Effects of verapamil, zatebradine, and E-4031 on the pacemaker location and rate in response to sympathetic stimulation in dog hearts.

To investigate whether slow inward Ca2+ current (ICa), hyperpolarization-activated inward current (If), and a rapid type of delayed rectifier K+ current (IKr) similarly act on the pacemaker location, sinoatrial node region, and subsidiary superior and inferior pacemaker regions, we studied the effects of verapamil, zatebradine, and E-4031 on the atrial rate and the 3-ms earliest activation region (EAR) determined from the isochronal activation sequence map in the autonomically decentralized heart of the anesthetized dog. Three blockers decreased atrial rate similarly. Verapamil shifted the EAR from the SA node region to the inferior pacemaker region. The EAR induced by zatebradine was variable, but the EAR induced by E-4031 tended to shift to the inferior pacemaker region. Sympathetic nerve stimulation increased atrial rate and shifted the EAR to the superior pacemaker region. Verapamil attenuated the increased atrial rate by 28%, and it shifted the EAR to the lower pacemaker regions consistently. Zatebradine also attenuated the increased rate by 53% and shifted the EAR from the anterior to the posterior-superior right atrium. On the other hand, E-4031 affected neither the rate nor the EAR in response to sympathetic stimulation. These results suggest that ICa, If, and IKr inhibitors differentially influence the pacemaker activity among three pacemaker regions when sympathetic tone is absent or present and that the role of ICa, If, and IKr of the pacemaker cells distributed in the atrial pacemaker complex is different in the dog heart in situ.