Acute Effects of Zatebradine on Cardiac Conduction and Repolarization

Abstract

Zatebradine, a potent bradycardic agent, is believed to act selectively at the sinoatrial node. The selectivity of such a property relative to various electrophysiologic classes of action is not well defined. To characterize the electrophysiologic properties of zatebradine, the corrected sinus node recovery time, sinoatrial conduction time, conduction intervals, atrial effective refractory period and monophasic action potential duration in the ventricle were measured before and after incremental doses of zatebradine (0.1-1.5 mg/kg) in 15 anesthetized dogs. The electrophysiologic effects of zatebradine developed immediately after a single IV bolus dose, reaching steady-steady-state at 15 minutes with the maximum effect evident at 0.75 mg/kg. The IC50 was 0.23 mg/kg. There was no significant effect on the sinus node recovery time. The PR interval on the electrocardiogram was significantly increased when the dose was higher than 0.25 mg/kg. The duration of the P wave and the PA interval were not changed. Zatebridine greatly increased the AH (from 135 to 178 milliseconds) without changing the HH and HV intervals in His bundle recordings. The EC50 of this effect was 0.58 mg/kg. The QRS interval was not changed. The QTc was significantly increased from 0.43 to 0.56 s½ (P < 0.05). The action potential duration was significantly increased by high dose zatebradine (> 0.5 mg/kg), the EC50 for this effect was 0.76 mg/kg. The atrium effective refractory period was significantly increased (31%) with an EC50 0.69 mg/kg. These results indicate that zatebradine selectively inhibits sinus node automaticity at low doses. The inhibition of the AV nodal conduction and the lengthening of the refractory period and repolarization in the atria and the ventricles occur at higher dose.