Contribution of the neuronal sodium channel NaV1.8 to sodium- and calcium-dependent cellular proarrhythmia. (July 2020)

• Record Type: Journal Article
• Authors: Bengel, Philipp; Ahmad, Shakil; Tirilomis, Petros; Trum, Maximilian; Dybkova, Nataliya; Wagner, Stefan; Maier, Lars S.; Hasenfuß, Gerd; Sossalla, Samuel
• Is Part Of: Journal of molecular and cellular cardiology. Volume 144(2020)
• Page Start: 35
• Page End: 46
• Publication Date: 2020-07
• Subjects: Sodium channels -- Late sodium current -- Arrhythmias -- Calcium -- SR-Ca2+-leak; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2020.05.002
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Objective: In myocardial pathology such as heart failure a late sodium current (INaL ) augmentation is known to be involved in conditions of arrhythmogenesis. However, the underlying mechanisms of the INaL generation are not entirely understood. By now evidence is growing that non-cardiac sodium channel isoforms could also be involved in the INaL generation. The present study investigates the contribution of the neuronal sodium channel isoform NaV 1.8 to arrhythmogenesis in a clearly-defined setting of enhanced INaL by using anemone toxin II (ATX-II) in the absence of structural heart disease. Methods: Electrophysiological experiments were performed in order to measure INaL, action potential duration (APD), SR-Ca 2+ -leak and cellular proarrhythmic triggers in ATX-II exposed wild-type (WT) and SCN10A −/− mice cardiomyocytes. In addition, WT cardiomyocytes were stimulated with ATX-II in the presence or absence of NaV 1.8 inhibitors. INCX was measured by using the whole cell patch clamp method. Results: In WT cardiomyocytes exposure to ATX-II augmented INaL, prolonged APD, increased SR-Ca 2+ -leak and induced proarrhythmic triggers such as early afterdepolarizations (EADs) and Ca 2+ -waves. All of them could be significantly reduced by applying NaV 1.8 blockers PF-01247324 and A-803467. Both blockers had no relevant effects on cellular electrophysiology of SCN10A −/− cardiomyocytes. Moreover, in SCN10A −/− -cardiomyocytes, the ATX-II-dependent increase in INaL, SR-Ca 2+ -leak and APD prolongation was less than in WT and comparable to the results which were obtained with WT cardiomyocytes being exposed to ATX-II and NaV 1.8 inhibitors in parallel. Moreover, we found a decrease in reverse mode NCX current and reduced CaMKII-dependent RyR2-phosphorylation after application of PF-01247324 as an underlying explanation for the Na + -mediated Ca 2+ -dependent proarrhythmic triggers. Conclusion: The current findings demonstrate that NaV 1.8 is a significant contributor for INaL -induced arrhythmic triggers. Therefore, NaV 1.8 inhibition under conditions of an enhanced INaL constitutes a promising antiarrhythmic strategy which merits further investigation. Graphical abstract: Unlabelled Image Highlights: NaV 1.8 profoundly contributes to INaL generation. NaV 1.8 significantly contributes to INaL -mediated SR-Ca 2+ leak. Inhibition of NaV 1.8 reduces the occurrence of EADs and diastolic Ca 2+ -release. Na + /Ca 2+ exchanger reverse mode is abrogated by inhibition of NaV 1.8-dependent INaL .