Negative chronotropic and dromotropic effects of E-4031, an IKr blocker, on the atrioventricular node in anesthetized...

To investigate the effect of the delayed rectifier K+ current (IK) on the atrioventricular (AV) node of the heart in situ, we studied the direct effects of (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(methylsulfonyl-aminobenzoyl)piperidi ne (E-4031), an IKr (a rapid type of IK) blocker, on the AV junctional rate, atrio-His interval (AH interval), and right ventricular pressure, and the cardiac responses to sympathetic nerve stimulation in the anesthetized dog heart. AV junctional rhythm was induced by clamping the sinoatrial (SA) pacemaker area. E-4031 (0.01-3 mumol/kg, i.v.) attenuated the AV junctional rate dose dependently. The junctional negative chronotropic effect was less than the decrease in sinus rate induced by E-4031 in the same doses. E-4031 did not affect the junctional rate increased by sympathetic stimulation. In the paced heart, E-4031 slightly increased the AH interval but did not change right ventricular pressure responses. E-4031 attenuated neither positive dromotropic nor positive ventricular pressure responses to sympathetic stimulation. After E-4031 treatment, zatebradine (a hyperpolarization-activated current blocker) additively decreased the junctional rate and the junctional positive chronotropic responses to sympathetic stimulation. These results suggest that IKr has much less effect on AV nodal pacemaker activity than on SA nodal pacemaker activity, and an IKr blocker, E-4031, unlike zatebradine, does not antagonize the junctional positive chronotropic responses to sympathetic activation in anesthetized dog heart.