Absence of Functional Na v 1.8 Channels in Non-diseased Atrial and Ventricular Cardiomyocytes.

Autor: Casini S; Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands. s.casini@amsterdamumc.nl., Marchal GA; Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands., Kawasaki M; Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands., Nariswari FA; Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands., Portero V; Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands., van den Berg NWE; Department of Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands., Guan K; Institute of Pharmacology and Toxicology, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany., Driessen AHG; Department of Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands., Veldkamp MW; Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands., Mengarelli I; Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands., de Groot JR; Department of Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands., Verkerk AO; Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands.; Department of Medical Biology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands., Remme CA; Department of Experimental Cardiology, Amsterdam UMC, Meibergdreef 15, Amsterdam, 1105 AZ, The Netherlands.
Jazyk: angličtina
Zdroj: Cardiovascular drugs and therapy [Cardiovasc Drugs Ther] 2019 Dec; Vol. 33 (6), pp. 649-660.
DOI: 10.1007/s10557-019-06925-6
Abstrakt: Purpose: Several studies have indicated a potential role for SCN10A/Na V 1.8 in modulating cardiac electrophysiology and arrhythmia susceptibility. However, by which mechanism SCN10A/Na V 1.8 impacts on cardiac electrical function is still a matter of debate. To address this, we here investigated the functional relevance of Na V 1.8 in atrial and ventricular cardiomyocytes (CMs), focusing on the contribution of Na V 1.8 to the peak and late sodium current (I Na ) under normal conditions in different species.
Methods: The effects of the Na V 1.8 blocker A-803467 were investigated through patch-clamp analysis in freshly isolated rabbit left ventricular CMs, human left atrial CMs and human-induced pluripotent stem cell-derived CMs (hiPSC-CMs).
Results: A-803467 treatment caused a slight shortening of the action potential duration (APD) in rabbit CMs and hiPSC-CMs, while it had no effect on APD in human atrial cells. Resting membrane potential, action potential (AP) amplitude, and AP upstroke velocity were unaffected by A-803467 application. Similarly, I Na density was unchanged after exposure to A-803467 and Na V 1.8-based late I Na was undetectable in all cell types analysed. Finally, low to absent expression levels of SCN10A were observed in human atrial tissue, rabbit ventricular tissue and hiPSC-CMs.
Conclusion: We here demonstrate the absence of functional Na V 1.8 channels in non-diseased atrial and ventricular CMs. Hence, the association of SCN10A variants with cardiac electrophysiology observed in, e.g. genome wide association studies, is likely the result of indirect effects on SCN5A expression and/or Na V 1.8 activity in cell types other than CMs.
Databáze: MEDLINE
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