title: Antiarrhythmic Mechanisms of SK Channel Inhibition in the Rat Atrium.
abstract: BACKGROUND
  SK channels have functional importance in the cardiac atrium of many species, including humans. Pharmacological blockage of SK channels has been reported to be antiarrhythmic in animal models of atrial fibrillation; however, the exact antiarrhythmic mechanism of SK channel inhibition remains unclear.
  
  
  OBJECTIVE
  We speculated that together with a direct inhibition of repolarizing SK current, the previously observed depolarization of the atrial resting membrane potential (RMP) after SK channel inhibition reduces sodium channel availability, thereby prolonging the effective refractory period and slowing the conduction velocity (CV). We therefore aimed at elucidating these properties of SK channel inhibition and the underlying antiarrhythmic mechanisms using microelectrode action potential (AP) recordings and CV measurements in isolated rat atrium. Automated patch clamping and two-electrode voltage clamp were used to access INa and IK,ACh, respectively.
  
  
  RESULTS
  The SK channel inhibitor N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) exhibited antiarrhythmic effects. ICA prevented electrically induced runs of atrial fibrillation in the isolated right atrium and induced atrial postrepolarization refractoriness and depolarized RMP. Moreover, ICA (1-10 μM) was found to slow CV; however, because of a marked prolongation of effective refractory period, the calculated wavelength was increased. Furthermore, at increased pacing frequencies, SK channel inhibition by ICA (10-30 μM) demonstrated prominent depression of other sodium channel-dependent parameters. ICA did not inhibit IK,ACh, but at concentrations above 10 μM, ICA use dependently inhibited INa.
  
  
  CONCLUSIONS
  SK channel inhibition modulates multiple parameters of AP. It prolongs the AP duration and shifts the RMP towards more depolarized potentials through direct ISK block. This indirectly leads to sodium channel inhibition through accumulation of state dependently inactivated channels, which ultimately slows conduction and decreases excitability. However, a contribution from a direct sodium channel inhibition cannot be ruled. We here propose that the primary antiarrhythmic mechanism of SK channel inhibition is through direct potassium channel block and through indirect sodium channel inhibition.
authors: *Danish National Research Foundation Centre for Cardiac Arrhythmia and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; †Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; and ‡Acesion Pharma, Copenhagen, Denmark.
authors: Lasse
authors: L
authors: Skibsbye
authors: Xiaodong
authors: X
authors: Wang
authors: Lene Nygaard
authors: LN
authors: Axelsen
authors: Sofia Hammami
authors: SH
authors: Bomholtz
authors: Morten Schak
authors: MS
authors: Nielsen
authors: Morten
authors: M
authors: Grunnet
authors: Bo Hjorth
authors: BH
authors: Bentzen
authors: Thomas
authors: T
authors: Jespersen
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000503:physiopathology; D016280:Atrial Function, Right / Q000187:drug effects* / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006325:Heart Atria / Q000187:drug effects; D008297:Male; D009924:Organ Culture Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D014982:Xenopus laevis
chemical_list: D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D051640:Small-Conductance Calcium-Activated Potassium Channels