Antifibrillatory efficacy of ersentilide, a novel β-adrenergic and I(kr) blocker, in conscious dogs with a healed myocardial infarction

Objectives: I(Kr) blockade is ineffective in preventing ventricular fibrillation elicited by the interaction between acute myocardial ischemia and elevated sympathetic activity. This depends in part on the fact that adrenergic activation offsets more than 50% of the action potential prolonging effect of I(Kr) blockade, and thus impairs its primary mechanism of action. This study examined the antifibrillatory effect of ersentilide (CK-3579), a novel antiarrhythmic agent which combines blockade of the rapid component of the delayed rectifier potassium channel (I(Kr)) with relatively weak β-adrenergic blockade, in a conscious canine model of lethal arrhythmias. Methods: Ersentilide was tested in 19 dogs with a healed myocardial infarction (MI) undergoing two minutes of circumflex artery occlusion (CAO) during sub-maximal treadmill exercise. Epicardial monophasic action potential duration was measured before and after ersentilide in 8 anesthetized open chest dogs at baseline and during stimulation of the left stellate ganglion at constant paced heart rate. Results: In the control tests 13 of the 19 dogs had ventricular fibrillation (VF) during the exercise and ischemia test, 6 did not. During a subsequent exercise test, ersentilide prevented VF in 85% (11 of 13) of the high risk animals and showed no proarrhythmic effects in the 6 dogs without arrhythmias in the initial test. Ersentilide lowered heart rate at all levels of exercise and during acute myocardial ischemia. The antifibrillatory effect was maintained in 3 of 4 dogs in which heart rate was kept at control levels by atrial pacing. Ersentilide prolonged left ventricular monophasic action potential duration by 30% (from 179±6 ms to 233±5 ms, p