The Selective Na v1.8 Sodium Channel Blocker A-803467 Affects Electrical Activity in Intracardiac Neurons, but not in Cardiomyocytes

Abstract

Background. Recently we observed differential myocardial expression of the brain-type sodium channel isoform Scn10a between two inbred mouse strains, both harboring the Scn5a-1798insD+/- mutation and displaying different severity of conduction disease. The functional role of Scn10a in the heart is as yet unknown, and we therefore investigated expression and channel activity of NaV1.8 (encoded by Scn10a) in intracardiac neurons and myocardium of the murine heart.Methods. Immunocytochemistry was performed using anti-NaV1.8 antibody on mouse embryos and adult murine cardiac tissue sections. The effect of the NaV1.8 blocker A-803467 (500 nM) on action potentials (AP's) and sodium current (INa) properties was assessed in isolated intracardiac neurons and ventricular myocytes.Results. In embryonic and adult heart tissue sections, NaV1.8 staining was observed at the epicardial surface, and within the myocardium in between cardiomyocytes. The NaV1.8 blocker A-803467 had no effect on either mean INa density or INa kinetic properties in isolated myocytes, but clearly reduced INa density in intracardiac neurons (−344±51 pA/pF versus control −448±61; mean±SEM, n=11). In addition, the slow component of the current decay (τslow) at −20 mV was accelerated in the presence of A-803467 (2.8±0.3 ms versus control 3.4±0.4 ms; mean±SEM, n=5) and V1/2 of voltage-dependent inactivation was shifted by −9.6 mV (−73.6±2.0 mV versus control −64.0±1.6 mV; mean±SEM, n=5). This is consistent with a reduction in slowly inactivating brain-type sodium current with depolarized voltage-dependent inactivation. In AP measurements A-803467 did not affect cardiomyocyte upstroke velocity, but reduced AP firing frequency in intracardiac neurons by 50%.Conclusion. The sodium channel NaV1.8 is expressed in murine heart, and is functionally present in intracardiac neurons, but absent in cardiomyocytes. Thus, NaV1.8 may influence myocardial electrophysiological properties through its contribution to cardiac neuronal activity.