Positive inotropic and negative chronotropic effects of OPC-8490, a newly developed cardiotonic, in isolated, blood-perfused canine heart preparations.

Abstract

When a new cardiotonic, OPC-8490 (3, 4-dihydro-6-[4-(4-oxo-4-phenylbutyl)-1-piperazinylcarbonyl]- 2(1H)- quinolinone citrate), was administered into the jugular vein of a support dog, at doses of 0.1, 0.3 and 1 mumol/kg, decreases in heart rate and arterial blood pressure were dose-dependently induced in intact support dogs. One and a half min after administration, positive inotropic and slight negative chronotropic responses were observed in isolated right atria perfused with arterial blood of support dogs. Administration of OPC-8490 into the sinus node artery of the isolated atrium induced positive inotropic and biphasic chronotropic effects, an initial brief positive (Ph1) followed by a long-lasting negative (Ph2) chronotropic effect in a dose-related manner. OPC-8490 at 1000 nmol caused a triphasic, Ph1 followed by Ph2 and slight positive (Ph3) chronotropic effects and an inotropic effect. In the left ventricular muscle preparation driven electrically at 2 Hz, 10-3000 nmol of OPC-8490 increased contractile force in a dose related manner. OPC-8490-induced responses were not significantly modified by propranolol or atropine. When isoproterenol (0.04 nmol/min) increased the basal sinus rate and contractile force of isolated atria, the Ph1 was suppressed and the Ph3 became clear, although the negative phase (Ph2) was not changed. The positive inotropic effect was not significantly changed. When intramural vagal nerve stimulation decreased sinus rate and contractile force, the positive inotropic and negative (Ph2) chronotropic effects were depressed. Verapamil significantly depressed the positive inotropic but not the chronotropic responses to OPC-8490. The positive inotropic effect of OPC-8490 was depressed by pinacidil but not changed by ouabain, although the chronotropic responses to OPC-8490 were not changed. These results suggest that cardiac responses to OPC-8490 involve several mechanisms including cyclic AMP dependent, Ca channel-dependent, potassium current-inhibitory and/or other mechanisms in the dog heart.