Calcitonin gene-related peptide (CGRP) was studied in rat isolated atria to ascertain the role of cyclic nucleotides in the positive chronotropic and inotropic actions of this novel cardiac neuropeptide. In electrically driven left and right atria, CGRP (3-100 nM) caused concentration-dependent increases in contractile tension that developed slowly and persisted for greater than 30 min while CGRP remained in the bath. In spontaneously beating right atria, CGRP (3-100 nM) caused concentration-dependent prolonged increases in heart rate and small transient increases in contractile force. CGRP (100 nM, 2 min) elevated adenosine 3',5'-cyclic monophosphate (cAMP) content in left atria 2-fold and right atria 1.6-fold. Time courses and concentration-response relationships for cAMP elevation correlated well with chronotropic and inotropic responses. Guanosine 3',5'-cyclic monophosphate (cGMP) levels in both atria were not altered by CGRP. Compared with norepinephrine (NE), CGRP was 14-fold more potent at increasing rate [50% effective concentration (EC50) = 4.55 +/- 0.48 nM for CGRP and 64.8 +/- 10.5 nM for NE] and 60-fold more potent at increasing contractile force (EC50 = 3.31 +/- 0.57 nM for CGRP and 201 +/- 18 nM for NE). Preincubation with atenolol (3 microM) or indomethacin (3 microM) did not alter chronotropic, inotropic, and cAMP responses to CGRP in atria, indicating that these responses were not mediated by released catecholamines or prostaglandins. The data are consistent with the hypothesis that CGRP causes positive chronotropic and isotropic effects via activation of cAMP responses in rat atrial myocardium.