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

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Azimilide dihydrochloride blocks both the rapid (I(Kr)) and slow (I(Ks)) components of the delayed rectified K+ current; dofetilide blocks only I(Kr). Their efficacies were assessed on atrial flutter reentrant circuits in dogs with surgically induced right atrial enlargement. Multiple biopsies of the tricuspid valve and banding of the pulmonary artery in male mongrel dogs made them susceptible, about 3 weeks postoperatively, to stimulation-induced sustained (5 min or longer) atrial flutter. Azimilide 3 mg/kg administered intravenously (i.v.) terminated flutter in 8 of 8 dogs, but a slower, nonsustained arrhythmia could be reinduced in 5. In these 5 dogs, azimilide 10 mg/kg terminated flutter and prevented reinduction. This dose increased effective refractory period significantly 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 microg/kg i.v. terminated flutter in 6 of 6 dogs, but the arrhythmia could be reinduced. At 3 microg/kg, flutter terminated in all dogs and could not be reinduced. Dofetilide also increased the effective refractory period significantly more in the slow zone (17%) than in the normal zone (12%) and increased cycle length (33%), leading to interruption of the arrhythmia circuit. In the canine right atrial enlargement model of circus movement atrial flutter, both azimilide 10 mg/kg i.v. and dofetilide 3 microg/kg i.v. were 100% effective in terminating flutter and preventing reinduction. Efficacy relied on a similar mechanism of differentially prolonged refractoriness in the slow conduction component of the reentrant circuit where drug-induced termination occurred.