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 (a_na) was measured to determine if this agent might produce its inotropic effects by increasing a_na 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) a decrease in action potential duration in both ventricular and Purkinje tissues: (b) a cumulative dose-dependent increase in contractile force in ventricular muscle but not in Purkinje strands: (c) no change in a_Na in Purkinje fibers to accompany the positive inotropic effect of this agent; (d) a shift in the doseresponse relation by fourfold in the presence of β-adrenergic blockade with sotalol (10^-7 M); (e) an enhancement of diastolic depolarization in Purkinje fibers resulting in automaticity that is accelerated by overdrive: and (f) 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 β-adrenergic receptors. This action occurs in conjunction with its ability to inhibit phosphodies-terase, 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 a_Na or dramatic changes in the action potential plateau or duration.