Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: A beneficial off-target effect?⋆

Abstract

BackgroundRecent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed.ObjectiveThe aim of this study was to investigate whether tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex.MethodsWe used a conscious cough model in guinea pigs, isolated vagal sensory nerve and isolated airway neuron tissue– and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques.ResultsInhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel–mediated responses. Complementary data were generated in airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes.ConclusionFor the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action.

Downregulation of the cough reflex by aclidinium and tiotropium in awake and anesthetized rabbits

“…Apart from the study by Birrell et al [17] on guinea pigs, there are a few other investigations on the antitussive effects of tiotropium both in animal species [44] and patients [12,13,16,18,19]. Recently, at variance with previous and present results, a lack of tiotropium antitussive effects on ozone-induced hypertussive responses in rabbits has been reported [7].…”

“…According to previous results [17,18], bronchodilation does not seem to be the mechanism by which LAMAs downregulate cough responses. This conclusion is also supported by the results of several studies showing the inability of bronchodilation or bronchoconstriction to alter cough receptor sensitivity and produce cough ([46e50], see also [18] for further Refs.).…”

“…The time interval of 90 min between drug administration and cough challenge was higher than that of 1 h used by Birrell et al [17]. It was scheduled to ensure the complete development of bronchodilator effects (see Methods).…”

“…Tiotropium was the first LAMA, reaching the market in 2002 [17]. Dicpinigaitis et al [18] reported that tiotropium (1 h after its inhalation) inhibits cough induced by capsaicin, a transient receptor potential vanilloid type 1 (TRPV1) agonist, in patients with upper respiratory tract infections.…”

“…Furthermore, tiotropium inhalation has been shown to improve cough and other symptoms in patients with chronic pulmonary disease due to sulphur mustard lung injury [19]. More recently, it has been shown that inhaled tiotropium attenuates after 1 h cough induced by capsaicin in the guinea pig and that this effect is mediated by TRPV1 receptors through a mechanism unrelated to its anticholinergic activity [17]. However, Clay et al [7] have reported that, in contrast to the guinea pig, the ozone-induced hypertussive responses to citric acid are not inhibited by tiotropium in the rabbit.…”