Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy.
Cardiovasc Res
; 118(7): 1728-1741, 2022 06 22.
Article
em En
| MEDLINE
| ID: mdl-34028533
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 ANDRESULTS:
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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fibrilação Atrial
/
Canais de Potássio de Domínios Poros em Tandem
/
Bloqueadores dos Canais de Potássio
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cardiovasc Res
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Alemanha