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Antiarrhythmic effect of the Ca2+-activated K+ (SK) channel inhibitor ICA combined with either amiodarone or dofetilide in an isolated heart model of atrial fibrillation

  • Jeppe Egedal Kirchhoff
  • Jonas Goldin Diness
  • Lea Abildgaard
  • Majid Sheykhzade
  • Morten Grunnet
  • Thomas JespersenEmail author
Ion channels, receptors and transporters

Abstract

Dose is an important parameter in terms of both efficacy and adverse effects in pharmacological treatment of atrial fibrillation (AF). Both of the class III antiarrhythmics dofetilide and amiodarone have documented anti-AF effects. While dofetilide has dose-related ventricular side effects, amiodarone primarily has adverse non-cardiac effects. Pharmacological inhibition of small conductance Ca2+-activated K+ (SK) channels has recently been reported to be antiarrhythmic in a number of animal AF models. In a Langendorff model of acutely induced AF on guinea pig hearts, it was investigated whether a combination of the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) together with either dofetilide or amiodarone provided a synergistic effect. The duration of AF was reduced with otherwise subefficacious concentrations of either dofetilide or amiodarone when combined with ICA, also at a subefficacious concentration. At a concentration level effective as monotherapy, dofetilide produced a marked increase in the QT interval. This QT prolonging effect was absent when combined with ICA at non-efficacious monotherapy concentrations. The results thereby reveal that combination of subefficacious concentrations of an SK channel blocker and either dofetilide or amiodarone can maintain anti-AF properties, while the risk of ventricular arrhythmias is reduced.

Keywords

Combination therapy Antiarrhythmic drugs QT prolongation Amiodarone Dofetilide hERG1 and calcium-activated potassium channels 

Abbreviations

AF

Atrial fibrillation

ICA

N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine

SK

Small conductance Ca2+-activated K+

ACh

Acetylcholine

TdP

Torsade de Pointes

BID

Bis in die (twice a day)

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© Springer-Verlag Berlin Heidelberg 2016

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Jeppe Egedal Kirchhoff
    • 1
    • 2
  • Jonas Goldin Diness
    • 1
    • 3
  • Lea Abildgaard
    • 3
  • Majid Sheykhzade
    • 2
  • Morten Grunnet
    • 2
    • 3
    • 4
  • Thomas Jespersen
    • 1
    Email author
  1. 1.The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical SciencesUniversity of CopenhagenCopenhagen NDenmark
  2. 2.Department of Drug Design and Pharmacology, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  3. 3.Acesion PharmaCopenhagenDenmark
  4. 4.Lundbeck A/SCopenhagenDenmark

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