In vitro and in vivo myocardial effects of a cyclic AMP phosphodiesterase inhibitor structurally related to natural cardenolides.

The myocardial effects of the lactonic deoxybenzoin glucoside, AP 10, an ATPases and cyclic AMP phosphodiesterases inhibitor, were investigated in vitro and in vivo. AP 10 showed marked positive inotropic effects on spontaneously beating frog and mammal isolated hearts. This drug induced a substantial increase in cyclic AMP atrial level comparable to that observed with papaverine in the rat. Its inotropic effects on stimulated rat left atria were moderate and suppressed by reserpine pretreatment, in contrast with papaverine inotropic effects which were not significantly modified. As papaverine (10(-5) M), AP 10 (10(-4) M) shifted to the left the atrial dose-response curve for isoproterenol. The positive inotropic effects of AP 10 were more pronounced at low calcium concentrations. Furthermore, AP 10 prolonged the time course of tension decline in stimulated rat left atria exposed to Ca++ free medium. AP 10 (1 mg/kg) did not induce any in vivo hemodynamic disturbance in both anaesthetized and conscious dogs and significantly improved ventricular automaticity in anaesthetized dogs (0.5 mg/kg). This drug was also compared to quinidine in two in vivo experimental arrhythmias. AP 10 was more effective than quinidine in preventing ouabain-induced arrhythmias in conscious rabbits and electrically-induced atrial fibrillation in conscious dogs. Despite its ATPases inhibiting properties and some structural similarities with cardiac glycosides, AP 10 did not show a typical "digitalis-like" pharmacological profile. It exhibited some of the myocardial features which characterize phosphodiesterase inhibitors as caffeine, papaverine or Ro 7-2956. An interesting particularity of AP 10 action was its capacity to prevent experimental arrhythmias.