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Kirstine Færgemand Præstegaard

Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Maria Mathilde Haugaard
  • ,
  • Eva Zander Hesselkilde
  • ,
  • Steen Pehrson
  • ,
  • Helena Carstensen
  • ,
  • Mette Flethøj
  • ,
  • Kirstine Færgemand Præstegaard
  • Ulrik Svane Sørensen, Acesion Pharma
  • ,
  • Jonas Goldin Diness, Acesion Pharma
  • ,
  • Morten Grunnet, Acesion Pharma
  • ,
  • Rikke Buhl
  • ,
  • Thomas Jespersen, Danish National Foundation Research Centre in Arrhythmias (DARC) and Department of Biomedical Sciences, University of Copenhagen

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.

CONCLUSION: 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.

Original languageEnglish
JournalHeart Rhythm
Pages (from-to)825-35
Number of pages11
Publication statusPublished - Apr 2015

    Research areas

  • 1-Naphthylamine/analogs & derivatives, Animals, Anti-Arrhythmia Agents/pharmacology, Atrial Fibrillation/drug therapy, Disease Models, Animal, Electrophysiologic Techniques, Cardiac, Heart Atria/metabolism, Horses, Immunohistochemistry, Microscopy, Confocal, Models, Anatomic, Myocytes, Cardiac/drug effects, Small-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors, Treatment Outcome

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