Vol. 302, Issue 1, 283-289, July 2002

Antiarrhythmic Efficacy of Combined I_Ks and -Adrenergic Receptor Blockade

Joseph J. Lynch, Jr., Joseph J. Salata, Audrey A. Wallace, Gary L. Stump, David B. Gilberto, Hossain Jahansouz, Nigel J. Liverton, Harold G. Selnick and David A. Claremon

Departments of Pharmacology (J.J.L., J.J.S., A.A.W., G.L.S.), Laboratory Animal Medicine (D.B.G.), Pharmaceutical Research and Development (H.J.), and Medicinal Chemistry (N.J.L., H.G.S., D.A.C.), Merck Research Laboratories, West Point, Pennsylvania

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 -adrenergic blocking dose of timolol. Administered individually, neither 0.3 µg/kg i.v. L-768673 nor 1.0 µg/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 µg/kg i.v. L-768673 + 1.0 µg/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 -adrenergic blockade may constitute a potential pharmacologic strategy for prevention of malignant ischemic ventricular arrhythmias.