© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Antifibrillatory efficacy of ersentilide, a novel β-adrenergic and Ikr blocker, in conscious dogs with a healed myocardial infarction
aW.K. Warren Medical Research Institute, Oklahoma City OK 73190, USA
bDepartment of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City OK 73190, USA
cCardiology Section of the Department of Internal Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City OK 73190, USA
dDipartimento di Cardiologia, Università di Pavia, IRCCS Policlinico S. Matteo, Pavia, Italy
eCentro di Fisiologia Clinica e Ipertensione, IRCCS Ospedale Maggiore, Università di Milano, Milano, Italy
* Corresponding author. University of Oklahoma, Health Sciences Center, Dept. of Physiology, P.O. Box 26901, BMSB 653, Oklahoma City OK 73190, USA. Tel.: +1 (405) 271 2226; Fax: +1 (405) 271 3181; E-mail: philip-adamson @uokhsc.edu
Objectives: IKr 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 IKr 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 (IKr) 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<0.001) at a 360 ms cycle length and completely prevented its shortening during sympathetic stimulation. Conclusions: The combination of IKr and weak β-adrenergic blockade, using ersentilide, represents a very effective and safe antiarrhythmic intervention able to overcome the limitations present in drugs devoid of any antiadrenergic effect. Such a combination may be very useful in the management of post-myocardial infarction patients at high arrhythmic risk.
KEYWORDS Sudden death; K-channel; Autonomic nervous system; Myocardial infarction; Antiarrhythmic agents