Effects of the novel antiarrhythmic agent azimilide on experimental atrial fibrillation and atrial electrophysiologic properties

Objectives: This study was designed to evaluate how the atrial electrophysiological and antiarrhythmic effects of azimilide compare with those of the specific rapid delayed rectifier (I-K1) blocker dofetilide. Background: Azimilide, a new class III drug, was initially believed to be a highly selective blocker of the slow delayed rectifier (I-K5), but recent studies suggest that azimilide potently blocks I-K1,. Thus, it has been suggested that azimilide's in vivo effects may simply be due to I-K1 blockade, Methods: Dose regimens producing stable effects over time were developed, and two dose levels of azimilide (10 and then 20 mg/kg) or dofetilide (0.08 and then 0.16 mg/kg) were administered to morphine/chloralose-anesthetized dogs during sustained vagal atrial fibrillation (AF). Epicardial mapping was used to measure conduction velocity and AF cycle length. Results: Azimilide terminated AF in 13/14 dogs (93%), while dofetilide terminated AF in 6/12 (50%, P < 0.05). While dofetilide had strong reverse use-dependent effects on atrial ERP (e.g. at lower doses, dofetilide increased ERP by 51 +/- 3% at a basic cycle length, BCL, of 400 ms and by 17 +/- 3% at a BCL of 200 ms), azimilide's effects on ERP were rate-independent (ERP increased at lower dose by 38.6%, BCL 400 ms; 35 +/- 10%, BCL 200 ms). Neither drug affected conduction. Conclusions: Azimilide is effective against experimental AF, and increases ERP with a frequency dependence different from the I-K1 blocker dofetilide, suggesting that azimilide's actions on atrial tissue cannot be attributed exclusively to I-K1 block, and that effects on other currents (such as I-K5) are likely to be important. (C) 1998 Elsevier Science B.V.