Inhibition of Small-Conductance Ca 2+ -Activated K + Channels Terminates and Protects Against Atrial Fibrillation

Abstract

Background— 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. Methods and Results— In isolated, perfused guinea pig hearts, AF could be induced in all control hearts (n=7) with a combination of 1 μmol/L acetylcholine combined with electric stimulation. Pretreatment with 3 μmol/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 μmol/L), UCL1684 (1 μmol/L), or ICA (1 μmol/L) terminated AF in all hearts, comparable to 10 μmol/L amiodarone. In isolated, perfused rat hearts, AF was induced with electric stimulation; 10 μmol/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 μmol/L acetylcholine and burst pacing; 10 μmol/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). Conclusions— 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.