Isolated, perfused rat hearts were used to study the effects of verapamil, excess calcium ions or excess magnesium ions on changes in heart cyclic AMP and myocardial force of contraction. Verapamil caused a dose-dependent decrease in force of contraction and a nondose-related reduction in cyclic AMP. Perfusion of hearts with medium containing 5 m M calcium produced a significant rise in cyclic AMP, but no change in contractile force. The depressant effects of verapamil on contractility and cyclic AMP were reversed by 5 m M calcium; excess calcium in the perfusion fluid also containing verapamil prevented the myocardial depresant effects of verapamil. Acutely elevating the magnesium concentration in the perfusion medium decreased force of contraction, accentuated the negative inotropic effect of verapamil, but did not decrease cyclic AMP or enhance the verapamil-induced reduction in cyclic AMP.