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, A Paasche, Natasa Jávorszky, Susanne Rinné, Henry Sutanto, Antonius Büscher, Kathrin I. Foerster, Antje Blank, Ibrahim El‐Battrawy, Xin Li, Siegfried Lang, U. Tochtermann, Jamila Kremer, Rawa Arif, Matthias Karck, Niels Decher, Gunther van Loon, İbrahim Akın, Martin Borggrefe, Stefan M. Kallenberger, Jordi Heijman, Walter E. Haefeli, Hugo A. Katus, Constanze Schmidt
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.