Abstract 14423: Blocking Scn10a Channels in Heart Reduces Late Sodium Current and is Antiarrhythmic
Rationale: While the sodium channel 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 effect of Nav1.8 block on isolated mouse and rabbit ventricular myocytes.
Methods and results: We first demonstrated that Scn10a transcripts are identified in mouse heart. Next, we confirmed using heterologous expression that the Nav1.8 blocker A-803467 is highly specific for Nav1.8 current over that of Nav1.5, the canonical cardiac sodium channel encoded by SCN5A. The IC50 for block of peak inward current was ∼10nM (Nav1.8) versus >>1000nM (Nav1.5); we also established that the blocker did not inhibit Nav1.5-mediated late current (INa-L) even when it was augmented by ATX-II or by three LQT3 mutations. We then demonstrated that a low concentration (30nM) of A-803467 completely inhibited INa-L generated by a 200 ms pulse to 0 mV in mouse or rabbit ventricular myocytes, while peak current was <10% affected. Action potentials were shortened: in rabbit, baseline APD90 at 2 Hz was 303±20 ms and 215±20 ms on drug (±SE, n=7, p<0.01). Early afterdepolarizations elicited by 5nM ATX-II were promptly suppressed by A-803467 in both mouse (7/8) and rabbit (3/5) myocytes. Further, we found that there was no late current seen and no APD90 shortening with A-803467 in ventricular myocytes (n=8) from Scn10a knockout mice.
Conclusion: SCN10A expression contributes to late sodium current in heart, and may represent a new target for antiarrhythmic intervention.
- © 2012 by American Heart Association, Inc.