Positive inotropic effect of calcitonin gene-related peptide mediated by cyclic AMP in guinea pig heart

The mechanism of cardiac actions of rat calcitonin gene-related peptide (CGRP) was analyzed on isolated guinea pig hearts. CGRP exerted a positive inotropic effect in a dose-dependent manner on the electrically driven left atria but not on the ventricles. Immunohistochemical studies demonstrated that CGRP-like immunoreactive nerves were distributed densely in the myocardia of the atria but only sparsely in those of the ventricles. The CGRP-induced augmentation of the contraction was accompanied by the shortening of the time to peak force and the increase in the relaxation velocity. The positive inotropic response to CGRP was significantly enhanced by isobutylmethylxanthine and was attenuated by adenosine. CGRP increased the action potential amplitude and prolonged action potential duration at the level of 50% repolarization in the left atria. In the preparations, which were partially depolarized with an increase in extracellular potassium, CGRP induced slow response action potentials. These electrophysiological results indicate that CGRP causes an increase in the slow inward Ca2+ current. The cyclic AMP content in the left atria significantly increased following the addition of CGRP, the time course of which was nearly consistent with that of the augmentation of the contractile force. In the membrane preparation of the atria, the activity of adenylate cyclase was enhanced by CGRP in a dose-dependent manner. These effects of CGRP are qualitatively similar to those of beta-adrenoceptor stimulation. It is concluded that the CGRP-induced response in the guinea pig atria is attributed to the activation of adenylate cyclase via stimulation of its specific receptor and the subsequent increase in the intracellular cyclic AMP level.