Search of upstream drugs for treatment of atrial fibrillation using a new canine atrial fibrillation model

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Electropharmacological effects of chronically administered amiodarone and candesartan on atria having been remodeled against congestive heart failure were assessed using the canine chronic atrioventricular block dogs weighing about 10 kg. Amiodarone was administered orally in a dose of 200 mg/body/day for initial 7 days followed by 100 mg for following 21 days (n=7), whereas candesartan was administered in a dose of 12 mg/body/day for 28 days (n=7). All animals survived 4 weeks of the experimental period, which indicates lack of risks for inducing cardiohemodynamic collapse or torsade de pointes by these drugs. Plasma amiodarone concentration was 353 ng/ml at 4 weeks, whereas intravenous administration of 30 ng/kg of angiotensin II increased the mean blood pressure by 18 mmHg at control, which was significantly decreased to 1 mmHg after the 4 weeks of candesartan treatment. Amiodarone prolonged the atrial effective refractory period without affecting inter-atrial conduction time and decreased the duration of the burst pacing-induced atrial fibrillation, whereas candesartan hardly affected these variables. These results indicate that amiodarone will become a pragmatic pharmacological strategy against atrial fibrillation in patients with chronically compensated heart failure, and suggest that much higher dose of candesartan may need to exert its efficacy in this model.