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 language | English |
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Pages (from-to) | 1728-1741 |
Number of pages | 14 |
Journal | Cardiovascular Research |
Volume | 118 |
Issue number | 7 |
Early online date | 24 May 2021 |
DOIs | |
Publication status | Published - 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