Cardiotonic activity of a new inotropic agent, 3, 4-dihydro-6-[4-(3, 4-dimethoxybenzoyl)-1-piperazinyl] - 2(lh)–quinolinone (opc-8212), in the dog with and without β-blocker and ca++ -antagonist pretreatment

Hemodynamic effects of a new inotropic agent, OPC-8212 (2(lH)–quinolinone derivative) were studied in anesthetized open chest dogs pretreated with propranolol and diltiazem. Three doses (1, 3 and 10 mg/kg) of OPC-8212 were administered intravenously and the net hemodynamic effect (% change) was obtained by subtraction of the effect of the solvent from the gross effect, since the vehicle has a transient, but significant hemodynamic effect. The maximal inotropic effect occurred 3 minutes after administration: LV dP/dt max and cardiac output (CO) increased by 19 ± 2.5% and 28 ± 8.5%, respectively, at 3 mg/kg. These cardiotonic effects were dose-dependent, whereas heart rate, peak LV pressure (PLVP) and mean aortic pressure were minimally changed at any dose. Accordingly, systemic vascular resistance (SVR) decreased in a dose-dependent manner although the decrease was much less than that in administration of isoproterenol. The inotropic effect was not blocked by β-adrenoceptor blockade (propranolol 1 mg/kg), indicating that the cardiotonic action of this agent is not due to β-adrenergic stimulation. Thus, this agent could reverse β-blocker-induced heart failure. During infusion of diltiazem (0.1 mg/kg/min following bolus intravenous administration of 0.5 mg/kg), the increases in LV dP/dt max and CO due to OPC-8212 were similar to those in the control study. In contrast to the effects under β-adrenoceptor blockade, however, decreased PLVP was restored by OPC-8212. Neither chronotropic nor rrhythmogenic effects were observed in the control or with either pharmacological intervention. These results indicate that OPC-8212 has a potent inotropic action with modest vasodilatory effect even with propranolol or diltiazem pretreatment. Thus, OPC-8212 can be used in combination with β-adrenoceptor antagonists and Ca++ -channel blockers, and also can reverse the heart failure induced by mismanagement of these cardio-depressant agents.