Effects of adrenomedullin on hypertrophic responses induced by angiotensin II, endothelin-1 and phenylephrine.

We examined whether adrenomedullin (AM), a vasoactive peptide with significant expression and binding sites in the heart, modulates the hypertrophic response in cultured neonatal rat ventricular myocytes. Myocyte hypertrophy was induced by treating the cells with angiotensin II (Ang II), endothelin-1 (ET-1) or alpha-adrenergic agonist, L-phenylephrine (PHE). All treatments resulted in a hypertrophic response as reflected by increased protein synthesis and expression of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) genes. AM treatment resulted in a complete inhibition of the Ang II-induced increase in ANP and BNP gene expression and secretion. In contrast, no inhibitory effect was seen in either ET-1-induced natriuretic peptide gene expression or PHE-induced ANP and BNP gene expression and secretion. AM had only a modest effect on basal levels of natriuretic peptide secretion and gene expression. When AM mRNA levels in isolated neonatal rat myocytes treated for 48 h with Ang II, ET-1 or PHE were measured, only Ang II induced a consistent increase in AM gene expression. These results indicate that AM is not invariably associated with attenuation of the hypertrophic response but its effect is dependent on the stimulus activating myocyte hypertrophy. AM may form an important autocrine/paracrine growth-inhibitory loop in Ang II-induced myocyte hypertrophy.