Contribution of the neuronal sodium channel Na_V1.8 to sodium- and calcium-dependent cellular proarrhythmia.

OBJECTIVE:In myocardial pathology such as heart failure a late sodium current (I_NaL) augmentation is known to be involved in conditions of arrhythmogenesis. However, the underlying mechanisms of the I_NaL generation are not entirely understood. By now evidence is growing that non-cardiac sodium channel isoforms could also be involved in the I_NaL generation. The present study investigates the contribution of the neuronal sodium channel isoform Na_V1.8 to arrhythmogenesis in a clearly-defined setting of enhanced I_NaL by using anemone toxin II (ATX-II) in the absence of structural heart disease. METHODS:Electrophysiological experiments were performed in order to measure I_NaL, action potential duration (APD), SR-Ca²⁺-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 Na_V1.8 inhibitors. I_NCX was measured by using the whole cell patch clamp method. RESULTS:In WT cardiomyocytes exposure to ATX-II augmented I_NaL, prolonged APD, increased SR-Ca²⁺-leak and induced proarrhythmic triggers such as early afterdepolarizations (EADs) and Ca²⁺-waves. All of them could be significantly reduced by applying Na_V1.8 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 I_NaL, SR-Ca²⁺-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 Na_V1.8 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 Ca²⁺-dependent proarrhythmic triggers. CONCLUSION:The current findings demonstrate that Na_V1.8 is a significant contributor for I_NaL-induced arrhythmic triggers. Therefore, Na_V1.8 inhibition under conditions of an enhanced I_NaL constitutes a promising antiarrhythmic strategy which merits further investigation. Copyright © 2020 Elsevier Ltd. All rights reserved.

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