We examined the effects of calcitonin gene-related peptide (CGRP) on the membrane currents of single atrial and ventricular cells of guinea pig heart. The tightseal whole-cell voltage-clamp technique was used. In atrial cells, like isoproterenol, CGRP increased the L-type Ca channel current (ICa.L) in a concentration-dependent manner. Human CGRP-(8-37), a putative CGRP receptor antagonist, completely abolished the CGRP-induced increase of ICa.L. Although the effects of CRGP were similar to those of isoproterenol, propranolol, a fl-adrenergic receptor antagonist, did not affect the CGRP-induced increase of ICa.L. After ICa.L had been maximally activated by isoproterenol (2 gM) or intracellular cyclic adenosine 5'-monophosphate (100 gM), CGRP failed to increase Ica.L. Acetylcholine antagonized the effects of CGRP on Ica.L. Unlike the effects on atrial cells, CGRP had no significant effects on the membrane currents of ventricular myocytes. Thes results indicate that CGRP increases Ica.L via adenylate cyclase activation by binding to specific membrane receptors in cardiac atrial myocytes. Furthermore, CGRP receptors are expressed in atrial cells but probably not in ventricular cells.