Comparison of the rate dependent effects of dofetilide and ibutilide in the newborn heart

This study compared the rate dependent changes in atrial and ventricular monophasic action potential duration in the newborn canine heart in response to two Class III antiarrhythmic agents: dofetilide, a pure Ikr blocker, and ibutilide, a Na+ channel opener. Newborn dogs were anesthetized with pentobarbital, vagotomized, and given propranolol to eliminate autonomic responses. A 4 Fr electrical catheter was placed in the right atrium for pacing. Monophasic action potential durations (APDs) at 90% repolarization (APD90) were recorded from the epicardial surface of the left ventricle and atrium with Ag-AgCl2 suction electrodes. APD90 was measured as cardiac cycle length was shortened by pacing, in the control condition and following two doses of dofetilide (n = 8) or ibutilide (n = 9). Slopes of the APD90 versus decreasing paced cycle length (PCL) relationships were then compared. Large dose dependent increases in atrial and ventricular APD90 were observed after dofetilide and ibutilide. In the neonatal atrium, there were no changes in the APD90 versus PCL relationship with either drug, indicating no rate dependency of drug effect. In contrast, in the ventricle, a steeper APD90 versus PCL slope was noted after dofetilide and ibutilide, indicating a significant loss of drug effect at faster heart rates (i.e., reverse rate dependency). In spite of probable different cellular mechanisms of action, the rate dependent characteristics of dofetilide and ibutilide are identical in the neonatal heart. There is no evidence of (reverse) rate dependency in the atrium, predicting that both agents would be effective at rapid atrial tachycardia rates. For both, however, marked reverse rate dependency is observed in the neonatal ventricle.