Effects of Azimilide on the Muscarinic Acetylcholine Receptor-Operated K(+) Current and Experimental Atrial Fibrillation in Guinea-Pig Hearts

　　阿齐利特是一个III类的抗心律失常药，我们用膜片钳技术在豚鼠的心房细胞检测到了一个乙酰胆碱受体相关钾电流I(K.ACh)和一个矫正的延迟钾电流(IK)，阿齐利特对实验性房颤的影响也在离体动物心脏实验中得到验证。在单个心房肌细胞阿齐利特同时抑制快速钾电流(Kr)和缓慢钾电流(Ks)，阿齐利特以一个浓度相关的模式抑制由卡巴胆碱(CCh, 1 muM)，腺苷(10 muM)和细胞内的GTPgammaS负荷诱导的电流(K.ACh)。阿齐利特对卡巴胆碱，腺苷和GTPgammaS诱导的I(K.ACh)的负荷半浓度抑制值分别是1.25, 29.1, and 20.9 muM，试验提示，阿齐利特主要通过阻滞M-受体抑制I(K.ACh)。在有或没有毒蕈碱刺激的情况下，阿齐利特浓度依赖(0.3 - 10 muM)的延长动作电位间期。在离体心脏，灌注卡巴胆碱缩短左房的单相动作电位（MAP）间期和有效不应期(ERP)，降低房颤阈值。增加的阿齐利特剂量通过延长MAP 和 ERP间期抑制房颤发生。I(K.ACh)抑制可能是阿齐利特预防副交感性房颤的机制之一。

　　（来源：J Pharmacol Sci. 2007 Oct 27）

Effects of Azimilide on the Muscarinic Acetylcholine Receptor-Operated K(+) Current and Experimental Atrial Fibrillation in Guinea-Pig Hearts.

Nishida A, Reien Y, Ogura T, Uemura H, Tamagawa M, Yabana H, Nakaya H.
Department of Pharmacology, Chiba University Graduate School of Medicine, Japan.

Effects of azimilide, a class III antiarrhythmic drug, on the acetylcholine (ACh) receptor-operated K(+) current (I(K.ACh)) and the delayed rectifier K(+) current (I(K)) were examined in guinea-pig atrial cells using patch-clamp techniques. Effects of azimilide on experimental atrial fibrillation (AF) were also examined in isolated guinea-pig hearts. In single atrial myocytes, azimilide inhibited both the rapid (I(Kr)) and slow component of I(K) (I(Ks)). Azimilide inhibited the I(K.ACh) induced by carbachol (CCh, 1 muM), adenosine (10 muM), and intracellular loading of GTPgammaS (100 muM) in a concentration-dependent manner. The IC(50) values of azimilide for inhibiting the CCh-, adenosine-, and GTPgammaS-induced I(K.ACh) were 1.25, 29.1, and 20.9 muM, respectively, suggesting that azimilide inhibits I(K.ACh) mainly by blocking the muscarinic receptors. Azimilide concentration-dependently (0.3 - 10 muM) prolonged the action potential duration (APD) in the absence and presence of muscarinic stimulation. In isolated hearts, perfusion of CCh shortened the duration of the monophasic action potential (MAP) and effective refractory period (ERP) of the left atrium and lowered the atrial fibrillation threshold (AFT). Addition of azimilide inhibited the induction of AF by prolonging the duration of MAP and ERP. The I(K.ACh) inhibition by azimilide may at least in part contribute to the effectiveness to prevent parasympathetic-type AF.