SAKATA Junichiro Miyazaki Medical College, 1st Dept.of Internal Med., Research associate, 医学部, 助手 (30253818)
KITAMURA Kazuo Miyazaki Medical College, 1st Dept.of Internal Med., Assistant Professor, 医学部, 講師 (50204912)
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¥7,100,000 (Direct Cost : ¥7,100,000)
Fiscal Year 1996 : ¥1,400,000 (Direct Cost : ¥1,400,000)
Fiscal Year 1995 : ¥1,600,000 (Direct Cost : ¥1,600,000)
Fiscal Year 1994 : ¥4,100,000 (Direct Cost : ¥4,100,000)
We have discovered a novel hypotensive peptide, designated "adrenomedullin" , in human pheochromocytoma by monitoring the elevating activity of platelet cAMP.In addition, a novel 20 residues hypotensive peptide, termed "proadrenomedullin N-terminal 20 peptide" (PAMP), has been found to be processed from proadrenomedullin. In this research, to clarify the physiological and pathophysiological role of AM and PAMP,we investigate the biological effects, distribution, and secretion of AM and PAMP.
It was found to elicit a potent and long lasting hypotensive effect in anesthetized rats. AM stimulated cAMP formation in a dose-dependent manner in cultured rat vascular smooth muscle cells as well as endothelial cells. In addition to the cardiovascular effects of AM,several biological effects including natriuretic activity and inhibition of aldosterone secretion have been elucidated. These effects suggest an important role of AM in the cardiovascular control.
Proadrenomedullin contains a unique twe
nty amino acid sequence followed by Gly-Lys-Arg in the N-terminal region. It is possible that a novel 20 residues peptide, termed "proadrenomedullin N-terminal 20 peptide" (PAMP) with carboxyl terminus of Arg-CONH_2, is processed from proadrenomedullin. We demonstrated that PAMP exists in vivo and elicits a potent hypotensive activity in anesthetized rats. By RNA blot analysis, AM mRNA was found to be highly expressed in several tissues including ventricle, lung, aorta and kidney as well as in adrenal medulla. In addition, the gene for human AM has been isolated from a human genomic library and its structure was determined. The genomic DNA of human AM consists of 4 exons and 3 introns, and the AM gene is situated in a single locus of chromosome 11.
A specific and sensitive radioimmunoassay for human AM has been developed and distribution and characterization of immunoreactive AM in human tissue and plasma have been investigated. Immunoreactive AM was found to be abundant in normal adrenal medulla, and was ubiquitously present in all tissues examined. Further, we have clarifid that plasma AM as well as PAMP concentrations significantly increased significantly in various cardiovascular diseases including hypertension and congestive heart failure. Less