Key result
The NaV1.8 blocker A-803467 had no effect on peak or late sodium currents in non-diseased atrial and ventricular cardiomyocytes, demonstrating the absence of functional NaV1.8 channels in these cells.
Why the study?
The mechanism by which SCN10A/NaV1.8 impacts cardiac electrical function and arrhythmia susceptibility remained a matter of debate.
Functional NaV1.8 channels are absent in non-diseased atrial and ventricular cardiomyocytes, suggesting that SCN10A variants affect cardiac electrophysiology through indirect mechanisms.
NaV1.8 blockade shows minimal effects in non-diseased cardiomyocytes; leaves open indirect SCN5A modulation in disease states.
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.
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Casini et al. (2019) studied Non-diseased atrial and ventricular cardiomyocytes. A-803467 vs. Baseline (physiological conditions) was evaluated on Peak and late sodium current (INa) density and action potential duration. The NaV1.8 blocker A-803467 had no effect on peak or late sodium currents in non-diseased atrial and ventricular cardiomyocytes, demonstrating the absence of functional NaV1.8 channels in these cells.
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