Cyclic Adenosme Monophosphate Modulation of Slow Calcium Influx Channels in Guinea Pig Hearts

The relationship between cellular levels of cyclic adenosine monophosphate (AMP) and slow inward calcium ion (Ca) current was studied in isolated perfused guinea pig hearts in which fast sodium ion (Na) channels had been inactivated by depolarization with potassium ions (K) or blockade with tetrodotoxin. Perfusion with 22 mM K depolarized cardiac tissue to approximately -40 mv and rendered hearts inexcitable. Tetrodotoxin (3 x 10 "'M) blocked excitability without altering resting membrane potential. Excitability and contractions could be restored to these hearts with a variety of inotropic agents that also raised the measured tissue levels of cyclic AMP or with high concentrations of Ca. The magnitude of steady-state tension developed by restored hearts was directly related to the external Ca concentration as well as to the concentration of the restoring agent used. The tension of restored hearts was markedly reduced by Ca-channel antagonists. Elevation of cyclic AMP levels preceded restoration of excitability to inactivated hearts. A highly significant positive correlation was found between the magnitude of Ca-dependent tension developed by restored hearts and the level of cyclic AMP in those hearts. Glucagon and ouabain, inotropic drugs that do not elevate myocardial levels of cyclic AMP, failed to restore depolarized or tetrodotoxin-blocked hearts. Therefore, cyclic AMP appears to modulate slow Ca influx channels in myocardial cells.