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

10 Citations (Web of Science)


AIMS: TASK-1 (K2P3.1) two-pore domain potassium channels are atrial-specific and significantly upregulated 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 the present 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 d 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 d 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.

CONCLUSIONS: Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.

TRANSLATIONAL PERSPECTIVE: Pharmacological suppression of atrial TASK 1 potassium currents prolongs atrial refractoriness with no effects on ventricular repolarization, resulting in atrial-specific class III antiarrhythmic effects. In our preclinical pilot study the respiratory stimulant doxapram was successfully administered for cardioversion of acute AF as well as rhythm control of persistent AF in a clinically relevant porcine animal model.

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


  • Antiarrhythmic pharmacotherapy
  • Arrhythmia
  • Atrial fibrillation
  • Doxapram
  • Electrical remodelling
  • Potassium channel
  • Rhythm control
  • TASK-1
  • LEAK

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