Activation of Phosphorylase by Cyclic AMP without Augmentation of Contractility in the Perfused Guinea Pig Heart

Abstract

This study was designed to determine whether intracellular cyclic AMP augments myocardial contractility directly. Isolated guinea pig hearts were perfused with media containing cyclic AMP and other adcninc nucleotides with or without 3% dimethylsulfoxide (DMSO) to facilitate myocardial uptake. Phosphorylase b to a transformation, detennined fluorometrically, was used as an index of increased intracellular cyclic AMP. Heart rate, left ventricular pressure and dP/dt were assessed in isovolumic preparations. DMSO, 3%, did not significantly affect myocardial performance or mask increased contractility produced by epinephrine. Cyclic AMP, 10 -4 M , with or without DMSO depressed left ventricular pressure and dP/dt modestly, even when heart rate was maintained constant by pacing. Phosphorylase activation increased from a control value of 16.5±1.44% (mean± SE , N =12) to 40.0±3.1% ( N =19) following perfusion with 10 -4 M cyclic AMP with 3% DMSO; DMSO alone increased phosphorylase much less. 5'-AMP with DMSO compared to DMSO alone did not activate phosphorylase. The results indicate that increased intracellular cyclic AMP, achieved in the absence of adrenergic stimulation, does not increase myocardial contractility. Thus, they support the view that the positive inotropic effect produced by catecholamines is not mediated by a direct action of cyclic AMP on the contractile apparatus.