Role of NaV1.7 in Action Potential Conduction along Human Bronchial Vagal Afferent C-fibers

BACKGROUND AND PURPOSE The purpose of this study was to determine the role of NaV 1.7 in action potential conduction in C-fibres in the bronchial branches of the human vagus nerve. EXPERIMENTAL APPROACH Bronchial branches of the vagus nerve were dissected from human donor tissue. The C-wave of the electrically evoked compound action potential was quantified in the absence and presence of increasing concentrations of the selective NaV 1.7 blocking drugs, PF-05089771 and ST-2262, as well as the NaV 1.1, 1.2, and 1.3 blocking drug ICA121-431. The efficacy and potency of these inhibitors were compared to the standard NaV 1 blocker, tetrodotoxin. We then compared the relative potencies of the NaV 1 blockers in inhibiting the C-wave of the compound action potential, with their ability to inhibit parasympathetic cholinergic contraction of human isolated bronchi, a response previously shown to be strictly dependent on NaV 1.7 channels. KEY RESULTS The selective NaV 1.7 blockers inhibited the C-wave of the compound action potential with potencies similar to that observed in the NaV 1.7 bronchial contractions assay. Using rt-PCR, we noted that NaV 1.7 mRNA was strongly expressed and transported down the vagus nerve bundles. CONCLUSIONS AND IMPLICATIONS NaV 1.7 blockers can prevent action potential conduction in the majority of vagal C-fibres arising from human bronchi. Blockers of NaV 1.7 channels may therefore have value in inhibiting the responses to excessive airway C-fibre activation in inflammatory airway disease, responses that include coughing as well as reflex bronchoconstriction and secretions.