Positive inotropic effects of adrenomedullin on rat papillary muscle

Adrenomedullin is a peptide recently isolated from pheochromocytoma that ha s vasorelaxant and long-lasting hypotensive activities. Plasma levels of ad renomedullin are elevated in patients with congestive heart failure, but th e effects of adrenomedullin on the cardiac function are unclear. We, thus, investigated the effects of adrenomedullin on the contraction of rat papill ary muscles. We measured the isometric tension and cAMP contents of isolate d rat papillary muscles. Adrenomedullin exhibited concentration-dependent i notropic effects. Adrenomedullin also significantly increased intracellular contents of cAMP. Addition of the calcitonin gene-related peptide (CGRP) r eceptor antagonist inhibited both contractile force and cAMP generation of papillary muscles stimulated by adrenomedullin. The adrenomedullin-induced inotropic effect was further increased in the presence of the phosphodieste rase inhibitor, 3-isobutyl-1-methyl-xanthine (IBMX), while the effect was s ignificantly suppressed by KT5720 and Rp-8-bromoadenosine-3',5'-cyclic mono phosphorothioate (Rp-8-Br-cAMPS), protein kinase A inhibitors. These result s indicate that adrenomedullin has positive inotropic effects on the heart, at least partially through a cAMP-dependent pathway. (C) 2000 Elsevier Sci ence B.V. All rights reserved.