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Acid evoked coughing in anesthetized guinea pigs depends upon Acid‐Sensing Ion Channel (ASIC)‐dependent activation of capsaicin‐insensitive vagal afferent neurons

Citric acid (CA) evoked cough in anesthetized guinea pigs (GPs) depends upon the activation of nodose ganglia neurons that are acid‐sensitive but capsaicin‐insensitive and project to the laryngeal, tracheal and mainstem bronchial mucosa. Using single cell PCR and diminazene (DZ), a potent and selective inhibitor of ASICs, we have addressed the hypothesis that acid evoked cough in anesthetized guinea pigs is ASIC dependent. In vitro, DZ inhibited 1mM CA evoked action potential (AP) discharge in the capsaicin‐insensitive afferent neurons projecting to the trachea (CA evoked 44±7, 36±9, 15±4 and 1±1 APs in control preparations and following treatment with 1, 10 and 100μM DZ, respectively; n=3–5). In vivo, DZ inhibited cough evoked by CA (0.001–2M) applied topically to the tracheal mucosa (CA evoked 8±1, 6±1, 3±2 and 0±0 coughs in control and in GPs pretreated topically with 1, 10 and 100μM DZ, respectively; n=4–8). By contrast, the TRPV1 antagonist SB366791 (10μM) nearly abolished 0.1μM capsaicin‐evoked contractions of the GP trachea in vitro but was without effect on CA evoked cough (8±1 coughs; n=5). Single cell PCR revealed that nodose ganglia neurons retrogradely labeled from the trachea do not express TRPV1 mRNA (0/9) but do (8/9) express either ASIC1 (6/9) and/or ASIC3 (5/9) mRNA. Together, these data implicate ASICs in the acid evoked coughing evoked from the airway mucosa.