Local Anesthetic Like Inhibition of the Cardiac Na
Nav1.5
cardiac sodium channel
chloroquine
hydroxychloroquine
patch-clamp
Journal
Journal of experimental pharmacology
ISSN: 1179-1454
Titre abrégé: J Exp Pharmacol
Pays: New Zealand
ID NLM: 101530345
Informations de publication
Date de publication:
2022
2022
Historique:
received:
21
05
2022
accepted:
16
10
2022
entrez:
17
11
2022
pubmed:
18
11
2022
medline:
18
11
2022
Statut:
epublish
Résumé
Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ) are successfully deployed for different diseases beyond the prophylaxis and treatment of malaria. Both substances exhibit antiviral properties and have been proposed for prophylaxis and treatment of COVID-19 caused by SARS-CoV-2. CQ and HCQ cause similar adverse events including life-threatening cardiac arrhythmia generally based on QT-prolongation, which is one of the most reported adverse events for both agents associated with the treatment of COVID-19. Various drugs known to induce QT-prolongation have been proven to exert local anesthetic (LA)-like properties regarding their impact on the cardiac Na This in vitro study aims to investigate the effects of CQ and HCQ on Nav1.5-generated sodium currents to identify possible LA-like mechanisms that might contribute to their arrhythmogenic properties. The effects of CQ and HCQ on Nav1.5-generated sodium currents by HEK-293 cells expressing either wild-type human Nav1.5 or mutant Nav1.5 F1760A are measured using the whole-cell patch-clamp technique. Both agents induce a state-dependent inhibition of Nav1.5. Furthermore, CQ and HCQ produce a use-dependent block of Nav1.5 and a shift of fast and slow inactivation. Results of experiments investigating the effect on the LA-insensitive mutant Nav1.5-F1760A indicate that both agents at least in part employ the proposed LA-binding site of Nav1.5 to induce inhibition. This study demonstrated that CQ and HCQ exert LA-typical effects on Nav1.5 involving the proposed LA binding site, thus contributing to their arrhythmogenic properties.
Identifiants
pubmed: 36385942
doi: 10.2147/JEP.S375349
pii: 375349
pmc: PMC9653037
doi:
Types de publication
Journal Article
Langues
eng
Pagination
353-365Informations de copyright
© 2022 Hage et al.
Déclaration de conflit d'intérêts
The authors report no conflicts of interest in this work.
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