Class III Antiarrhythmic Drug Cavutilide Does Not Increase the Susceptibility of the Ventricles to Phenylephrine-Induced Tachyarrhythmias Due to the Direct Dependence of the Effect on the Frequency of Myocardial Activation.

Abstract

Class III antiarrhythmic drugs used for the treatment of supraventricular tachyarrhythmias can induce polymorphic ventricular tachycardia known as "torsade de pointes" (TdP). This adverse side effect of antiarrhythmic drugs is more pronounced in impaired ventricular perfusion and limits the use of the drugs. In this work, the effects of the antiarrhythmic drug cavutilide were studied in a model of phenylephrine-induced potentiation of TdP. Cavutilide was administered acutely in combination with phenylephrine in non-anesthetized rabbits under continuous ECG monitoring. Cavutilide in the presence of phenylephrine induced pronounced ventricular extrasystoles almost without episodes of ventricular tachycardia or TdP paroxysms. The reference antiarrhythmic drug dofetilide under the same model conditions caused prolonged, multiple episodes of monomorphic ventricular tachycardia and frequent, repetitive paroxysms of high-frequency TdP. Thus, cavutilide demonstrates very low tendency to induce TdP under conditions of impaired myocardial perfusion, which can be explained by direct type of the dependence of its effect on the frequency of myocardium activation.