COMPARATIVE-ASSESSMENT OF IBUTILIDE, D-SOTALOL, CLOFILIUM, E-4031, AND UK-68,798 IN A RABBIT MODEL OF PROARRHYTHMIA

Class III agents have been associated with development of a polymorphi c ventricular tachycardia (PVT) known as torsades de pointes. We compa red the class III agent ibutilide, which prolongs repolarization throu gh enhancement of an inward sodium current, with the potassium channel blockers E-4031, UK-68,798, clofilium, and D-sotalol for proarrhythmi c effects in an anesthetized rabbit model. In these animals, prolongat ion of repolarization during alpha1 stimulation with methoxamine produ ces early after depolarizations (EADs) and a pause-dependent torsades de pointes-like PVT. Agents were compared over dosage ranges that prod uced maximal increases in QTc interval and monophasic action potential duration (MAPD). PVT typically developed after atrio-ventricular (A-V ) conduction block and slowing of heart rate (HR), and was preceded by development of repolarization arrhythmias characterized by EADs and t riggered activity producing extrasystolic beats. Ibutilide administrat ion resulted in significantly lower EAD amplitudes and a lower inciden ce of repolarization arrhythmias and PVT as compared with administrati on of other class III agents. The percentage of rabbits developing PVT for each agent was ibutilide 12%, D-sotalol 70%, E-4031 56%, UK-68,79 8 69%, and clofilium 80%. Rabbits receiving saline vehicle instead of a class III agent never developed conduction or repolarization abnorma lities or PVT. Under the conditions of this study at doses that genera te maximal class III effects, ibutilide produces lesser increases in Q Tc interval and MAPD, and EADs of lower amplitude, resulting in a lowe r incidence of repolarization arrhythmias and PVT as compared with oth er class III agents.