論文 - 北村 和雄
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Increased plasma concentration of adrenomedullin in patients with subarachnoid hemorrhage 査読あり
Kikumoto K., Kubo A., Hayashi Y., Minamino N., Inoue S., Dohi K., Kitamura K., Kangawa K., Matsuo H., Furuya H.
Anesthesia and Analgesia 87 ( 4 ) 859 - 863 1998年10月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Anesthesia and Analgesia
Adrenomedullin (AM) is a potent hypotensive peptide originally identified in pheochromocytoma tissues. Impaired cardiovascular conditions, such as hypertension, myocardial infarction, and septic shock, stimulate production of AM. This study was performed to determine whether subarachnoid hemorrhage (SAH) altered plasma AM concentration. Plasma concentrations of AM in 17 patients with SAH were measured for 2 wk after the onset of SAH by AM- specific radioimmunoassay. Plasma concentrations of AM were increased in patients with SAH throughout the study period, compared with those in control subjects. Plasma concentrations of AM in patients classified as Hunt and Kosnik grade III or IV were significantly higher than those classified as Hunt and Kosnik grade I or II on the day of and the day after the onset of SAH. However, plasma concentrations of AM were unaffected by angiographic vasospasm. These findings suggest that plasma concentrations of AM are increased in patients with SAH and may reflect the severity of SAH. Implications: Adrenomedullin has been reported to affect the cerebral circulation. This study was performed to determine whether subarachnoid hemorrhage, a typical cerebrovascular disorder, altered plasma adrenomedullin concentrations. We found that plasma adrenomedullin concentrations increased in patients with Subarachnoid hemorrhage, although no relationship was found between plasma adrenomedullin concentration and angiographic vasospasm. Plasma adrenomedullin concentration may reflect the severity of hemorrhage.
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Adrenomedullin and related peptides 査読あり
Kitamura K.
Folia Pharmacologica Japonica 112 ( 3 ) 137 - 146 1998年9月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Folia Pharmacologica Japonica
'Adrenomedullin (AM)' is a novel hypotensive peptide discovered in human pheochromocytoma by monitoring the elevating activity of platelet cAMP. It has potent and long-lasting vasodilator effects in several vascular systems. In addition, a novel 20-residue hypotensive peptide, termed 'proadrenomedullin N-terminal 20 peptide' (PAMP), is processed from proadrenomedullin. Although initially isolated from human pheochromocytoma tissue and porcine adrenal medullae, AM mRNA is highly expressed in several organs including cardiovascular tissues. Taken together with its widespread distribution and its ability to influence the bioactivity of cells in situ, AM may function as a paracrine or autocrine hormone rather than a classical endocrine system. Furthermore, ubiquitous expression of AM mRNA may indicate its various biological functions as well as the existence of a novel circulation control system. Plasma AM as well as PAMP concentrations significantly increased in various cardiovascular diseases including hypertension, chronic renal failure and congestive heart failure. The present review summarizes the recent advances in AM research and showed that AM and PAMP are important vasoactive peptides, such investigations should enable the elucidation of the basic physiologic mechanisms of novel circulatory homeostasis.
DOI： 10.1254/fpj.112.137
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Measurement of plasma and urinary adrenomedullin in patients with IgA nephropathy 査読あり
Kubo A., Iwano M., Minamino N., Sato H., Nishino T., Hirata E., Akai Y., Shiiki H., Kitamura K., Kangawa K., Matsuo H., Dohi K.
Nephron 78 ( 4 ) 389 - 394 1998年4月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Nephron
In this study, we measured plasma and urinary adrenomedullin (AM) concentrations in 47 patients with IgA nephropathy. Controls were 39 healthy volunteers. Plasma and urinary AM values were measured by specific radioimmunoassay. The plasma AM concentrations were higher, and the urinary AM levels were lower in patients with IgA nephropathy than in healthy volunteers. Plasma AM concentrations showed a positive correlation with serum creatinine and blood urea nitrogen, whereas urinary AM levels correlated negatively with serum creatinine and blood urea nitrogen. The plasma AM concentrations showed a positive correlation with fractional excretions of sodium and potassium. Renal biopsy specimens of patients without renal failure were scored for activity (percentage of glomeruli demonstrating cellular crescent formation, degree of mesangial proliferation and interstitial infiltration; total score = 9). Urinary AM levels were shown to be lower in the group with a high activity (score 3-9) as compared with the group with a low activity (score 0-2) based on renal biopsy. Thus, urinary levels of AM are affected by the degree of the activity in IgA nephropathy, and AM may participate in the pathophysiology of IgA nephropathy.
DOI： 10.1159/000044966
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Saita M., Shimokawa A., Kunitake T., Kato K., Hanamori T., Kitamura K., Eto T., Kannan H.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology 274 ( 4 43-4 ) R979 - R984 1998年4月
掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Physiology - Regulatory Integrative and Comparative Physiology
Adrenomedullin (ADM) is reported to be a peripherally acting hypotensive peptide, but its central actions are unclear. We investigated the effects of centrally administered ADM on blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) in conscious rats and sinoaortic-denervated (SAD) rats. We also investigated the receptors interacting with ADM using two putative antagonists. Intracerebroventricular administration of ADM in doses of 0.1 and 0.5 nmol/kg caused tachycardia and early inhibition of RSNA. Central ADM (1.0 nmol/kg) induced hypertension, tachycardia, and a decrease followed by an increase in RSNA. In SAD rats, increases in BP, HR, and RSNA at the late phase were enhanced by central ADM (1.0 nmol/kg), whereas the early decrease in RSNA remained. Thus the inhibition of RSNA via central ADM may be unrelated to the arterial baroreceptor reflex. Pretreatment with antagonists human calcitonin gene-related peptide-(8-37) and human ADM-(22- 52) significantly suppressed the central actions of ADM. The findings suggest that ADM is involved as a neuropeptide in the receptor-mediated central regulation of the cardiovascular system and RSNA.
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Nakamura T., Honda K., Ishikawa S.E., Kitamura K., Eto T., Saito T.
Endocrine Journal 45 ( 2 ) 241 - 246 1998年4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：Endocrine Journal
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 ± 0.44 pmol/l 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年3月
掲載種別：研究論文（学術雑誌） 出版者・発行元：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 S., Ishiyama Y., Matsuo T., Imamura T., Sakata J., Kitamura K., Koiwaya Y., Eto T.
Hypertension Research 21 ( 1 ) 23 - 28 1998年3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
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 inRNA 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) vs. 3.24±0.16 fmol/ml, p< 0.001; urinary AM, 16.36±3.21 vs. 36.12±6.09 fmol/ml, p<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.
DOI： 10.1291/hypres.21.23
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Adrenomedullin: A Possible Autocrine or Paracrine Inhibitor of Hypertrophy of Cardiomyocytes 査読あり
Tsuruda T., Kato J., Kitamura K., Kuwasako K., Imamura T., Koiwaya Y., Tsuji T., Kangawa K., Eto T.
Hypertension 31 ( 1 ) 505 - 510 1998年1月
掲載種別：研究論文（学術雑誌） 出版者・発行元：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 査読あり
Kitani M., Sakata J., Asada Y., Kitamura K., Eto T.
Annals of Clinical Biochemistry 35 ( 5 ) 643 - 648 1998年
掲載種別：研究論文（学術雑誌） 出版者・発行元：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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Kita T., Kitamura K., Kuwasako K., Kawamoto M., Eto T.
Journal of Hypertension 16 ( 12 SUPPL. ) 2057 - 2062 1998年
掲載種別：研究論文（学術雑誌） 出版者・発行元：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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アドレノメデュリンとPAMPの発見の経緯とその構造 査読あり
寒川賢治、北村和雄
医学のあゆみ 184 ( 1 ) 3 - 9 1998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と関連ペプチド 査読あり
北村和雄
日本薬理学雑誌 112 ( 3 ) 137 - 146 1998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とPAMP 査読あり
北村和雄
医学のあゆみ 185 ( 1 ) 71 - 74 1998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および関連ペプチドの測定と問題点 査読あり
北村和雄
医学のあゆみ 184 ( 1 ) 21 - 25 1998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および関連ペプチド 査読あり
北村和雄
循環科学 18 ( 12 ) 1132 - 1135 1998年
掲載種別：研究論文（学術雑誌）
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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 査読あり
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年
掲載種別：研究論文（学術雑誌）
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心血管系への生理作用 査読あり
石山雄一郎、北村和雄
医学のあゆみ 184 ( 1 ) 44 - 48 1998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 査読あり
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年
掲載種別：研究論文（学術雑誌）
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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 査読あり
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による循環調節 査読あり
江藤胤尚、北村和雄、加藤丈司
臨床高血圧 4 ( 3 ) 155 - 168 1998年
掲載種別：研究論文（学術雑誌）