Mark A. Birrell , PhD, Sara J. Bonvini , BSc, Eric Dubuis , PhD, Sarah A. Maher , PhD, Michael A. Wortley , PhD, Megan S. Grace , PhD, Kristof Raemdonck , PhD, John J. Adcock , PhD, Maria G. Belvisi , PhD ∗
1 March 2014
Sensory nerves, vagus, cough, ion channels, capsaicin, anticholinergics, [Ca2+]i, Intracellular calcium, COPD, Chronic obstructive pulmonary disease, DiI, DilC18(3)-1,1′-dioctacetyl-3,3,3′,3′-tetramethyl-indocarbocyanine perchlorate, DMSO, Dimethyl sulfoxide, ECS, Extracellular solution, K50, 50 mmol/L potassium chloride extracellular solution, LAMA, Long-acting muscarinic receptor antagonist, MCh, Methacholine, Penh, Enhanced pause, PGE2, Prostaglandin E2, RTX, Resiniferatoxin, TRP, Transient receptor potential, URI, Upper respiratory tract infection
Recent 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.
The aim of this study was to investigate whether tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex.
We 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.
Inhaled 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.
For 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.