Antiarrhythmic efficacy of combined I(Ks) and beta-adrenergic receptor blockade
Joseph J Lynch1, Joseph J Salata, Audrey A Wallace
1Department of Pharmacology, Merck Research Laboratories, WP46-300, West Point, PA 19486, USA. joseph_lynch@merck.com
Abstract:
Suppression of malignant ventricular arrhythmias by selective blockade of the cardiac slowly activating delayed rectifier current (I(Ks)) has been demonstrated with the benzodiazepine L-768673 [(R)-2-(2,4-trifluoromethyl-phenyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoro-ethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide] in canine models of recent and healed myocardial infarction. The present study extends the initial antiarrhythmic assessment of I(Ks) blockade by demonstrating prevention of ischemic malignant arrhythmias in dogs with recent (8.0 +/- 0.4 days) anterior myocardial infarction with the coadministration of a subeffective dose of L-768673 and a subeffective, minimally beta-adrenergic blocking dose of timolol. Administered individually, neither 0.3 microg/kg i.v. L-768673 nor 1.0 microg/kg i.v. timolol prevented the induction of ventricular tachyarrhythmia (VT) by programmed ventricular stimulation (PVS) or the development of malignant ventricular arrhythmia in response to acute coronary artery thrombosis. In contrast, coadministration of 0.3 microg/kg i.v. L-768673 + 1.0 microg/kg i.v. timolol suppressed the induction of VT by PVS (8/10, 80% rendered noninducible versus 1/10, 10% noninducible in vehicle group; p < 0.01) and prevented the development of acute ischemic lethal arrhythmias (3/10, 30% incidence versus 8/10, 80% incidence in vehicle group; p < 0.05). Concomitant administration of low-dose L-768673 + timolol produced modest increases in QTc and paced QT intervals (4.5 +/- 1.2 and 5.5 +/- 1.4%; both p < 0.01), increases in noninfarct zone relative and effective refractory periods (7.0 +/- 1.7 and 12.3 +/- 3.0%; both p < 0.01), and lesser increases in infarct zone relative and effective refractory periods (5.3 +/- 1.6 and 5.8 +/- 1.4%; both p < 0.01). These findings suggest that concomitant low-dose I(Ks) and beta-adrenergic blockade may constitute a potential pharmacologic strategy for prevention of malignant ischemic ventricular arrhythmias.
Insights
Selective blockade of the cardiac slowly activating delayed rectifier current (I(Ks)) with L-768673 and timolol prevented malignant ventricular arrhythmias in canine models. This combination therapy offers a potential strategy for preventing ischemic arrhythmias.
Area of Science:
- Cardiology
- Pharmacology
- Electrophysiology
Background:
- Malignant ventricular arrhythmias pose a significant threat following myocardial infarction.
- Selective blockade of the cardiac slowly activating delayed rectifier current (I(Ks)) has shown promise in suppressing these arrhythmias.
- The benzodiazepine L-768673 is a known I(Ks) blocker, and its antiarrhythmic effects require further investigation in combination therapies.
Purpose of the Study:
- To evaluate the efficacy of combining a subeffective dose of L-768673 with a subeffective, minimally beta-adrenergic blocking dose of timolol.
- To determine if this combination prevents experimentally induced malignant ventricular arrhythmias in a canine model of recent myocardial infarction.
- To assess the electrophysiological effects of the combined drug administration on cardiac repolarization and refractoriness.
Main Methods:
- Canine models with recent anterior myocardial infarction were subjected to programmed ventricular stimulation (PVS) and acute coronary artery thrombosis.
- Drugs were administered intravenously: L-768673 (0.3 μg/kg), timolol (1.0 μg/kg), or the combination.
- Ventricular tachyarrhythmia (VT) induction, incidence of lethal arrhythmias, and electrophysiological parameters (QTc, paced QT, refractory periods) were measured.
Main Results:
- Individually, neither L-768673 nor timolol prevented VT induction or lethal arrhythmias.
- The combination of L-768673 and timolol significantly suppressed VT induction by PVS (80% vs. 10% in vehicle group, p < 0.01).
- Combined therapy also prevented acute ischemic lethal arrhythmias (30% vs. 80% incidence in vehicle group, p < 0.05) with modest increases in QT intervals and refractory periods.
Conclusions:
- Coadministration of subeffective doses of L-768673 and timolol effectively prevents malignant ischemic ventricular arrhythmias in a canine model.
- This combination therapy demonstrates a synergistic antiarrhythmic effect, surpassing the efficacy of individual agents.
- Concomitant low-dose I(Ks) blockade and beta-adrenergic blockade represent a potential pharmacologic strategy for managing life-threatening ventricular arrhythmias.
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