Efficacy of the Class III Antiarrhythmic Agent Azimilide in Rodent Models of Ventricular Arrhythmia

Abstract

Azimilide exhibited antiarrhythmic activity in several rodent models of ventricular arrhythmias. In the mouse chloroform model, azimilide provided limited efficacy by the i.p. route (50% at 100 mg/kg versus 20% by vehicle), and no efficacy by the oral route (300 mg/kg). In a rat model in which arrhythmias are induced by ligation and reperfusion of the left descending coronary artery (CALR model), azimilide provided dose-dependent (1-18 mg/kg) efficacy by the intravenous route. The estimated dose that suppressed ventricular fibrillation (VF) was 5.0 mg/kg i.v. At 18 mg/kg i.v. azimilide also partially suppressed ventricular tachyarrhythmia (VT) and extrasystoles (VES). Rats dosed orally (100 mg/kg) were fully protected from VF. In isolated guinea pig hearts exposed to 1 microM ouabain, azimilide at 10 microM prevented the VT and VF seen in 69% and 23%, respectively, of control hearts. In anesthetized guinea pigs, azimilide at 10 and 30 mg/kg i.v. increased the dose of ouabain required to induce VES. While sematilide, dofetilide, and E-4031 significantly 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 other class III agents, since azimilide had less efficacy in the mouse chloroform model, could suppress VT and VES as well as VF in the CALR rat model, and protected from or did not aggravate cardiac glycoside-induced arrhythmias in guinea pigs. These results demonstrating the antiarrhythmic efficacy of azimilide in the intact animal suggest that the compound has a different profile than other class III agents.

Pharmacology of Azimilide Dihydrochloride (NE‐10064), A Class III Antiarrhythmic Agent

“…In contrast, hearts treated with clofilium, d,I-sotalol, dofetilide, d-sotalol, E-403 1, or sematilide had a higher incidence of VT than control hearts (8).…”

“…administered azimilide, 100 mgkg, significantly protected 50% of 20 mice but was less effective orally, providing only 20% to 25% protection at 300 mgkg p.0. (8). In anesthetized guinea pigs infused with ouabain, azimilide, 10 and 30 mgkg i.v., significantly raised the threshold dose for the onset of ventricular arrhythmias (8).…”

State-Dependent Blocking Actions of Azimilide Dihydrochlo-ride (NE-10064) on Human Cardiac Na+ Channels

“…The IC50 values for azimilide-induced block of the human Na + channel was smaller than that of canine ventricular myocytes, 12 but larger than its plasma concentration in the clinical setting. 4 These results indicate that azimilide produces a greater tonic block in WT currents at more depolarized membrane potentials. The voltage-dependent properties of azimilide block indicated higher affinity of this agent for the inactivated state of the WT currents than for the resting state.…”

“…4 The higher affinity of azimilide for the inactivated state channel could cause a strong blocking action on the Na + channels in the diseased heart with depolarized membrane potentials. Because the activated state blocker generally blocks cardiac conduction independent of the action potential duration, azimilide can similarly block the conduction of the atrial action potential with a short effective refractory period as pilsicainide.…”

“…[1][2][3] These in vitro electrophysiologic properties of azimilide could account for its antiarrhythmic and antifibrillatory actions in a number of animal models, which could be classified as class III antiarrhythmic actions. [4][5][6][7][8][9][10] It has been reported that azimilide interacts with other cardiac ion channels, blocking the L-type Ca 2+ channel, the inward rectifier K + channel, and the Na + channel, 11-13 but so far there have not been any systematic studies of the effects of azimilide on the cardiac Na + channels and little is known about the statedependent azimilide block of the Na + channels, although a few reports indicated that azimilide blocked cardiac peak Circulation Journal Vol. 68, July 2004 and late Na + currents.…”