Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Tokyo, Japan.
Circ Arrhythm Electrophysiol. 2011 Feb;4(1):94-102. doi: 10.1161/CIRCEP.110.951608. Epub 2010 Dec 14.
The acetylcholine-activated K(+) current (I(K,ACh)) is a novel candidate for atrial-specific antiarrhythmic therapy. The present study investigates the involvement of I(K,ACh) in atrial fibrillation (AF) using NTC-801, a novel potent and selective I(K,ACh) blocker.
The effects of NTC-801, substituted 4-(aralkylamino)-2,2-dimethyl-3,4-dihydro-2H-benzopyran-3-ol, on I(K,ACh) and other cardiac ionic currents (I(Na), I(CaL), I(to), I(Kur), I(Kr), I(Ks), I(Kl), I(KATP), and I(f)) and on atrial and ventricular action potentials were examined in vitro. NTC-801 potently inhibited carbachol-induced I(K,ACh) in guinea pig atrial cells and the GIRK1/4 current in Xenopus oocytes with IC(50) values of 5.7 and 0.70 nmol/L, respectively. NTC-801 selectively inhibited I(K,ACh) >1000-fold over other cardiac ionic currents. NTC-801 (10 to 100 nmol/L) reversed the action potential duration (APD(90)) shortened by carbachol or adenosine in atrial cells, whereas it did not affect APD(90) at 100 nmol/L in ventricular cells. Antiarrhythmic effects of NTC-801 were evaluated in 3 AF models in vivo. NTC-801 significantly prolonged atrial effective refractory period without affecting ventricular effective refractory period under vagal nerve stimulation. NTC-801 dose-dependently converted AF to normal sinus rhythm in both vagal nerve stimulation-induced (0.3 to 3 μg · kg(-1) · min(-1) IV) and aconitine-induced (0.01 to 0.1 mg/kg IV) models. In a rapid atrial pacing model, NTC-801 (3 μg · kg(-1) · min(-1) IV) significantly decreased AF inducibility with a prolonged atrial effective refractory period that was frequency-independent.
A selective I(K,ACh) blockade induced by NTC-801 exerted anti-AF effects mediated by atrial-selective effective refractory period prolongation. These findings suggest that I(K,ACh) may be important in the development and maintenance of AF.
乙酰胆碱激活的钾电流（I（KACh））是一种新型的抗心律失常治疗的候选药物。本研究使用新型强效和选择性 I（KACh）阻断剂 NTC-801 研究在心房颤动（AF）中的作用。
在体外研究了 NTC-801（取代的 4-（芳基烷基氨基）-2,2-二甲基-3,4-二氢-2H-苯并吡喃-3-醇）对 I（KACh）和其他心脏离子电流（I（Na），I（CaL），I（to），I（Kur），I（Kr），I（Ks），I（Kl），I（KATP）和 I（f））以及心房和心室动作电位的影响。NTC-801 以 5.7 和 0.70 nmol/L 的 IC50 值在豚鼠心房细胞中强烈抑制毒蕈碱诱导的 I（KACh）和 Xenopus 卵母细胞中的 GIRK1/4 电流。NTC-801 选择性抑制 I（KACh）> 1000 倍，超过其他心脏离子电流。NTC-801（10 至 100 nmol/L）逆转了毒蕈碱或腺苷引起的心房细胞动作电位时程（APD（90））缩短，但在 100 nmol/L 时对心室细胞的 APD（90）没有影响。NTC-801 的抗心律失常作用在体内 3 种 AF 模型中进行了评估。NTC-801 在迷走神经刺激下显著延长心房有效不应期，而不影响心室有效不应期。NTC-801 剂量依赖性地将 AF 转换为正常窦性心律，无论是在迷走神经刺激诱导（0.3 至 3μg·kg（-1）·min（-1）静脉内）还是在乌头碱诱导（0.01 至 0.1mg/kg 静脉内）模型中。在快速心房起搏模型中，NTC-801（3μg·kg（-1）·min（-1）静脉内）显著降低了 AF 的诱导性，并延长了与频率无关的心房有效不应期。
NTC-801 诱导的选择性 I（KACh）阻断作用通过心房选择性有效不应期延长发挥抗 AF 作用。这些发现表明，I（KACh）可能在 AF 的发生和维持中起重要作用。
