Effects of MDL 19205 (piroximone), a new cardiotonic agent, on electrophysiological, mechanical, and intracellular ionic characteristics of sheep cardiac tissues.

This study was undertaken to characterize the cardiac electrophysiological and mechanical effects of MDL 19205, a new and potent nonglycoside, positive inotropic agent. In addition, intracellular Na+ activity (aiNa) was measured to determine if this agent might produce its inotropic effects by increasing aiNa and secondarily by increasing intracellular calcium via Na+ -Ca2+ exchange. Experiments were conducted in free-running trabecular muscles and Purkinje fibers obtained from sheep hearts. The following were the most significant effects of MDL 19205: a decrease in action potential duration in both ventricular and Purkinje tissues; a cumulative dose-dependent increase in contractile force in ventricular muscle but not in Purkinje strands; no change in aiNa in Purkinje fibers to accompany the positive inotropic effect of this agent; a shift in the dose-response relation by approximately fourfold in the presence of beta-adrenergic blockade with sotalol (10(-7) M); an enhancement of diastolic depolarization in Purkinje fibers resulting in automaticity that is accelerated by overdrive; and a potentiation of the positive inotropic effects of MDL 19205 by 8-bromo-cAMP (1 mM), indicating a potent phosphodiesterase inhibitory action of MDL 19205. These results suggest that MDL 19205 exerts at least part of its positive inotropic and automatic actions through stimulation of beta-adrenergic receptors. This action occurs in conjunction with its ability to inhibit phosphodiesterase, thus promoting an accumulation of cAMP in cardiac cells. Other intracellular actions may also contribute to the effect of this drug, but they do not rely on an increase in aiNa or dramatic changes in the action potential plateau or duration.