Blocking Scn10a Channels in Heart Reduces Late Sodium Current and Is Antiarrhythmic

Abstract

Rationale While the sodium channel locus SCN10A has been implicated by genome-wide association studies as a modulator of cardiac electrophysiology, the role of its gene product Nav1.8 as a modulator of cardiac ion currents is unknown. Objective We determined the electrophysiological and pharmacological properties of Nav1.8 in heterologous cell systems and assessed the antiarrhythmic effect of Nav1.8 block on isolated mouse and rabbit ventricular cardiomyocytes. Methods and results We first demonstrated that Scn10a transcripts are identified in mouse heart and that the blocker A-803467 is highly specific for Nav1.8 current over that of Nav1.5, the canonical cardiac sodium channel encoded by SCN5A. We then showed that low concentrations of A-803467 selectively block “late” sodium current and shorten action potentials in mouse and rabbit cardiomyocytes. Exaggerated late sodium current is known to mediate arrhythmogenic early afterdepolarizations in heart, and these were similarly suppressed by low concentrations of A-803467. Conclusion SCN10A expression contributes to late sodium current in heart, and represents a new target for antiarrhythmic intervention.

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

“…The new I Na description was scaled such that peak current amplitudes during the AP were unaltered. Recent results suggest that Nav1.8 is responsible for the late sodium current in cardiomyocytes 37,39 . We therefore left the existing persistent sodium current of the model unaltered.…”

Cardiac ion channels

“…14,15 Subsequently, Nav1.8 expression was demonstrated in mouse and human cardiac myocytes and intracardiac neurons. 16 In cardiac myocytes, block of Nav1.8 reduces late Na C current and shortens action potential duration, 17 while block of Nav1.8 in intracardiac neurons reduces action potential frequency. 18 How these observations relate to cardiac conduction is not entirely clear.…”

Neuronal Na v 1.8 Channels as a Novel Therapeutic Target of Acute Atrial Fibrillation Prevention

“…Compared with SCN5A ‐ SCN3B transfected TSA‐201 cells, the current density was significantly increased and was sensitive to A‐803467 when SCN10A were added together with SCN5A ‐ SCN3B . Since others' and our studies have reported the extremely low current density in SCN10A ‐ SCN3B transfected cell lines,9, 21 it is reasonable to deduce that the increased current is not an arithmetic addition of current component produced by SCN10A . It implies that SCN10A might interact with SCN5A as a new sodium complex (Figure 8), and A‐803467 could have an effect on SCN10A‐SCN5A complex, as indicated in our patch clamp study.…”