Role of Na(V)1.7 in action potential conduction along human bronchial vagal afferent C-fibres

Background and Purpose The purpose of this study was to determine the role of Na(V)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 Na(V)1.7 blocking drugs, PF-05089771 and ST-2262, as well as the Na(V)1.1, 1.2, and 1.3 blocking drug ICA121-431. The efficacy and potency of these inhibitors were compared to the standard Na(V)1 blocker, tetrodotoxin. We then compared the relative potencies of the Na(V)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 Na(V)1.7 channels. Key Results The selective Na(V)1.7 blockers inhibited the C-wave of the compound action potential with potencies similar to that observed in the Na(V)1.7 bronchial contractions assay. Using rt-PCR, we noted that Na(V)1.7 mRNA was strongly expressed and transported down the vagus nerve bundles. Conclusions and Implications Na(V)1.7 blockers can prevent action potential conduction in the majority of vagal C-fibres arising from human bronchi. Blockers of Na(V)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.