Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 179, Issue 2, Pages 242-251Publisher
WILEY
DOI: 10.1111/bph.15686
Keywords
asthma; C-fibres; cough; sodium channel; vagus nerve
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Funding
- National Institutes of Health [R35HL155671]
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The study found that selective Na(V)1.7 blockers can effectively inhibit the C-wave of compound action potentials and parasympathetic cholinergic contractions in human isolated bronchi. In addition, Na(V)1.7 mRNA was found to be strongly expressed and transported down the vagus nerve bundles.
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.
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