Abstract
Dronedarone is a novel class III antiarrhythmic drug that is widely used in atrial fibrillation. It has been shown in native cardiomyocytes that dronedarone inhibits cardiac inwardly rectifying current IK1 at high concentrations, which may contribute both its antifibrillatory efficacy and its potential proarrhythmic side effects. However, the underlying mechanism has not been studied in further detail to date. In the mammalian heart, heterotetrameric assembly of Kir2.x channels is the molecular basis of IK1 current. Therefore, we studied the effects of dronedarone on wild-type and mutant Kir2.x channels in the Xenopus oocyte expression system. Dronedarone inhibited Kir2.1 currents but had no effect on Kir2.2 or Kir2.3 currents. Onset of block was slow but completely reversible upon washout. Blockade of Kir2.1 channels did not exhibit strong voltage dependence or frequency dependence. In a screening with different Kir2.1 mutants lacking specific binding sites within the cytoplasmic pore region, we found that residue E224 is essential for binding of dronedarone to Kir2.1 channels. In conclusion, direct block of Kir2.1 channel subunits by dronedarone through binding at E224 may underlie its inhibitory effects on cardiac IK1 current.
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Acknowledgments
Financial support for this study was granted by the DFG (Projects ZI1177/1-1 to Dr. Zitron and SCHO1350/2-1 to Dr. Scholz) and the University of Heidelberg: Postdoc Fellowship Programme of the Faculty of Medicine to Dr. Scherer. We thank C. Jeckel for excellent technical assistance.
Ethical standards
All animal studies have been approved by the ethics committee of the University of Heidelberg and have been performed in accordance with the ethical standards laid down in the 1964 declaration of Helsinki and its later amendments (current version 2013). The manuscript does not contain clinical studies or patient data.
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The authors declare that they have no conflict of interest.
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Xynogalos, P., Seyler, C., Scherer, D. et al. Class III antiarrhythmic drug dronedarone inhibits cardiac inwardly rectifying Kir2.1 channels through binding at residue E224. Naunyn-Schmiedeberg's Arch Pharmacol 387, 1153–1161 (2014). https://doi.org/10.1007/s00210-014-1045-6
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DOI: https://doi.org/10.1007/s00210-014-1045-6