OPC-8490

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.

Whether beneficial hemodynamic effects of cardiovascular drugs are due to changes in the inotropic or loading conditions has been difficult to determine in clinical settings. In this study, the end-systolic pressure-volume relationship, known as a load-independent measurement of cardiac contractility, was obtained by a volumetric conductance catheter and transient inferior vena caval occlusion. We applied this technique to determine the major mode of hemodynamic action of a new inotropic vasodilator, OPC-8490, in comparison to that of dobutamine. In 7 patients with anterior myocardial infarction, an 8F conductance catheter with pressure micromanometer was inserted into the left ventricle. Absolute volume calibration was accomplished by injection of hypertonic saline into the pulmonary artery. Left ventricular pressures and volumes were simultaneously and continuously measured during transient inferior vena caval occlusion using a balloon catheter. Left ventricular end-systolic pressure-volume relationships were determined during the initial 8-sec of balloon occlusion, before baroreceptor-mediated cardiac stimulation was initiated. OPC-8490 decreased both the left ventricular systolic pressure and end-systolic volume without changing the heart rate. Dobutamine increased the systolic pressure and heart rate but decreased the end-systolic volume. The reduction in the end-systolic volume with dobutamine, was caused by an increase in the slope of the end-systolic pressure-volume relationship, while with OPC-8490, it resulted from a decrease in the end-systolic pressure without an appreciable change in the slope of the end-systolic pressure-volume relationship.(ABSTRACT TRUNCATED AT 250 WORDS)