Cardiovascular actions of OPC-18790: A novel positive inotropic agent with little chronotropic action

Abstract

OPC-18790 [(+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]- 2(1H)-quinolinone], a novel positive inotropic agent, was investigated in several in vitro and in vivo experiments to elucidate its cardiovascular effects and its mechanism of action. In isolated blood-perfused dog heart preparations, OPC-18790 increased contractile force at 10 to 1,000 nmol i.a.; increased coronary arterial blood flow at 30 to 1,000 nmol; and decreased sinus rate slightly at 1,000 nmol. Atrio-ventricular nodal conduction was slightly facilitated with OPC-18790 (10 to 1,000 nmol), whereas ventricular automaticity tended to decrease. OPC-18790 (10(-6) to 10(-4) M) increased contractile force in isolated ventricular muscles of dogs, cats, rabbits and guinea pigs but not rats. OPC-18790 increased left ventricular contractile force dose-dependently in anesthetized open-chest dogs and in conscious dogs with slight or no changes in heart rate and blood pressure. The positive inotropic effect of OPC-18790 was not affected by beta-blockade. OPC-18790 (10(-5) to 10(-4) M) prolonged the duration of action potential in guinea pig papillary muscles. Na+, K(+)-ATPase was not inhibited, but peak-III phosphodiesterase (low Km cyclic AMP specific fraction, inhibited by cyclic GMP) was inhibited by OPC-18790 (IC50 = 0.41 x 10(-6) M) in dog myocardium. However, such an inhibitory action of phosphodiesterase can hardly be reconciled with the lack of a positive chronotropic effect shown by OPC-18790. Thus, these results suggest that OPC-18790 may have an additional mechanism. The cardiovascular effects revealed by this study suggest that OPC-18790 may exert a beneficial effect in the treatment of congestive heart failure.

Effects of OPC-18790, a New Positive Inotropic Agent, on Canine Ventricular Arrhythmias

“…We reported that the lengthening effect of class I antiarrhythmic drugs on IVCT correlated well with the antiarrhythmic potency of these drugs on digitalis and coronary ligation VTs. In an in vivo study (1), OPC 18790 decreased the AV conduction time, but had no effect on the intraventricular conduction. We do not know the reason for the discrepancy between the two results, but as judged by the high doses needed to produce these effects, they may not play a significant role in their effect on the arrhythmias.…”

“…OPC-18790 is a newly synthesized positive inotropic agent with vasodilator activity and reported to be devoid of digitalis-like and catecholamine-like actions (1,2). Its chemical structure, (±)-6-[3-(3,4-dimethoxybenzyl amino)-2-hydroxypropoxy]-2(1H)-quinolinone, is similar to that of vesnarinone (OPC-8212), a positive inotropic drug without vasodilating action, and phosphodiesterase (PDE) inhibiting action is one of the common positive inotropic mechanisms between the two drugs (3 5).…”

“…Since the Ca channel opening effect is expected to occur from the PDE inhibiting actions of OPC-18790, alterations in the cardiac electrophysiological properties such as increas ing latent pacemaker activities or aggravation of delayed afterdepolarizations may occur and initiate or aggravate arrhythmias. On the other hand, OPC-18790 has been reported to prolong the action potential duration (1), which may cause an antiarrhythmic action. Since the oc currence of arrhythmias is deleterious in the treatment of cardiac failure, the present experiment was designed to ex amine the effects of OPC-18790 on blood-perfused isolat ed canine sinoatrial (SA) node and papillary muscle (PM) preparations and on various types of canine ventricular arrhythmias.…”

Effects of Toborinone (OPC-18790), a New Positive Inotropic Agent, on Action Potential in Guinea Pig Sinoatrial Node: Compared with Milrinone and E-4031

“…From this point of view, toborinone may act as an IK blocker rather than a PDE III inhibitor in the sinoatrial node. In the previous study, toborinone limited the increase in sinoatrial node activity (1,4). Since E-4031 prolonged CL in the present and previous studies (10) in the sinoatrial node preparation, one possible mechanism for the lack of positive chronotropism of toborinone may be in part due to its blocking action on IK.…”

“…known as OPC-18790 in former publications) is a novel positive inotropic agent (1,2). This compound has an inhibitory action on the peak III phosphodiesterase (PDE III) of isolated heart in dogs (1) and humans (3).…”