title: Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses.
abstract: BACKGROUND
  Small-conductance calcium-activated potassium (SK) channels have been found to play an important role in atrial repolarization and atrial fibrillation (AF).
  
  
  OBJECTIVE
  The purpose of this study was to investigate the existence and functional role of SK channels in the equine heart.
  
  
  METHODS
  Cardiac biopsies were analyzed to investigate the expression level of the most prominent cardiac ion channels, with special focus on SK channels, in the equine heart. Subcellular distribution of SK isoform 2 (SK2) was assessed by immunohistochemistry and confocal microscopy. The electrophysiologic and anti-AF effects of the relative selective SK channel inhibitor NS8593 (5 mg/kg IV) were evaluated in anesthetized horses, focusing on the potential of NS8593 to terminate acute pacing-induced AF, drug-induced changes in atrial effective refractory period, AF duration and vulnerability, and ventricular depolarization and repolarization times.
  
  
  RESULTS
  Analysis revealed equivalent mRNA transcript levels of the 3 SK channel isoforms in atria compared to ventricles. Immunohistochemistry and confocal microscopy displayed a widespread distribution of SK2 in both atrial and ventricular cardiomyocytes. NS8593 terminated all induced AF episodes (duration ≥15 minutes), caused pronounced prolongation of atrial effective refractory period, and reduced AF duration and vulnerability. QRS duration and QTc interval were not affected by treatment.
  
  
  CONCLUSIONS
  SK channels are widely distributed in atrial and ventricular cardiomyocytes and contribute to atrial repolarization. Inhibition by NS8593 terminates pacing-induced AF of short duration and decreases AF duration and vulnerability without affecting ventricular conduction and repolarization. Thus, inhibition by NS8593 demonstrates clear atrial antiarrhythmic properties in healthy horses.
authors.affiliation: Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: mmha@sund.ku.dk.
authors.forename: Maria Mathilde
authors.initials: MM
authors.lastname: Haugaard
authors.affiliation: Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Eva Zander
authors.initials: EZ
authors.lastname: Hesselkilde
authors.affiliation: Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Taastrup, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Pehrson
authors.affiliation: Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Helena
authors.initials: H
authors.lastname: Carstensen
authors.affiliation: Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Flethøj
authors.affiliation: Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kirstine Færgemand
authors.initials: KF
authors.lastname: Præstegaard
authors.affiliation: Acesion Pharma, Copenhagen, Denmark.
authors.forename: Ulrik Svane
authors.initials: US
authors.lastname: Sørensen
authors.affiliation: Acesion Pharma, Copenhagen, Denmark.
authors.forename: Jonas Goldin
authors.initials: JG
authors.lastname: Diness
authors.affiliation: Acesion Pharma, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.affiliation: Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Buhl
authors.affiliation: Danish National Foundation Research Centre in Arrhythmias (DARC) and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006736:Horses; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D008953:Models, Anatomic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D016896:Treatment Outcome
chemical_list: C515166:(R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine; D000889:Anti-Arrhythmia Agents; D051640:Small-Conductance Calcium-Activated Potassium Channels; D015057:1-Naphthylamine
keywords: Antiarrhythmic drugs; Atrial electrophysiology; Atrial fibrillation; Equine; Horse; NS8593; Pacing; Programmed electrical stimulation; Reverse transcription polymerase chain reaction