SPECIFIC EFFECTS OF ZATEBRADINE ON SINUS NODE FUNCTION - SUPPRESSION OF AUTOMATICITY, PROLONGATION OF SINOATRIAL CONDUCTION AND PACEMAKER SHIFT IN THE DENERVATED CANINE HEART

We evaluated the cardiac electrophysiological effects of zatebradine i n eight anesthetized and autonomically denervated canines, with partic ular emphasis on the effects on sinus node automaticity and sinoatrial conduction (SACT), both at rest and after atrial overdrive pacing. Si nus node function was assessed by using the recorded sinus node electr ogram and also by applying a previously validated mathematical model o f sinus node function which allows separate evaluation of effects of p acing on SACT and suppression of automaticity. Other standard electrop hysiological parameters also were measured. Tests were performed befor e and after incremental doses of zatebradine (0.0625, 0.125 and 0.25 m g/kg). Zatebradine caused a significant, dose-related increase in card iac cycle length. There also was a significant, dose-related increase in both suppression of automaticity and SACT (independent of changes i n cycle length) after zatebradine. The only other significant electrop hysiological effect was a relatively minor increase in the ventricular effective refractory period (13%). Higher doses of zatebradine were a ssociated with spontaneous pacemaker shift characterized by loss of th e sinus node electrogram and variation in P-wave morphology. Our resul ts confirm that the effects of zatebradine are relatively specific for the sinus node. These included: 1) prolongation of resting sinus cycl e length; 2) enhanced suppression of automaticity after overdrive paci ng; 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.