Effects of adrenomedullin on cultured rat cardiac myocytes and fibroblasts.
The direct effects of adrenomedullin, a novel vasorelaxant peptide, on protein synthesis and atrial natriuretic peptide release in myocytes and on DNA and collagen syntheses in fibroblasts were examined using cultured ventricular cardiocytes. The protein synthesis of cardiac myocytes was not affected by adrenomedullin under non-stimulated conditions. Endothelin-1-induced protein synthesis in myocytes was slightly but significantly elevated by adrenomedullin. Likewise, the secretion of atrial natriuretic peptide from myocytes stimulated by endothelin-1 was increased by adrenomedullin. In cardiac fibroblasts, adrenomedullin clearly inhibited DNA synthesis and collagen production in a dose-dependent manner under both basal and angiotensin II-stimulated conditions. DNA and collagen syntheses by cardiac fibroblasts were suppressed by both 8-bromo cAMP and forskolin. Furthermore, a cAMP-specific phosphodiesterase inhibitor decreased DNA and collagen syntheses in fibroblasts and enhanced the inhibitory effects of adrenomedullin on these syntheses. Our observations suggest that adrenomedullin has opposite effects on cultured cardiac myocytes and fibroblasts and that the effects of adrenomedullin at least on fibroblasts are probably mediated through a cAMP-dependent pathway. As adrenomedullin is produced and secreted from both types of cardiac cells, adrenomedullin may play a role as an autocrine/paracrine modulator in the process of cardiac remodeling, mainly by suppressing mitogenesis and collagen synthesis in fibroblasts.
Horio
T
T
Division of Hypertension, Department of Medicine, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Japan. thorio@jsc.ri.ncvc.go.jp
Nishikimi
T
T
Yoshihara
F
F
Matsuo
H
H
Takishita
S
S
Kangawa
K
K
D053607:Adrenomedullin; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D014176:Protein Biosynthesis; D051381:Rats; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D010455:Peptides; D010726:Phosphodiesterase Inhibitors; D014665:Vasodilator Agents; D000804:Angiotensin II; D053607:Adrenomedullin; D009320:Atrial Natriuretic Factor; D003094:Collagen; D004247:DNA; D000242:Cyclic AMP