Mode and mechanism of action of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone (OPC-8212), a novel positive inotropic drug, on the dog heart

Abstract

Mode and mechanism of action of 3,4-dihydro-6-[4-(3,4- dimethoxybenzoyl )-1-piperazinyl]-2(1H)- qu inolinone ( OPC -8212) were investigated exclusively on dogs both in vivo and in vitro. When assessed by intra-arterial administration in isolated, blood-perfused papillary muscle, sinoatrial node and atrioventricular (AV) node preparations, OPC -8212 produced a positive inotropic effect scarcely causing either positive or negative chronotropic and coronary vasodilator effects. AV nodal conduction was slightly facilitated with OPC -8212, whereas ventricular automaticity was rather suppressed. No arrhythmias were produced. Thus, OPC -8212 is highly specific for force. In heart-lung preparations OPC -8212 improved cardiac function depressed with pentobarbital, and caused bradycardia. In trabecular muscles of the right ventricle (hereafter simply called ventricular muscles) OPC -8212 produced a concentration-dependent positive inotropic effect in the presence of the beta 1-adrenoceptor antagonist, atenolol. This indicates that the positive inotropic effect of OPC -8212 is not mediated through a beta-adrenoceptor mechanism. In ventricular muscles OPC -8212 increased plateau potentials of normal action potentials in the presence of atenolol. In K+-depolarized ventricular muscles OPC -8212 increased overshoot potentials and durations of slow response action potentials in the presence of atenolol. These suggest an increase in the slow inward current to underlie the positive inotropic effect of OPC -8212. In ventricular muscles OPC -8212 shortened total duration of contraction and time to peak tension in the presence of atenolol. In ventricular muscles OPC -8212 increased force of contraction and intracellular concentrations of cyclic AMP in a parallel way in time course in the presence of atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)