PDF(Pubmed)
Abstract：
UNASSIGNED: 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+ channel Nav1.5. Inhibition of Nav1.5 is considered as the primary mechanism of cardiotoxicity caused by LAs. However, the mechanism of the arrhythmogenic effects of CQ and HCQ related to Nav1.5 has not yet been fully investigated. Therefore, the exact mechanism of how CQ and HCQ affect the sodium currents generated by Nav1.5 need to be further elucidated.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■氯喹（CQ）及其衍生物羟氯喹（HCQ）已成功用于预防和治疗疟疾以外的其他疾病。这两种物质均具有抗病毒特性，已被建议用于预防和治疗SARS-CoV-2引起的COVID-19。CQ和HCQ引起类似的不良事件，包括通常基于QT延长的危及生命的心律失常，这是与COVID-19治疗相关的两种药物报告最多的不良事件之一。已证明已知可诱导QT延长的各种药物在其对心脏Na通道Nav1.5的影响方面具有局部麻醉剂（LA）样特性。Nav1.5的抑制被认为是由LA引起的心脏毒性的主要机制。然而,与Nav1.5相关的CQ和HCQ的致心律失常作用机制尚未得到充分研究.因此,CQ和HCQ如何影响Nav1.5产生的钠电流的确切机制需要进一步阐明.
■这项体外研究旨在研究CQ和HCQ对Nav1.5产生的钠电流的影响，以确定可能导致其心律失常特性的LA样机制。
使用全细胞膜片钳技术测量CQ和HCQ对表达野生型人Nav1.5或突变体Nav1.5F1760A的HEK-293细胞的Nav1.5产生的钠电流的影响。
■两种药剂均诱导Nav1.5的状态依赖性抑制。此外，CQ和HCQ产生Nav1.5的使用依赖性阻断和快速和缓慢失活的转变。研究对LA不敏感的突变体Nav1.5-F1760A的作用的实验结果表明,两种试剂至少部分地使用所提出的Nav1.5的LA结合位点来诱导抑制。
■这项研究表明，CQ和HCQ对Nav1.5产生LA典型效应，涉及拟议的LA结合位点，从而有助于它们的心律失常特性。
■这项体外研究旨在研究CQ和HCQ对Nav1.5产生的钠电流的影响，以确定可能导致其心律失常特性的LA样机制。
使用全细胞膜片钳技术测量CQ和HCQ对表达野生型人Nav1.5或突变体Nav1.5F1760A的HEK-293细胞的Nav1.5产生的钠电流的影响。
■两种药剂均诱导Nav1.5的状态依赖性抑制。此外，CQ和HCQ产生Nav1.5的使用依赖性阻断和快速和缓慢失活的转变。研究对LA不敏感的突变体Nav1.5-F1760A的作用的实验结果表明,两种试剂至少部分地使用所提出的Nav1.5的LA结合位点来诱导抑制。
■这项研究表明，CQ和HCQ对Nav1.5产生LA典型效应，涉及拟议的LA结合位点，从而有助于它们的心律失常特性。
