Antitussive effects of Na_V 1.7 blockade in Guinea pigs

Our previous studies implicated the voltage-gated sodium channel subtype Na_V 1.7 in the transmission of action potentials by the vagal afferent nerves regulating cough and thus identified this channel as a rational therapeutic target for antitussive therapy. But it is presently unclear whether a systemically administered small molecule inhibitor of Na_V 1.7 conductance can achieve therapeutic benefit in the absence of side effects on cardiovascular function, gastrointestinal motility or respiration. To this end, we have evaluated the antitussive effects of the Na_V 1.7 selective blocker Compound 801 administered systemically in awake guinea pigs or administered topically in anesthetized guinea pigs. We also evaluated the antitussive effects of ambroxol, a low affinity Na_V blocker modestly selective for tetrodotoxin resistant Na_V subtypes. Both Compound 801 and ambroxol dose-dependently inhibited action potential conduction in guinea pig vagus nerves (assessed by compound potential), with ambroxol nearly 100-fold less potent than the Na_V 1.7 selective Compound 801 in this and other Na_V 1.7-dependent guinea pig and human tissue-based assays. Both drugs also inhibited citric acid evoked coughing in awake or anesthetized guinea pigs, with potencies supportive of an Na_V 1.7-dependent mechanism. Notably, however, the antitussive effects of systemically administered Compound 801 were accompanied by hypotension and respiratory depression. Given the antitussive effects of topically administered Compound 801, we speculate that the likely insurmountable side effects on blood pressure and respiratory drive associated with systemic dosing make topical formulations a viable and perhaps unavoidable therapeutic strategy for targeting Na_V 1.7 in cough.