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

利用新的犬房颤模型寻找治疗房颤的上游药物

• 批准号: 17590216
• 负责人: SUGIYAMA Atsushi
• 金额: $ 2.24万
• 依托单位: University of Yamanashi
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590216/
• 关键词: atrial fibrillation; atrioventricular block; amiodarone; candesartan; upstream; アップストリーム治療薬; 発作性心房細動モデル犬; アンジオテンシンII; うっ血性心不全; カテーテルアブレーション法; MRI; ANP

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.

用体重约10 kg的犬慢性房室传导阻滞评价了胺碘酮和坎地沙坦对充血性心力衰竭重构心房的电药理学作用。胺碘酮以200 mg/人/天的剂量口服给药，最初7天，随后100 mg给药，随后21天（n=7），而坎地沙坦以12 mg/人/天的剂量给药，持续28天（n=7）。所有动物在实验期均存活4周，这表明这些药物没有诱导心脏血流动力学衰竭或尖端扭转型室性心动过速的风险。4周时胺碘酮的血浆浓度为353 ng/ml，而静脉注射30 ng/kg血管紧张素II使对照组的平均血压升高18 mmHg，坎地沙坦治疗4周后显著降低至1 mmHg。胺碘酮延长心房有效不应期而不影响心房传导时间，缩短短阵起搏诱导的房颤持续时间，而坎地沙坦几乎不影响这些变量。这些结果表明，胺碘酮将成为一个实用的药理学策略，对房颤患者的慢性代偿性心力衰竭，并建议，更高剂量的坎地沙坦可能需要发挥其疗效在这个模型中。

项目成果

Halothane sensitizes the guinea pig heart to pharmacological IKr blockade : comparison with urethane anesthesia

氟烷使豚鼠心脏对药物 IKr 阻断敏感：与聚氨酯麻醉的比较

• 发表时间: 2005
• 期刊: J Pharmacol Sci 99・2
• 作者: Sakaguchi Y;Sugiyama A;Takao S;Akie Y;Takahara T;Hashimoto K
• 通讯作者: Hashimoto K

The chronic atrioventricular block dog as a model of lethal ventricular tachyarrhythmia: cardiovascular and neurohumoral profiles and its potential arrhythmogenic mechanisms.

慢性房室传导阻滞狗作为致命性室性快速心律失常的模型：心血管和神经体液特征及其潜在的致心律失常机制。

• 发表时间: 2007
• 期刊: Basic ＆ Clinical Pharmacology ＆ Toxicology (印刷中)
• 作者: Takahara A;Sugiyama A;Satoh Y;Iwasaki H;Nakamura Y;Hashimoto K
• 通讯作者: Hashimoto K

Halothane sensitizes the guinea pig heart to pharmacological I_<kr> blockade : comparison with urethane anesthesia

氟烷使豚鼠心脏对药理学 I_<kr> 阻断敏感：与聚氨酯麻醉的比较

• 发表时间: 2005
• 期刊: J Pharmacol Sci 99-2
• 作者: Sakaguchi Y;Sugivama A;Takao S;Akie Y;Takahara T;Hashimoto K
• 通讯作者: Hashimoto K

Long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect the histamine H_1 blocker terfenadine-induced torsadesde pointes arrhythmias.

房室传导阻滞引起的长期心动过缓可重塑犬心脏，以检测组胺H_1阻滞剂特非那定引起的尖端扭转型室速心律失常。

• 发表时间: 2006
• 期刊: Br J Pharmacol 147・6
• 作者: Takahara A;Sugiyama A;Ishida Y;Wang K;Nakamura Y;Hashimoto K
• 通讯作者: Hashimoto K

Long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect the histamine H_I blocker terfenadine-induced torsades de pointes arrhythmias

房室传导阻滞引起的长期心动过缓可重塑犬心脏以检测组胺H_I阻滞剂特非那丁诱发的尖端扭转型心律失常

• 发表时间: 2006
• 期刊: Br J Pharmacol 1147-6
• 作者: Takahara A;Sugivama A;Ishida Y;Wang K;Nakamura Y;Hashimoto K
• 通讯作者: Hashimoto K