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

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Abstract
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[c]AMP and cGMP concentrations in guinea pig ventricles. Associated with changes in nucleotide content were positive inotropic effects and activation of glycogen phosphorylase. Pretreatment of animals with reserpine to deplete endogenous catecholamine stores or pretreatment of hearts with propranolol failed to alter ionophore-induced changes. Histamine (H2) receptor blockade with metiamide abolished the positive inotropic effects and activation of glycogen phosphorylase induced by A23187. In metiamide-treated hearts, the ionophore-induced increase in cAMP concentration was attenuated, whereas the increase in cGMP content persisted. A23187 produced a negative inotropic effect in hearts taken from rats treated with reserpine. cAMP levels and glycogen phosphorylase activity were unchanged, cGMP concentrations were markedly increased. Apparently A23187 produces both indirect and direct effects on guinea pig ventricles. The indirect effects are mediated primarily by histamine, released from tissue mast cells by the ionophore. Histamine in turn increases cAMP levels, which leads to activation of phosphorylase and positive inotropic effects. The direct biochemical effect of A23187 is an increase in cGMP concentrations.