Abstract

We evaluated the cardiac electrophysiological effects of zatebradine in eight anesthetized and autonomically denervated canines, with particular emphasis on the effects on sinus node automaticity and sinoatrial conduction (SACT), both at rest and after atrial overdrive pacing. Sinus node function was assessed by using the recorded sinus node electrogram and also by applying a previously validated mathematical model of sinus node function which allows separate evaluation of effects of pacing on SACT and suppression of automaticity. Other standard electrophysiological parameters also were measured. Tests were performed before and after incremental doses of zatebradine (0.0625, 0.125 and 0.25 mg/kg). Zatebradine caused a significant, dose-related increase in cardiac cycle length. There also was a significant, dose-related increase in both suppression of automaticity and SACT (independent of changes in cycle length) after zatebradine. The only other significant electrophysiological effect was a relatively minor increase in the ventricular effective refractory period (13%). Higher doses of zatebradine were associated with spontaneous pacemaker shift characterized by loss of the sinus node electrogram and variation in P-wave morphology. Our results confirm that the effects of zatebradine are relatively specific for the sinus node. These included: 1) prolongation of resting sinus cycle length; 2) enhanced suppression of automaticity after overdrive pacing; 3) prolongation of SACT; and 4) induction of sinus node pacemaker shifts. This agent should be used cautiously in patients with possible sinus node dysfunction.