Investigation of Electrophysiologic Mechanisms for the Antiarrhythmic Actions of R 56865 in Cardiac Glycoside Toxicity

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Abstract
R 56865 is an experimental compound that has been shown to ameliorate the effects of cardiac glycoside toxicity and myocardial ischemia. We evaluated the direct electrophysiological effects of R 56865 and its effects on the electrophysiological sequelae of ouabain toxicity in vivo and in vitro. In normal anesthetized dogs, R 56865 alone at doses of 0.04 to 0.16 mg/kg i.v. had no effect on atrial, AV nodal, or ventricular conduction times and refractoriness, but at doses of 0.64 to 2.5 mg/kg it tended to increase these parameters. In ouabain-pretreated dogs, R 56865 (0.08 to 0.32 mg/kg i.v.) dose-relatedly reduced ouabain-inducd ventricular arrhythmias. In normal isolated canine Purkinje fibers, R 56865 (1–10 μM) reduced Vmax at short pacing cycle lengths and decreased the action potential duration at concentrations of 0.1 to 10 μM.R 56865 at concentrations through 10 μ had no significant effect on normal action potentials of canine ventricular muscle and slow response action potentials in guinea pig papillary muscles. In Purkinje fibers exposed to toxic concentrations of ouabain, R 56865 (1 μM) reduced the delayed afterdepolarization (DAD) amplitude and inhibited triggered activity. R 56865 had no effect on normal automaticity in canine Purkinje fibers at 1 μ M, but 10 μ M significantly slowed it. R 56865 at 10 μ M did not affect isoproterenol-enhanced automaticity and only slightly reduced barium-induced abnormal automaticity that occurred at reduced membrane potentials. These results demonstrate that R 56865 reverses cardiac glycoside-induced arrhythmias in anesthetized dogs at doses that do not significantly affect conduction or refractoriness. Suppression of ouabain-induced DAD and triggered activity in isolated Purkinje fibers, at concentrations not affecting normal or abnormal automaticity, may be the mechanism of R 56865's antiarrhythmic actions in vivo. Suppression of DAD does not appear to be associated with blockade of voltage-dependent calcium channels, but R 56865 may prevent intracellular sodium overload by limiting excessive sodium entry during ouabain intoxication.

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