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The contractile and biochemical effects of the divalent cation ionophore A23187 were studied in isolated perfused guinea pig and rat ventricles. A23187 increased both cyclic adenosine 3′:5′-monophosphate (cyclic AMP) and cyclic guanosine 3′:5′-monophosphate (cyclic GMP) concentrations in guinea pig ventricles. Associated with these changes in nucleotide content were positive inotropic effects and activation of giycogen phosphorylase. Pretreatment of animals with reserpine to deplete endogenous catecholamine stores or pretreatment of hearts with propranolol failed to alter these ionophore-induced change*. In contrast, blockade of histamine (Hi) receptors with metiamide completely abolished the positive inotropic effects and activation of giycogen phosphorylase induced by A23187. In these metiamide-treated hearts, the ionophore-induced increase in cyclic AMP concentration was significantly attenuated, whereas the increase in cyclic GMP content persisted. A23187 produced a negative inotropic effect in hearts taken from rats treated with reserpine. In these rat hearts, cyclic AMP levels and giycogen phosphorylase activity were unchanged, whereas cyclic GMP concentrations were markedly increased. These results indicate that A23187 produces both indirect and direct effects on guinea pig ventricles. The indirect effects are mediated primarily by histamine, presumably released from tissue mast cells by the ionophore. Histamine in turn increases cyclic AMP levels, which leads to activation of phosphorylase and positive inotropic effects. The direct biochemical effect of A23187 is an increase in cyclic GMP concentrations. Ore Rea 44: 473-482, 1979

Indirect and direct effects of the divalent cation ionophore A23187 on guinea pig and rat ventricular myocardium.