Blocking Scn10a channels in heart reduces late sodium current and is antiarrhythmic.
BACKGROUND
Although 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.


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.


CONCLUSIONS
Scn10a expression contributes to late sodium current in heart and represents a new target for antiarrhythmic intervention.
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Tao
T
Yang
Thomas C
TC
Atack
Dina Myers
DM
Stroud
Wei
W
Zhang
Lynn
L
Hall
Dan M
DM
Roden
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D002461:Cell Line, Transformed; D005663:Furans / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D011817:Rabbits; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D015222:Sodium Channels / Q000502:physiology*
C520740:A 803467; D000814:Aniline Compounds; D000889:Anti-Arrhythmia Agents; D005663:Furans; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C568320:SCN5A protein, human; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; C568321:Scn5a protein, mouse; C568322:Scn5a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels