title: Inhibition of small-conductance Ca2+-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.
  
  
  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.affiliation: NeuroSearch A/S, Pederstrupvej 93, Ballerup, Denmark.
authors.forename: Jonas Goldin
authors.initials: JG
authors.lastname: Diness
authors.forename: Ulrik S
authors.initials: US
authors.lastname: Sørensen
authors.forename: Jakob Dahl
authors.initials: JD
authors.lastname: Nissen
authors.forename: Baha
authors.initials: B
authors.lastname: Al-Shahib
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.forename: Rie Schultz
authors.initials: RS
authors.lastname: Hansen
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials; D000473:Alkanes / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D002304:Cardiac Pacing, Artificial; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
chemical_list: C515166:(R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine; C110349:6,10-diaza-3(1,3),8(1,4)dibenzena-1,5(1,4)diquinolinacyclodecaphane; D000473:Alkanes; D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D011725:Pyridines; D011806:Quinolinium Compounds; D013844:Thiazoles; D015057:1-Naphthylamine; D000109:Acetylcholine