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 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). 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.
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 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). 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.
Authors: Sassan Rafizadeh; Zheng Zhang; Ryan L Woltz; Hyo Jeong Kim; Richard E Myers; Ling Lu; Dipika Tuteja; Anil Singapuri; Amir Ali Ziaei Bigdeli; Sana Ben Harchache; Anne A Knowlton; Vladimir Yarov-Yarovoy; Ebenezer N Yamoah; Nipavan Chiamvimonvat Journal: Proc Natl Acad Sci U S A Date: 2014-06-20 Impact factor: 11.205
Authors: Xiao-Dong Zhang; Valeriy Timofeyev; Ning Li; Richard E Myers; Dai-Min Zhang; Anil Singapuri; Victor C Lau; Chris T Bond; John Adelman; Deborah K Lieu; Nipavan Chiamvimonvat Journal: Cardiovasc Res Date: 2013-11-26 Impact factor: 10.787
Authors: Saagar Mahida; Robert W Mills; Nathan R Tucker; Bridget Simonson; Vincenzo Macri; Marc D Lemoine; Saumya Das; David J Milan; Patrick T Ellinor Journal: Cardiovasc Res Date: 2013-12-01 Impact factor: 10.787