Impact of Na+ channel blockers on transmural dispersion of refractoriness and arrhythmic susceptibility in guinea-pig left ventricle

Clinically, class Ib antiarrhythmic agents (selective INa blockers) are considered to be safe drugs, whereas class Ia and Ic agents (non-selective blockers of both INa and IKr, the rapid component of the delayed rectifier) may evoke proarrhythmia. I hypothesized that this difference is accounted for by differential drug effects on transmural dispersion of refractoriness, in the presence of the reciprocal distribution profile of INa and IKr across ventricular wall, as determined in previous studies. Specifically, less epicardial than endocardial INa reserve would likely contribute to a greater prolongation of the effective refractory period (ERP) at epicardium by the INa blocker, thereby reducing epicardial-to-endocardial ERP dispersion, with resulting antiarrhythmic effect. In contrast, less endocardial than epicardial IKr reserve would likely contribute to a greater prolongation of repolarization at the endocardium by the IKr blocker, thereby amplifying transmural ERP dispersion and inducing arrhythmia. In perfused guinea-pig hearts, dofetilide, a specific IKr blocker, as well as class Ia (quinidine, procainamide) and class Ic agents (flecainide), were found to prolong the QT interval and monophasic action potential duration, and elicited greater endocardial than epicardial ERP prolongation, thus markedly increasing transmural ERP dispersion. These changes were associated with episodes of monomorphic ventricular tachycardia in 30-40% of experiments. In contrast, class Ib agents (lidocaine, mexiletine) evoked greater epicardial than endocardial ERP lengthening, thereby decreasing transmural ERP dispersion, and produced no tachyarrhythmia. These findings suggest that transmural ERP dispersion is the electrophysiological determinant which may shape the profile of class I agent effects on arrhythmic susceptibility.