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

用体重约10 kg的犬慢性房室传导阻滞模型评价了长期给药胺碘酮和坎地沙坦对充血性心力衰竭犬心房重塑的电药理作用。胺碘酮200 mg/体/d，开始7d，然后100 mg/体/d，连续21d(n=7)，坎地沙坦12 mg/体/d，28d(n=7)。所有动物在试验期内存活了4周，这表明这些药物没有导致心脏血流动力学衰竭或尖端扭矩的风险。4周时血浆胺碘酮浓度为353 ng/ml，静脉注射血管紧张素II 30 ng/kg使对照组平均血压升高18 mm Hg，坎地沙坦治疗4周后平均血压降至1 mm Hg。胺碘酮延长心房有效不应期而不影响房室传导时间，缩短阵发性心房颤动持续时间，坎地沙坦对上述参数无明显影响。这些结果表明，胺碘酮将成为对抗慢性代偿性心力衰竭患者房颤的一种实用的药理学策略，并提示在这种模型中，更大剂量的坎地沙坦可能需要发挥其作用。

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.