Zatebradine slows ectopic ventricular rhythms in canine heart 24 hours after coronary artery ligation

Arrhythmias occur 24 h after occlusion of the left anterior descending (LAD) coronary artery in the canine heart and have been attributed to the abnormal spontaneous activity in subendocardial Purkinje fibers, which are markedly depolarized. The major current underlying normal automaticity in these fibers is if. Although the if activation range is generally considered to be more negative than the diastolic membrane potential in these depolarized fibers in infarcts, this activation range has been shown to shift in a positive direction in response to hormonal influences. Thus if could still mediate automaticity in these fibers in infarcts. Furthermore, recent reports indicate that a depolarizing diastolic current, probably if, also can be measured in ventricular muscle during abnormal experimental conditions, which may occur during ischemia. To test whether there is a role of if currents in sustaining ventricular ectopy, we administered the selective if channel blocker, zatebradine, 24 h after LAD ligation in canine hearts. We report that intravenous injections of zatebradine (0.25 or 1.0 mg/kg) significantly slow ventricular rhythms (with average reductions of 19 or 26%, respectively). Moreover, because zatebradine also slows sinus nodal rate, it can lead to an increased incidence of ectopic beats. However, during right atrial pacing, when sinus slowing has no effect on ventricular rhythms, capture of ventricular rhythms occurs at lower rates in the presence of zatebradine. The reduction of capture threshold is comparable to the reduction in the rate of the ectopic rhythm. Thus zatebradine eliminated the arrhythmia when the right atrium was paced at the original sinus rate.