Impact of Na⁺ channel blockers on transmural dispersion of refractoriness and arrhythmic susceptibility in guinea-pig left ventricle.
Clinically, class Ib antiarrhythmic agents (selective I(Na) blockers) are considered to be safe drugs, whereas class Ia and Ic agents (non-selective blockers of both I(Na) and I(Kr), 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 I(Na) and I(Kr) across ventricular wall, as determined in previous studies. Specifically, less epicardial than endocardial I(Na) reserve would likely contribute to a greater prolongation of the effective refractory period (ERP) at epicardium by the I(Na) blocker, thereby reducing epicardial-to-endocardial ERP dispersion, with resulting antiarrhythmic effect. In contrast, less endocardial than epicardial I(Kr) reserve would likely contribute to a greater prolongation of repolarization at the endocardium by the I(Kr) blocker, thereby amplifying transmural ERP dispersion and inducing arrhythmia. In perfused guinea-pig hearts, dofetilide, a specific I(Kr) 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.
Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark. osadchiy@hst.aau.dk
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Osadchii
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D001481:Basal Metabolism / Q000187:drug effects; D004198:Disease Susceptibility; D004699:Endocardium / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D010496:Pericardium / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D026941:Sodium Channel Blockers / Q000009:adverse effects* / Q000494:pharmacology*
D026941:Sodium Channel Blockers