Nattel S, Liu L, St-Georges D
Department of Medicine, Institut de Cardiologie de Montréal, Quebec, Canada.
Cardiovasc Res. 1998 Mar;37(3):627-35. doi: 10.1016/s0008-6363(97)00252-6.
This study was designed to evaluate how the atrial electrophysiological and antiarrhythmic effects of azimilide compare with those of the specific rapid delayed rectifier (IKr) blocker dofetilide.
Azimilide, a new class III drug, was initially believed to be a highly selective blocker of the slow delayed rectifier (IKs), but recent studies suggest that azimilide potently blocks IKr. Thus, it has been suggested that azimilide's in vivo effects may simply be due to IKr blockade.
Dose regimens producing stable effects over time were developed, and two dose levels of azimilide (10 and then 20 mg/kg) or dofetilide (0.08 and then 0.16 mg/kg) were administered to morphine/chloralose-anesthetized dogs during sustained vagal atrial fibrillation (AF). Epicardial mapping was used to measure conduction velocity and AF cycle length.
Azimilide terminated AF in 13/14 dogs (93%), while dofetilide terminated AF in 6/12 (50%, P < 0.05). While dofetilide had strong reverse use-dependent effects on atrial ERP (e.g. at lower doses, dofetilide increased ERP by 51 +/- 3% at a basic cycle length, BCL, of 400 ms and by 17 +/- 3% at a BCL of 200 ms), azimilide's effects on ERP were rate-independent (ERP increased at lower dose by 38 +/- 6%, BCL 400 ms; 35 +/- 10%, BCL 200 ms). Neither drug affected conduction.
Azimilide is effective against experimental AF, and increases ERP with a frequency dependence different from the IKr blocker dofetilide, suggesting that azimilide's actions on atrial tissue cannot be attributed exclusively to IKr block, and that effects on other currents (such as IKs) are likely to be important.
本研究旨在评估阿齐利特的心房电生理及抗心律失常作用与特异性快速延迟整流钾电流（IKr）阻滞剂多非利特相比如何。
阿齐利特是一种新型III类药物，最初被认为是慢延迟整流钾电流（IKs）的高度选择性阻滞剂，但最近的研究表明阿齐利特可有效阻断IKr。因此，有人提出阿齐利特的体内效应可能仅仅是由于IKr阻断。
制定了随时间产生稳定效应的给药方案，在持续性迷走神经介导的心房颤动（AF）期间，给吗啡/氯醛糖麻醉的犬给予两个剂量水平的阿齐利特（10mg/kg，然后20mg/kg）或多非利特（0.08mg/kg，然后0.16mg/kg）。采用心外膜标测测量传导速度和AF周期长度。
阿齐利特使13/14只犬（93%）的AF终止，而多非利特使6/12只犬（50%，P<0.05）的AF终止。虽然多非利特对心房ERP有强烈的反向使用依赖性效应（例如，在较低剂量时，多非利特在基础周期长度（BCL）为400ms时使ERP增加51±3%，在BCL为200ms时使ERP增加17±3%），但阿齐利特对ERP的效应与频率无关（在较低剂量时，BCL为400ms时ERP增加38±6%；BCL为200ms时ERP增加35±10%）。两种药物均不影响传导。
阿齐利特对实验性AF有效，其增加ERP的频率依赖性与IKr阻滞剂多非利特不同，这表明阿齐利特对心房组织的作用不能完全归因于IKr阻断，对其他电流（如IKs）的作用可能也很重要。
