Voltage-Gated Sodium Channels Mediating Conduction in Vagal Motor Fibers Innervating the Esophageal Striated Muscle.

The vagal motor fibers innervating the esophageal striated muscle are essential for esophageal motility including swallowing and vomiting. However, it is unknown which subtypes of voltagegated sodium channels (Na_V1s) regulate action potential conduction in these efferent nerve fibers. The information on the Na_V1s subtypes is necessary for understanding their potential side effects on upper gut, as novel inhibitors of Na_V1s are developed for treatment of pain. We used isolated superfused (35 °C) vagally-innervated mouse esophagus striated muscle preparation (mucosa removed) to measure isometric contractions of circular striated muscle evoked by electrical stimulation of the vagus nerve. Na_V1 inhibitors were applied to the de-sheathed segment of the vagus nerve. Tetrodotoxin (TTX) applied to the vagus nerve completely abolished electrically evoked contractions. The selective Na_V1.7 inhibitor PF-05089771 alone partially inhibited contractions and caused a >3-fold rightward shift in the TTX concentration-inhibition curve. The Na_V1.1, Na_V1.2 and Na_V1.3 group inhibitor ICA-121431 failed to inhibit contractions, or to alter TTX concentration-inhibition curves in the absence or in the presence of PF-05089771. RT-PCR indicated lack of Na_V1.4 expression in nucleus ambiguus and dorsal motor nucleus of the vagus nerve, which contain motor and preganglionic neurons projecting to the esophagus. We conclude that the action potential conduction in the vagal motor fibers to the esophageal striated muscle in the mouse is mediated by TTX-sensitive voltage gated sodium channels including Na_V1.7 and most probably Na_V1.6. The role of Na_V1.6 is supported by ruling out other TTX-sensitive Na_V1s (Na_V1.1-1.4) in the Na_V1.7-independent conduction. [ABSTRACT FROM AUTHOR]