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 -