Subcellular mechanism of the positive inotropic effect of a new quinolinone derivative OPC-8490 on the dog ventricular myocardium.

Abstract

OPC-8490 [3,4-dihydro-6-[4-(4-oxo-4-phenylbutyl)-1- piperazinylcarbonyl]-2(1H)-quinolinone citrate] elicited a positive inotropic effect in a concentration-dependent manner on the isolated dog ventricular trabeculae electrically driven at 0.5 Hz in Krebs-Henseleit solution bubbled with 95% O2-5% CO2 at 37 degrees C. The beta-adrenoceptor antagonist, bupranolol (3 x 10(-7) mol/l), did not influence the effect of OPC-8490. The maximal effect of OPC-8490 was 0.19 compared with isoproterenol (1.0). The time course of the increase in contractile force coincided with that of the concomitant cyclic AMP accumulation induced by OPC-8490. The concentration-response curve for the OPC-8490-induced increase in contractile force was superimposable on that of the elevation of cyclic AMP levels. OPC-8490 (10(-5) mol/l) shifted the concentration-response curve for isoproterenol to the left and upward. These results imply that the accumulation of cyclic AMP induced by OPC-8490 through an inhibition of peak III PDE may be responsible for its positive inotropic effect. However, the OPC-8490-induced increase in the contractile force was not abolished by carbachol (3 x 10(-6) mol/l) when the cyclic AMP accumulation caused by the compound was completely inhibited by carbachol. In addition, OPC-8490 did cause a change in the time course of isometric contractions characteristic of cyclic AMP accumulation. These findings indicate that both the cyclic AMP-dependent (peak III PDE inhibition) and the cyclic AMP-independent mechanisms (prolongation of action potential duration by inhibition of K+ conductance) may be involved in the positive inotropic effect of OPC-8490 on the dog ventricular muscle.