Efficacy of azimilide and dofetilide in the dog right atrial enlargement model of atrial flutter

Introduction: Azimilide dihydrochloride blocks both the rapid (I-Kr) and sl ow (I-Ks) components of the delayed rectified K+ current; dofetilide blocks only I-Kr. Their efficacies were assessed on atrial flutter reentrant circ uits in dogs with surgically induced right atrial enlargement. Methods and Results: Multiple biopsies of the tricuspid valve and banding o f the pulmonary artery in male mongrel dogs made them susceptible, about 3 weeks postoperatively, to stimulation-induced sustained (5 min or longer) a trial flutter. Azimilide 3 mg/kg administered intravenously (IV) terminated flutter in 8 of 8 dogs, but a slower, nonsustained arrhythmia could be rei nduced in 5. In these 5 dogs, azimilide 10 mg/kg terminated flutter and pre vented reinduction. This dose increased effective refractory period signifi cantly more in the slow conduction zone (25%) than in the normal zone (17%) and increased flutter cycle length (37%). Termination followed progressive conduction delay in the slow zone of the reentrant circuit. Dofetilide 1 m ug/kg IV terminated flutter in 6 of 6 dogs, but the arrhythmia could be rei nduced. At 3 mug/kg, flutter terminated in all dogs and could not be reindu ced. Dofetilide also increased the effective refractory period significantl y more in the slow zone (17%) than in the normal zone (12%) and increased c ycle length (33%), leading to interruption of the arrhythmia circuit. Conclusion: In the canine right atrial enlargement model of circus movement atrial flutter, both azimilide 10 mg/kg IV and dofetilide 3 mug/kg IV were 100% effective in terminating flutter and preventing reinduction. Efficacy relied on a similar mechanism of differentially prolonged refractoriness i n the slow conduction component of the reentrant circuit where drug-induced termination occurred.