a-803467 and Arrhythmias--Cardiac

Pharmacologic approaches for the treatment of atrial arrhythmias are limited due to side effects and low efficacy. Thus, the identification of new antiarrhythmic targets is of clinical interest. Recent genome studies suggested an involvement of SCN10A sodium channels (Na

Topics: Action Potentials; Aged; Aniline Compounds; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cells, Cultured; Disease Models, Animal; Female; Furans; Heart Rate; Humans; Male; Mice, Knockout; Middle Aged; Myocytes, Cardiac; NAV1.8 Voltage-Gated Sodium Channel; Picolinic Acids; Sodium Channel Blockers

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.. 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.. 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.. Scn10a expression contributes to late sodium current in heart and represents a new target for antiarrhythmic intervention.

Topics: Action Potentials; Aniline Compounds; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cell Line, Transformed; Furans; Humans; Mice; Mice, Knockout; NAV1.5 Voltage-Gated Sodium Channel; NAV1.8 Voltage-Gated Sodium Channel; Rabbits; Rats; Sodium Channel Blockers; Sodium Channels