Effects of the novel antiarrhythmic agent azimilide on experimental atrial fibrillation and atrial electrophysiologic properties.
OBJECTIVE
This study was designed to evaluate how the atrial electrophysiological and antiarrhythmic effects of azimilide compare with those of the specific rapid delayed rectifier (IKr) blocker dofetilide.


BACKGROUND
Azimilide, a new class III drug, was initially believed to be a highly selective blocker of the slow delayed rectifier (IKs), but recent studies suggest that azimilide potently blocks IKr. Thus, it has been suggested that azimilide's in vivo effects may simply be due to IKr 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 IKr blocker dofetilide, suggesting that azimilide's actions on atrial tissue cannot be attributed exclusively to IKr block, and that effects on other currents (such as IKs) are likely to be important.
Nattel
S
S
Department of Medicine, Institut de Cardiologie de Montréal, Quebec, Canada.
Liu
L
L
St-Georges
D
D
D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D016009:Chi-Square Distribution; D004285:Dogs; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D006325:Heart Atria / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006827:Hydantoins; D007093:Imidazoles / Q000627:therapeutic use*; D048289:Imidazolidines; D008297:Male; D010627:Phenethylamines / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use*; D026902:Potassium Channel Blockers; D013449:Sulfonamides / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010627:Phenethylamines; D010879:Piperazines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C086123:azimilide; C063533:dofetilide