Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy.
Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy.
复制标题
用多沙普仑治疗心房颤动：TASK-1 钾通道抑制作为一种新的药理学策略。
DOI：
10.1093/cvr/cvab177
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发表时间：
2022
影响因子：
10.8
通讯作者：
Tochtermann,Ur
中科院分区：
文献类型：
--
作者：
Wiedmann,Felix;Beyersdorf,Christoph;Zhou,XiaoBo;Kraft,Manuel;Paasche,Amelie;Jávorszky,Natasa;Rinné,Susanne;Sutanto,Henry;Büscher,Antonius;Foerster,KathrinI;Blank,Antje;El-Battrawy,Ibrahim;Li,Xin;Lang,Siegfried;Tochtermann,Ur
AimsTASK-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 resultsDoxapram 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.ConclusionRepurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.
