Abstract 14942: Late Sodium Current-Mediated Arrhythmias Are Inhibited in Scn10a Knockout Mouse Myocytes
Background: Genome-wide association studies have implicated variants in SCN10A as modulators of cardiac conduction, and multiple mechanisms accounting for this link have been proposed. In previous studies we have shown that Nav1.8 current, generated by SCN10A, activates and inactivates more positively than typical cardiac SCN5A-encoded Nav1.5 (peak Nav1.8 at ~0mV vs -30mV for Nav1.5). In addition, A-803467, thought to be a specific Nav1.8 blocker, inhibited late sodium current (INa-L) in mouse ventricular myocytes, suggesting the hypothesis that Nav1.8 channels contribute to INa-L-mediated arrhythmias. We have generated Scn10a knockout (KO) mice that now allow a direct test of this hypothesis.
Methods and Results: We measured action potential duration (APD) and early afterdepolarization (EAD) frequency in wild-type (WT) and KO ventricular myocytes at baseline and after exposure to the sodium channel opener ATX-II. High concentrations (>10nM) of ATX-II caused EADs in WT and KO. However, at a low concentration (1 nM), ATX-II markedly prolonged APD and caused EADs in 8/12 WT cells (Figure), while in KO, APD prolongation was attenuated and EADs were rare (1/12 cells). ATX-II increased INa-L at 0 mV in WT but not in KO myocytes, while it increased INa-L at -30 mV to a similar extent in WT and KO cells (Figure, ±SE, n=8 each).
Conclusions: These findings reinforce previous results that Scn10a contributes to INa-L in mouse ventricular myocytes. Further, arrhythmia frequency in Scn10a knockout myocytes was strikingly reduced when INa-L was stimulated, providing strong support for the idea that Scn10a inhibition is a potential antiarrhythmic target.
- © 2013 by American Heart Association, Inc.