Anti- or profibrillatory effects of Na + channel blockade depend on the site of application relative to gradients in repolarization

Introduction. Sodium channel blockers are associated with arrhythmic sudden death, although they are considered antiarrhythmic agents. The mechanism of these opposing effects is unknown. Methods. We used a model of induction of ventricular fibrillation (VF) based on selective perfusion of the vascular beds of isolated porcine hearts (n=8). One bed was perfused with sotalol (220 µM), the adjacent bed with pinacidil (80 µM), leading to repolarization heterogeneity (late repolarization in the sotalol-, early in the pinacidil-area). Premature stimulation from the area with the short action potential was performed. Epicardial activation/repolarization mapping was done. Results. In 3 of the 8 hearts VF was inducible prior to infusion of flecainide. In those hearts the Fibrillation Factor (FF), the interval between the last activation of the premature beat (S2) in the late repolarizing (sotalol) domain and the earliest S2 repolarization in the early repolarizing (pinacidil) domain, was significantly shorter than in the hearts without VF (33+/-22 vs 93+/-11 ms, m+/-SEM, p