Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy

Felix Wiedmann, Christoph Beyersdorf, Xiao-Bo Zhou, Manuel Kraft, Amelie Paasche, Natasa Jávorszky, Susanne Rinné, Henry Sutanto, Antonius Büscher, Kathrin I Foerster, Antje Blank, Ibrahim El-Battrawy, Xin Li, Siegfried Lang, Ursula Tochtermann, Jamila Kremer, Rawa Arif, Matthias Karck, Niels Decher, Gunther van LoonIbrahim Akin, Martin Borggrefe, Stefan Kallenberger, Jordi Heijman, Walter E Haefeli, Hugo A Katus, Constanze Schmidt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Aims: TASK-1 (K2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In this study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF. Methods and results: Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 days of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 days of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram. Conclusion: Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.

Original languageEnglish
Pages (from-to)1728-1741
Number of pages14
JournalCardiovascular Research
Volume118
Issue number7
Early online date24 May 2021
DOIs
Publication statusPublished - 22 Jun 2022

Keywords

  • Antiarrhythmic pharmacotherapy
  • Arrhythmia
  • Atrial fibrillation
  • Doxapram
  • Electrical remodelling
  • Potassium channel
  • Rhythm control
  • TASK-1
  • ACTION-POTENTIAL DURATION
  • SINOATRIAL CONDUCTION
  • K+ CHANNEL
  • LEAK
  • MECHANISMS

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