The relationship between adenosine 3',5'-monophosphate levels and systolic transmembrane calcium flux

The effects of inotropic agents on systolic transmembrane Ca++ flux were studied in isolated perfused guinea pig hearts depolarized with 22 mM K+. After depolarization, inotropic agents were added to the perfusion medium in an attempt to resotre excitability and contractions to the heart. Electrophysiological studies have shown that if excitability can be restored to the heart under these conditions, Ca++ carries the inward current of the action potential. Agents which putatively act by increasing intracellular levels of adenosine 3',5'-monophosphate (cyclic AMP) (isoproterenol, histamine, theophylline, papaverine, dibutyryl cyclic AMP) and Ca++ were found to restore excitability and contractions to K+-depolarized hearts. Threshold concentration for restoration by isoproterenol was 2 nM, and the strength of contractions developed by the restored heart were directly related to the dose of catecholamine used. Ca++ restoration was abolished by Ca++ antagonists (D 600, verapamil) but unaffected by beta blockade, whereas isoproterenol restoration was abolished by both. Ouabain, glucagon, and the divalent cation ionophore, A32187, failed to restore excitability to depolarized hearts. Correlative studies of tissue cyclic AMP levels were done. These data suggest that cyclic AMP can activate action potential-dependent Ca++ influx channels in myocardial cells.