most of the total AM immunoreactivity measured by E-AM-RIA represents immunoreactivity of AM-gly and that the concentration of immunoreactive mature AM in plasma is much lower than that of AM-gly. In practice, plasma concentration of AM-gly and mature AM in healthy volunteers was 2.7 ± 0.18 fmol/ml and 0.48 ± 0.05 fmol/ml, respectively. Furthermore, plasma concentration of AM-gly and total AM was significantly elevated in patients with hypertension compared to normotensive control. The present data indicate that most of circulating plasma AM immunoreactivity is occupied by AM-gly, an intermediate form of AM, which may reflect the process of production of AM in tissues.
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Hirano Shuji, Ishiyama Yuichiro, Matsuo Takeshi, Imamura Takuroh, Sakata Junichiro, Kitamura Kazuo, Koiwaya Yasushi, Eto Tanenao
Hypertension Research 21 ( 1 ) 23 - 28 1998.3
Language：English Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Hypertension
Adrenomedullin (AM) is a peptide with potent vasodilatory and hypotensive properties. Plasma AM levels in rats with experimentally induced hypertension, such as Dahl salt-sensitive rats and two-kidney, one-clip hypertensive rats, are higher than those in normotensive rats. We previously noted, however, that plasma AM levels in spontaneously hypertensive rats (SHR) are similar to those in Wistar-Kyoto rats. To define the role of AM in rats with severe hypertension, we investigated changes in circulating and tissue AM levels in stroke-prone spontaneously hypertensive rats (SHRSP/Izm). The immunoreactive rat AM levels in plasma, urine, and tissue measured with a sensitive radioimmunoassay, and the AM mRNA levels in various tissues in 15-wk-old SHRSP/Izm were compared with those in age-matched Wistar-Kyoto rats (WKY/Izm). The plasma and urinary AM levels in SHRSP/Izm were significantly lower than those in WKY/Izm [plasma AM, 2.14±0.06 (SE) <i>vs</i>. 3.24±0.16fmol/ml, <i>p</i><0.001; urinary AM, 16.36+3.21 <i>vs</i>. 36.12±6.09fmol/ml, <i>p</i><0.01]. A negative correlation was found between the plasma AM level and the systolic blood pressure in both SHRSP/Izm and WKY/Izm. Reverse-phase high-performance liquid chromatography showed that the molecular components of plasma immunoreactive AM in SHRSP/Izm were similar to those in WKY/Izm. Furthermore, tissue AM levels in various organs in SHRSP/Izm were not lower than those in WKY/Izm. In conclusion, low levels of circulating AM may contribute to the maintenance of high blood pressure in 15-wk-old SHRSP/Izm. These low plasma AM levels may be caused by accelerated metabolism of circulating AM in SHRSP/Izm. (<i>Hypertens Res</i> 1998; 21: 23-28)
DOI： 10.1291/hypres.21.23
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Adrenomedullin: A Possible Autocrine or Paracrine Inhibitor of Hypertrophy of Cardiomyocytes Reviewed
Tsuruda T., Kato J., Kitamura K., Kuwasako K., Imamura T., Koiwaya Y., Tsuji T., Kangawa K., Eto T.
Hypertension 31 ( 1 ) 505 - 510 1998.1
Publishing type：Research paper (scientific journal) Publisher：Hypertension
Adrenomedullin (AM), a potent vasodilator peptide, exists in the cardiac ventricle; however, the role of AM in the ventricular tissue remains unknown. In the present study, we investigated the production and secretion of AM in cultured neonatal rat cardiomyocytes, and we examined the effect of AM on de novo protein synthesis in these cells by measuring [() C]phenylalanine incorporation. The cardiomyocytes cultured with serum-free media secreted AM into the media in a time-dependent manner at the rate of 12.2 +/- 0.5 fmol/10 cells/48 hours (mean +/- SEM). Angiotensin II (1 micro mol/L) or 10% fetal bovine serum significantly (P <.01) increased the AM secretion by 115% and 305%, respectively. In addition, Northern blot analysis of total RNA extracted from the myocytes disclosed the expression of prepro-AM mRNA of 1.6 kb. Synthetic AM at 1 micro mol/L significantly reduced the 10-6 mol/L angiotensin II- and 10% fetal bovine serum-stimulated [() C]phenylalanine incorporation into the cells, by 16% (P <.05) and 20% (P <.01), respectively. The inhibitory effect of AM on the angiotensin II-stimulated [() C]phenylalanine incorporation was abolished dose-dependently by a calcitonin gene-related peptide receptor antagonist, CGRP(8-37). Furthermore, blockade of the action of endogenous AM by either 10-6 mol/L CGRP(8-37) or anti-AM monoclonal antibody significantly enhanced the basal and 10-6 mol/L angiotensin II-stimulated [() C]phenylalanine incorporation. In summary, cultured neonatal rat cardiomyocytes produce and secrete AM, and the secreted AM inhibits the protein synthesis of these cells. Thus, AM may act on cardiomyocytes as an autocrine or a paracrine factor modulating the cardiac growth. (Hypertension. 1998;31[part 2]:505-510.). © 1998 Lippincott Williams & Wilkins, Inc.
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Distribution and expression of adrenomedullin in human gastrointestinal tissue Reviewed
Kitani M., Sakata J., Asada Y., Kitamura K., Eto T.
Annals of Clinical Biochemistry 35 ( 5 ) 643 - 648 1998
Publishing type：Research paper (scientific journal) Publisher：Annals of Clinical Biochemistry
Adrenomedullin (AM) is a biologically active peptide recently isolated from phaeochromocytoma. We report here the distribution and characterization of immunoreactive AM and gene expression of AM in human gastrointestinal tissue. Using a sensitive radioimmunoassay system for the peptide, immunoreactive human AM was detected in the stomach, duodenum, jejunum, ileum and colon. The AM concentration of these tissues was about 0.4-0.8 pmol/g wet tissue. Reverse phase and gel filtration high-performance liquid chromatographies showed that most of the immunoreactive AM in stomach and jejunum was identical to authentic human AM. By northern blot analysis, human AM mRNA was found to be expressed ubiquitously in the human gastrointestinal tissues. Furthermore, an immunohistochemical study revealed that immunoreactive AM cells were present in the gastrointestinal glands. These results suggest that AM may play some role as a gastrointestinal hormone.
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アドレノメデュリンと関連ペプチド Reviewed
北村和雄
日本薬理学雑誌 112 ( 3 ) 137 - 146 1998
Publishing type：Research paper (scientific journal)
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アドレノメデュリンとPAMP Reviewed
北村和雄
医学のあゆみ 185 ( 1 ) 71 - 74 1998
Publishing type：Research paper (scientific journal)
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アドレノメデュリンおよび関連ペプチドの測定と問題点 Reviewed
北村和雄
医学のあゆみ 184 ( 1 ) 21 - 25 1998
Publishing type：Research paper (scientific journal)
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アドレノメデュリンおよび関連ペプチド Reviewed
北村和雄
循環科学 18 ( 12 ) 1132 - 1135 1998
Publishing type：Research paper (scientific journal)
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循環器系疾患における血中成熟型および中間型アドレノメデュリンの動態と意義 Reviewed
平山直輝、北村和雄、江藤胤尚
日本内分泌学会雑誌 74 ( 2 ) 621 - 621 1998
Publishing type：Research paper (scientific journal)
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心血管系への生理作用 Reviewed
石山雄一郎、北村和雄
医学のあゆみ 184 ( 1 ) 44 - 48 1998
Publishing type：Research paper (scientific journal)
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アドレノメデュリンの心血管系及び交感神経系に対する作用への延髄最後野の関与 Reviewed
斉田光彦、加藤和男、國武孝人、花森隆充、北村和雄、江藤胤尚、河南洋
日本内分泌学会雑誌 74 ( 2 ) 619 - 619 1998
Publishing type：Research paper (scientific journal)
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バルーン頚動脈内皮傷害後の内膜肥厚に及ぼすアドレノメデュリン持続静注の効果の検討 Reviewed
松井英三郎、加藤丈司、北村和雄、江藤胤尚、浅田祐士郎、住吉昭信
日本内分泌学会雑誌 74 ( 2 ) 619 - 619 1998
Publishing type：Research paper (scientific journal)
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アドレノメデュリンによる循環調節 Reviewed
江藤胤尚、北村和雄、加藤丈司
臨床高血圧 4 ( 3 ) 155 - 168 1998
Publishing type：Research paper (scientific journal)
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アドレノメデュリンとPAMPの発見の経緯とその構造 Reviewed
寒川賢治、北村和雄
医学のあゆみ 184 ( 1 ) 3 - 9 1998
Publishing type：Research paper (scientific journal)
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Kita T., Kitamura K., Kuwasako K., Kawamoto M., Eto T.
Journal of Hypertension 16 ( 12 SUPPL. ) 2057 - 2062 1998
Publishing type：Research paper (scientific journal) Publisher：Journal of Hypertension
Objective. Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are novel hypotensive peptides produced from the same precursor. A relationship between AM and the renin-angiotensin-aldosterone (RAA) axis was reported in several studies, but the response of the above two peptides to short-term modulation of the RAA axis in humans is not yet clear. Here, we assessed the responses of AM and PAMP in patients with varying RAA system status, including renovascular hypertension (RVH) and primary aldosteronism (PA). Design and methods. Essential hypertension (EHT), RVH and PA patients were hospitalized and maintained on a standard diet (NaCl 10 g/day). The patients underwent a captopril (25 mg) loading test. A renin-secretion stimulating test (furosemide 1 mg/kg, i.v. + 2 h of walking) and an ACTH loading test were performed for the PA patients. The plasma renin activity (PRA), plasma aldosterone concentration (PAC), and plasma AM and PAMP levels were monitored before and after the loadings. Results. In the basal state, significantly higher concentrations of AM and PAMP were shown in the RVH patients compared to the other groups. AM and PAMP were significantly correlated with PRA but not PAC in all patients. The AM and PAMP levels were not affected by the captopril loading with or without a hypotensive reaction. The AM and PAMP levels were increased only slightly despite the large increase in PAC induced in the PA patients by the renin-secretion stimulating and ACTH loading tests. Conclusion. The responses of plasma AM and PAMP to a short-term modulation of the RAA system were relatively small, despite the correlations observed between PRA and AM or PAMP.
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Plasma adrenomedullin in cerebrovascular disease: a possible indicator of endothelial injury Reviewed
K Kuwasako 1, O Kida, K Kitamura, J Kato, T Eto
Int Angiol 16 ( 4 ) 272 - 279 1997.12
Publishing type：Research paper (scientific journal)
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Kuwasako K., Kitamura K., Ishiyama Y., Washimine H., Kato J., Kangawa K., Eto T.
FEBS Letters 414 ( 1 ) 105 - 110 1997.9
Publishing type：Research paper (scientific journal) Publisher：FEBS Letters
Proadrenomedullin N-terminal 20 peptide (PAMP-20) is a potent hypotensive peptide processed from the adrenomedullin (AM) precursor. We developed a specific radioimmunoassay which recognizes the C-terminal region of PAMP-20. Using this radioimmunoassay, the distribution of immunoreactive (ir-) PAMP was determined in porcine tissues. High concentrations of ir-PAMP were observed in the adrenal medulla and in the atrium, and these values were comparable to the corresponding; concentrations of ir-AM. The concentration of ir-PAMP was almost the same as that of ir-AM in the kidney, while ir-PAMP was significantly lower than ir-AM in the ventricle, lung, and aorta. Reversed-phase high performance liquid chromatography in each porcine tissue sample revealed that two major peaks of ir-PAMP existed: one emerged at a position identical to that of authentic porcine PAMP-20; the other unknown peak was eluted earlier. The unknown peptide was purified to homogeneity from porcine adrenal medulla, and its complete amino acid sequence was determined. This peptide was found to be PAMP[9-20] with a C-terminal amide structure, and was named PAMP-12. Intravenous injections of PAMP-12 in anesthetized rats showed a significant hypotensive effect in a dose-dependent fashion, and the effect was comparable to that of PAMP-20. These data indicate that PAMP-12, a major component of ir-PAMP, is processed from the AM precursor, as is PAMP-20, and may participate in cardiovascular control.
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Effect of chronically infused adrenomedullin in two-kidney, one-clip hypertensive rats Reviewed
Khan A.I., Kato J., Ishiyama Y., Kitamura K., Kangawa K., Eto T.
European Journal of Pharmacology 333 ( 2-3 ) 187 - 190 1997.8
Publishing type：Research paper (scientific journal) Publisher：European Journal of Pharmacology
The hypotensive effect of chronically infused adrenomedullin, a potent vasodilator peptide, was examined in conscious two-kidney, one-clip (2K-1C) hypertensive and sham-operated rats. They were infused with 1.0 μg/h of synthetic human adrenomedullin for 14 days by means of osmotic minipumps. Control groups were infused on the same schedule with 0.9% saline. Systolic blood pressure was measured before and during the infusion. Plasma renin activity, aldosterone and human adrenomedullin concentrations were determined at day 14 of the infusion. A significant reduction of systolic blood pressure was observed in the adrenomedullin-infused 2K-1C rats at day 4, and systolic blood pressure remained significantly lower throughout the experiment compared to that of the control 2K-1C. A similar hypotensive effect was seen in the adrenomedullin-infused sham-operated rats. Both the plasma renin activity and aldosterone concentrations of the adrenomedullin-infused 2K-1C and sham groups were significantly reduced compared to those of the respective control, whereas, the plasma human adrenomedullin concentration in the adrenomedullin-infused groups was found to be within the physiological range. These findings demonstrated that chronically infused adrenomedullin had a hypotensive effect accompanied by significant reductions of plasma renin activity and plasma aldosterone concentration in 2K-1C hypertensive and sham-operated rats.
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NAGATA N.
Anesth Analg 84 ( 6 ) 1193 - 1197 1997.6
Publishing type：Research paper (scientific journal)