NeuroSearch A/S, Pederstrupvej 93, Ballerup, Denmark.
Circ Arrhythm Electrophysiol. 2010 Aug;3(4):380-90. doi: 10.1161/CIRCEP.110.957407. Epub 2010 Jun 19.
Recently, evidence has emerged that small-conductance Ca(2+)-activated K(+) (SK) channels are predominantly expressed in the atria in a number of species including human. In rat, guinea pig, and rabbit ex vivo and in vivo models of atrial fibrillation (AF), we used 3 different SK channel inhibitors, UCL1684, N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA), and NS8593, to assess the hypothesis that pharmacological inhibition of SK channels is antiarrhythmic.
In isolated, perfused guinea pig hearts, AF could be induced in all control hearts (n=7) with a combination of 1 micromol/L acetylcholine combined with electric stimulation. Pretreatment with 3 micromol/L NS8593, which had no effect on QT interval, prolonged the atrial effective refractory period by 37.1+/-7.7% (P<0.001) and prevented acetylcholine-induced AF (P<0.001, n=7). After AF induction, perfusion with NS8593 (10 micromol/L), UCL1684 (1 micromol/L), or ICA (1 micromol/L) terminated AF in all hearts, comparable to 10 micromol/L amiodarone. In isolated, perfused rat hearts, AF was induced with electric stimulation; 10 micromol/L NS8593 terminated AF and prevented reinduction of AF in all hearts (n=6, P<0.001). In all hearts, AF could be reinduced after washing. In isolated, perfused rabbit hearts, AF was induced with 10 micromol/L acetylcholine and burst pacing; 10 micromol/L NS8593 terminated AF and prevented reinduction of AF in all hearts (n=6, P<0.001). After washing, AF could be reinduced in 75% of the hearts (n=4, P=0.06). In an in vivo rat model of acute AF induced by burst pacing, injection of 5 mg/kg of either NS8593 or amiodarone shortened AF duration significantly to (23.2+/-20.0%, P<0.001, n=5, and 26.2+/-17.9%, P<0.001, n=5, respectively) as compared with injection of vehicle (96.3+/-33.2%, n=5).
Inhibition of SK channels prolongs atrial effective refractory period without affecting QT interval and prevents and terminates AF ex vivo and in vivo, thus offering a promising new therapeutic opportunity in the treatment of AF.
最近有证据表明，小电导钙激活钾（SK）通道在包括人类在内的许多物种的心房中主要表达。在大鼠、豚鼠和兔的体外和体内心房颤动（AF）模型中，我们使用了 3 种不同的 SK 通道抑制剂，UCL1684、N-（吡啶-2-基）-4-（吡啶-2-基）噻唑-2-胺（ICA）和 NS8593，以评估 SK 通道的药理学抑制是否具有抗心律失常作用的假说。
在分离的、灌注的豚鼠心脏中，用 1 μmol/L 乙酰胆碱联合电刺激可在所有对照心脏（n=7）中诱导 AF。预先用 3 μmol/L NS8593 预处理，对 QT 间期无影响，使心房有效不应期延长 37.1+/-7.7%（P<0.001），并防止乙酰胆碱诱导的 AF（P<0.001，n=7）。在 AF 诱导后，用 NS8593（10 μmol/L）、UCL1684（1 μmol/L）或 ICA（1 μmol/L）灌注可终止所有心脏的 AF，与 10 μmol/L 胺碘酮相当。在分离的、灌注的大鼠心脏中，用电刺激诱导 AF；10 μmol/L NS8593 终止 AF，并防止所有心脏再次诱导 AF（n=6，P<0.001）。在所有心脏中，AF 均可在洗涤后再次诱导。在分离的、灌注的兔心脏中，用 10 μmol/L 乙酰胆碱和爆发起搏诱导 AF；10 μmol/L NS8593 终止 AF，并防止所有心脏再次诱导 AF（n=6，P<0.001）。洗涤后，75%的心脏（n=4，P=0.06）可再次诱导 AF。在由爆发起搏诱导的急性大鼠 AF 体内模型中，注射 5 mg/kg 的 NS8593 或胺碘酮可显著缩短 AF 持续时间（分别为 23.2+/-20.0%，P<0.001，n=5 和 26.2+/-17.9%，P<0.001，n=5），与注射载体（96.3+/-33.2%，n=5）相比。
抑制 SK 通道可延长心房有效不应期，而不影响 QT 间期，并预防和终止体外和体内的 AF，因此为 AF 的治疗提供了一个有希望的新治疗机会。
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