|Budget Amount *help
¥12,700,000 (Direct Cost : ¥12,700,000)
Fiscal Year 1999 : ¥6,200,000 (Direct Cost : ¥6,200,000)
Fiscal Year 1998 : ¥6,500,000 (Direct Cost : ¥6,500,000)
Adrenomedullin (AM) is a potent vasorelaxant peptide 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, kidney and vascular wall as well as adrenal medulla. In this project, we have studied the gene expression of AM and its receptor(s), and also examined their pathophysiological significance in heart failure and sepsis.
We have previously reported pathophysiological significance of AM in heart failure. We further investigated (1) the effects of intravenous infusion of AM in heart failure of rats and patients, (2) pathophysiological significance of myocardial AM in hypertrophy and failing heart, and (3) direct effect of AM on cultured cardiac myocytes and fibroblasts. Intravenous infusion of AM significantly improved systemic hemodynamics, renal function and endocrine hormones in heart failure of rats and patients. In pressure and volume induced hypertrophy, myocardial AM level
s more rapidly increased compared with other molecular markers such as skeletal actin and β-myosin heavy chain. In the cultured cardiac myocytes and fibroblasts, AM had weak, but significant hypertrophic effects only when cardiac myocytes were stimulated by endothelin- 1. AM had inhibitory effects of cardiac fibroblasts proliferation and collagen production. These results suggest that intravenous infusion of AM may be a new therappeutic approach in heart failure and that myocardial AM may be a new biochemical marker in cardiac hypertrophy and failing heart.
Plasma concentrations of AM are markedly increased during sepsis, but the role of AM has not been clarified. Coexpression of calcitonin receptor- like receptor (CRLR) and receptor activity modifying protein (RAMP) 2 or 3 have been reported to form the adrenomedullin (AM) specific receptor. To elucidate the gene expression of mouse AM receptor, we cloned cDNAs of mouse AM receptor components and examined the expression of CRLR and RAMP1, 2 and 3 in several tissues from mice in a sepsis model induced by lipopolysaccharide (LPS). High expression of CRLR and RAMP2 mRNA was observed in lungs of normal mice, but it was markedly decreased in endotoxemic mice. It is suggested that the abundant binding sites of AM in lungs are formed by CRLR and RAMP2 in healthy subjects, and that their reduction should contribute to the increase of plasma AM concentrations during sepsis. In contrast, LPS treatment markedly increased RAMP3 gene expression in lungs, spleen and thymus. It is revealed that the distributions of receptor or binding sites of AM are changed in sepsis, and it is suggested that AM plays distinct roles in the clinical course of this syndrome. Less