Abstract 2516: YM758, a Novel hyperpolarization-Activated Inward Current Inhibitor, Suppressed Atrioventricular Conduction During Atrial Rapid Stimulation
The If channel is expressed by both sinoatrial node (SA) pacemaker cells and atrioventricular (AV) nodal cells. In the SA node, If plays a major role in spontaneous membrane depolarizations however, the effects of If in the AV node are not well characterized. This study investigated the electrophysiological effects of YM758, a novel, specific, If inhibitor, on AV nodal function in anesthetized dogs and its effects on ventricular rate in anesthetized pigs. Administration of YM758 (0.1 and 0.3 mg/kg, i.v.) significantly (p<0.1 vs control) prolonged the atrial-His (AH) interval (25±4 and 36±8 msec, respectively) during rapid atrial pacing with a cycle length of 400 msec (rapid cycle-400). Similar findings were observed at an atrial pacing cycle length of 300 msec (rapid cycle-300) (23±5 and 38±7 msec, respectively, p<0.01 vs. control). Conversely, YM758 showed no AH interval prolongation during sinus rhythm (3±4 msec). Verapamil (0.1 mg/kg i.v.) significantly prolonged the AH interval during rapid cycle-400, rapid cycle-300, and sinus rhythm (20±5, 61±13, and 22±4 msec, respectively, p<0.05 vs. control). YM758 (0.1 and 0.3 mg/kg) significantly prolonged the AV nodal effective refractory period during rapid cycle-400 (24±4 and 35±3 msec, respectively, p<0.01 vs. control) and verapamil showed the same effect (40±10 msec; p<0.01 vs. control). Based on these electrophysiological findings, the effect of YM758 on ventricular rate was investigated. In anesthetized pigs, continuous atrial burst pacing (50 Hz) stably increased the ventricular rate. YM758 (0.3 mg/kg i.v.) during burst pacing significantly reduced (−18±4 bpm, p<0.05) the ventricular rate compared to vehicle-treated animals (−5±4 bpm). These data show that If inhibition suppressed AV nodal electrical propagation under conditions of high frequency electrical pacing, limiting electrical conduction from the atria to the ventricles thereby reducing the ventricular rate. As such, If inhibition may be a useful therapeutic target to limit ventricular tachycardia seen in conditions such as atrial fibrillation.