Bengel, Philipp and Ahmad, Shakil and Tirilomis, Petros and Trum, Maximilian and Dybkova, Nataliya and Wagner, Stefan and Maier, Lars S. and Hasenfu, Gerd and Sossalla, Samuel (2020) Contribution of the neuronal sodium channel Na(v)1.8 to sodium- and calcium-dependent cellular proarrhythmia. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 144. pp. 35-46. ISSN 0022-2828, 1095-8584
Full text not available from this repository. (Request a copy)Abstract
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(v)1.8 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(v)1.8 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(v)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 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(v)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 Ca2+-dependent proarrhythmic triggers. Conclusion: The current findings demonstrate that Na(v)1.8 is a significant contributor for I-NaL-induced arrhythmic triggers. Therefore, Na(v)1.8 inhibition under conditions of an enhanced I-NaL constitutes a promising antiarrhythmic strategy which merits further investigation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-KINASE-II; VENTRICULAR MYOCYTES; HEART-FAILURE; RANOLAZINE; SCN10A; NA; CURRENTS; CAMKII; AFTERDEPOLARIZATIONS; PHOSPHORYLATION; Sodium channels; Late sodium current; Arrhythmias; Calcium; SR-Ca2+-leak |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Mar 2021 07:36 |
| Last Modified: | 19 Mar 2021 07:36 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44257 |
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