Inhibition of small-conductance Ca2+-activated K+ channels terminates and protects against atrial fibrillation

TY - JOUR

T1 - Inhibition of small-conductance Ca2+-activated K+ channels terminates and protects against atrial fibrillation

AU - Diness, Jonas Goldin

AU - Sørensen, Ulrik S

AU - Nissen, Jakob Dahl

AU - Al-Shahib, Baha

AU - Jespersen, Thomas

AU - Grunnet, Morten

AU - Hansen, Rie Schultz

AU - Jespersen, Thomas

PY - 2010/8

Y1 - 2010/8

N2 - Background-Recently, evidence has emerged that small-conductance Ca 2+-activated K2+ (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.D.

AB - Background-Recently, evidence has emerged that small-conductance Ca 2+-activated K2+ (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.D.

KW - 1-Naphthylamine

KW - Acetylcholine

KW - Action Potentials

KW - Alkanes

KW - Animals

KW - Anti-Arrhythmia Agents

KW - Atrial Fibrillation

KW - Cardiac Pacing, Artificial

KW - Dose-Response Relationship, Drug

KW - Electrocardiography

KW - Female

KW - Guinea Pigs

KW - Male

KW - Myocardium

KW - Perfusion

KW - Potassium Channel Blockers

KW - Potassium Channels, Calcium-Activated

KW - Pyridines

KW - Quinolinium Compounds

KW - Rabbits

KW - Rats

KW - Rats, Sprague-Dawley

KW - Thiazoles

KW - Time Factors

U2 - 10.1161/CIRCEP.110.957407

DO - 10.1161/CIRCEP.110.957407

M3 - Journal article

C2 - 20562443

SN - 1941-3149

VL - 3

SP - 380

EP - 390

JO - Circulation: Arrhythmia and Electrophysiology

JF - Circulation: Arrhythmia and Electrophysiology

IS - 4

ER -