EFFICACY OF THE CLASS-III ANTIARRHYTHMIC AGENT AZIMILIDE IN RODENT MODELS OF VENTRICULAR ARRHYTHMIA

Azimilide exhibited antiarrhythmic activity in several rodent models o f ventricular arrhythmias, In the mouse chloroform model, azimilide pr ovided limited efficacy by the ip route (50% at 100 mg/kg versus 20% b y vehicle), and no efficacy by the oral route (300 mg/kg), In a rat mo del in which arrhythmias are induced by ligation and reperfusion of th e left descending coronary artery (CALR model), azimilide provided dos e-dependent (1-18 mg/kg) efficacy by the intravenous route, The estima ted dose that suppressed ventricular fibrillation (VF) was 5.0 mg/kg i v. At 18 mg/kg iv azimilide also partially suppressed ventricular tach yarrhythmia (VT) and extrasystoles (VES), Rats dosed orally (100 mg/kg ) were fully protected from VF, In isolated guinea pig hearts exposed to 1 mu M ouabain, azimilide at 10 mu M prevented the VT and VF seen i n 69% and 23%, respectively, of control hearts. In anesthetized guinea pigs, azimilide at 10 and 30 mg/kg iv increased the dose of ouabain r equired to induce VES, While sematilide, dofetilide, and E-4031 signif icantly increased sensitivity to the arrhythmogenic actions of ouabain (by lowering the dose that caused VF), azimilide did not, Azimilide's antiarrhythmic profile in these rodent models differs from that of ot her class III agents, since azimilide had less efficacy in the mouse c hloroform model, could suppress VT and VES as well as VF in the CALR r at model, and protected from or did not aggravate cardiac glycoside-in duced arrhythmias in guinea pigs. These results demonstrating the anti arrhythmic efficacy of azimilide in the intact animal suggest that the compound has a different profile than other class III agents.