Abstract 2329: NaV1.8 Expression and Channel Activity in Intracardiac Neurons of the Murine Heart
Background and aim. We have recently 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 function of Scn10a in the heart is as yet unknown. We therefore aimed to investigate expression, localization and channel activity of NaV1.8 (encoded by Scn10a) in intracardiac neurons and myocardium of the murine heart.
Methods. Immunohistochemistry and immunocytochemistry was performed using an anti-NaV1.8 antibody on mouse embryos and adult murine cardiac tissue sections, and isolated murine cardiomyocytes and intracardiac neurons, respectively. The effect of the NaV1.8 blocker A-803456 (8 μM; Tocris) on sodium current (INa) properties was assessed in isolated murine intracardiac neurons and ventricular myocytes.
Results. In mouse embryos (ED17.5), NaV1.8 showed abundant staining in the dorsal root ganglia and expression in the heart. In embryonic and adult heart tissue sections, NaV1.8 staining was observed at the epicardial surface, and within the myocardium in between myocytes, consistent with a neuronal expression pattern. NaV1.8 staining was absent in isolated ventricular myocytes, but present in isolated intracardiac neurons, as evidenced by co-staining with tyrosine hydroxylase. The NaV1.8 blocker A-803467 had no effect on either mean INa density or INa kinetic properties in isolated myocytes, but significantly reduced INa density in intracardiac neurons (−19.5±2.3 pA/pF versus control −22.4±3.0; mean±SEM, n=5, p<0.05). A-803467 did not affect voltage dependency of INa activation or inactivation in intracardiac neurons, but the slow component of the current decay (τslow) at −40 mV was accelerated in the presence of A-803467 (7.7±2.3 ms versus control 9.7±2.7 ms; n=5; p<0.05), consistent with a decrease of slowly inactivating (brain-type) sodium current.
Conclusion. The brain-type sodium channel NaV1.8 is expressed in murine heart, and is functionally present in intracardiac neurons, but absent in cardiomyocytes. Thus, NaV1.8 may constitute a novel modifier of myocardial electrophysiology through its regulatory effects on cardiac neuronal activity.