| Project/Area Number |
06454344
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
内分泌・代謝学
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| Research Institution | NATIONAL CARDIOVASCULAR CENTER RESEARCH INSTITUTE |
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Principal Investigator |
KANGAWA Kenji National Cardiovasular Center Research Institution, Biochemistry, Director, 生化学部, 部長 (00112417)
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| Co-Investigator(Kenkyū-buntansha) |
KOJIMA Masayasu National Cardiovasular Center Research Institution, Biochemistry, Head, 生化学部, 室長 (20202062)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥7,300,000 (Direct Cost: ¥7,300,000)
Fiscal Year 1995: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1994: ¥5,700,000 (Direct Cost: ¥5,700,000)
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| Keywords | adrenomedullin (AM) / vasorelaxant peptide / cardiovascular disease / cAMP / cytokine / endotoxin shock / endothelial cells (EC) / vascular smooth muscle cells (VSMC) / 降圧ペプチド / 発現,分泌調節機序 / 培養血管内皮細胞(EC) / 培養血管び平滑筋細胞(VSMC) / 循環ホルモン / 局所因子 / 受容体解析 |
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| Research Abstract |
Adrenomedullin (AM) is a potent vasorelaxant peptide recently isolated from human pheochromocytoma tissue, and is structurally a member of CGRP family. mRNA of AM is highly expressed in several tissues including heart, lung and kidney as well as adrenal medulla. In this project, we have studied the expression and secretion of AM and characterization of its receptors.
The radioimmunoassay established for adrenomedullin has demonstrated that AM is circulating in blood and the plasma levels of AM in the patients of cardiovascular diseases are higher than those of healthy controls. We have found that cultured endothelial cells (EC) and vascular smooth muscle cells (VSMC) actively produce AM.Gene expression levels of AM in rat EC and VSMC were far higher than that in adrenal gland, and a significant levels of AMm RNA was detected in intact aorta.
Tumor necrosis factor (TNF), interleukin-1 (IL-1) and lipopolysaccharide (LPS), major factors inducing endotoxin shock, were shown to most potently
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stimulate production and gene transcription of AM both in VSMC and in EC.LPS injection into rat (5mg/kg) markedly increased plasma AM concentration (20 times of control), and positive AM gene transcription was observed in all the examined tissue of LPS-injected rat. These data indicate the possible paricipation of AM as a vasodilator in the blood pressure regulation in the endotoxin shock.
The receptors for AM in VSMC and EC have been characterized. AM and CGRP increased intracellular cAMP throuh their receptors both in VSMC and in EC.Both AM and CGRP-induced elevations of the cAMP in VSMC were abolished in the presence of CGRP-(8-37), a CGRP receptor antagonist. CGRP-(8-37) also inhibited the cAMP accumulation in EC by CGRP,but had no effect on that by AM.These findings indicate that at least two types of receptor for AM may be present, and one is specific for AM and the other is shared with AM and CGRP.The studies of action mechanism of AM suggest that NO pathway as well as cAMP pathway may be involved in the regulation of cardiovascular system by AM.
The present study indicates the presence of a local regulatory system of vascular tone by AM in the blood vessel. Less
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