798-6 Acute Effects of Zatebradine on Cardiac Conduction and Repolarization in Anesthetized Dogs

Abstract

Zatebradine, a potent bradycardic agent, is believed to act selectively at the sinoatrial node. However, the selectivity of such an action relative to various electrophysiologic classes of action is not well defined. To characterize tie electrophysiologic properties of zatebradine, the corrected sinus node recovery time (SNRT/sinus cycle length), sinoatrial conduction time (SACT), conduction intervals, effective refractory period in atrium (AERP) and monophasic action potential duration (APD 90 ) in ventricle were measured before (Ctrl) and after administration of incremental doses of zatebradine (Zat, 0.1–1.5 mg/kg) in 15 anesthetized dogs. The effects of zatebradine on various electrophysiologic parameters could be observed immediately after a single i.v. bolus and reached steady-state at 15 min. (Mean ± S.D.): HR SNRTc SACT (ms) P-A (ms) A-H (ms) H-V (ms) P (ms) P-R (ms) QRS (ms) QTc (ms) AERP(ms) VAPD 90 (ms) Ctrl 78 1.28 130 20 135 68 68 187 115 501 175 413 ±8 ±0.2 ±20 ±2 ±19 ±8 ±9 ±12 ±31 ±33 ±10 ±16 Zat 43 2.27 140 20 178 70 70 235 122 553 260 562 ±9 ±0.3 ±29 ±2 ±24 ±8 ±9 ±13 ±32 ±35 ±14 ±15 p <0.01 <0.001 NS NS <0.01 NS NS <0.01 NS <0.01 <0.01 <0.01 ED 50 0.23 0.22 – – 0.58 – – 0.57 – 0.76 0.60 0.78 (mg/kg) At low dose, Zat has a depressant effect on sinus nodal function; at higher doses, it has additional actions on A-V nodal function and lengthens repolarization reflecting effects on other ion channels.