title: Role of small-conductance calcium-activated potassium channels in atrial electrophysiology and fibrillation in the dog.
abstract: BACKGROUND
  Recent evidence points to functional Ca²⁺-dependent K⁺ (SK) channels in the heart that may govern atrial fibrillation (AF) risk, but the underlying mechanisms are unclear. This study addressed the role of SK channels in atrial repolarization and AF persistence in a canine AF model.
  
  
  RESULTS
  Electrophysiological variables were assessed in dogs subjected to atrial remodeling by 7-day atrial tachypacing (AT-P), as well as controls. Ionic currents and single-channel properties were measured in isolated canine atrial cardiomyocytes by patch clamp. NS8593, a putative selective SK blocker, suppressed SK current with an IC₅₀ of ≈5 μmol/L, without affecting Na⁺, Ca²⁺, or other K⁺ currents. Whole-cell SK current sensitive to NS8593 was significantly larger in pulmonary vein (PV) versus left atrial (LA) cells, without a difference in SK single-channel open probability (P(o)), whereas AT-P enhanced both whole-cell SK currents and single-channel P(o). SK-current block increased action potential duration in both PV and LA cells after AT-P; but only in PV cells in absence of AT-P. SK2 expression was more abundant at both mRNA and protein levels for PV versus LA in control dogs, in both control and AT-P; AT-P upregulated only SK1 at the protein level. Intravenous administration of NS8593 (5 mg/kg) significantly prolonged atrial refractoriness and reduced AF duration without affecting the Wenckebach cycle length, left ventricular refractoriness, or blood pressure.
  
  
  CONCLUSIONS
  SK currents play a role in canine atrial repolarization, are larger in PVs than LA, are enhanced by atrial-tachycardia remodeling, and appear to participate in promoting AF maintenance. These results are relevant to the potential mechanisms underlying the association between SK single-nucleotide polymorphisms and AF and suggest SK blockers as potentially interesting anti-AF drugs.
authors.affiliation: Research Center (X.-Y.Q., P.N., C.-T.W., H.H., M.H., M.A., S.N.), Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada; Cardiac and Circulatory Research Section (J.G.D., M.G.), Faculty of Health Sciences, University of Copenhagen and Acesion Pharma, Copenhagen, Denmark; Department of Clinical Pharmacology (B.J.J.M.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Division of Experimental Cardiology (X.-B.Z., D.D.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Chang-Gung Memorial Hospital and University Taoyuan (C.-T.W.), Taoyuan, Taiwan, China; Institute of Pharmacology (D.D.), Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Qi
authors.forename: Jonas G
authors.initials: JG
authors.lastname: Diness
authors.forename: Bianca J J M
authors.initials: BJ
authors.lastname: Brundel
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Zhou
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Wu
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.forename: Masahide
authors.initials: M
authors.lastname: Harada
authors.forename: Mona
authors.initials: M
authors.lastname: Aflaki
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001281:Atrial Fibrillation / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004285:Dogs; D022062:Electrophysiologic Techniques, Cardiac; D055724:Electrophysiological Phenomena / Q000502:physiology*; D006325:Heart Atria / Q000187:drug effects / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011667:Pulmonary Veins / Q000187:drug effects / Q000473:pathology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000502:physiology*
chemical_list: C515166:(R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine; D026902:Potassium Channel Blockers; D051640:Small-Conductance Calcium-Activated Potassium Channels; D015057:1-Naphthylamine
keywords: action potentials; anti-arrhythmia agents; electrophysiology; ion channels