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

https://doi.org/10.1016/j.jaci.2013.12.003Get rights and content
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Background

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.

Objective

The aim of this study was to investigate whether tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex.

Methods

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.

Results

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.

Conclusion

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.

Key words

Sensory nerves
vagus
cough
ion channels
capsaicin
anticholinergics

Abbreviations used

[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

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M.A.B., S.A.M., and M.S.G. were funded by project grants from the Medical Research Council (MRC UK: G0800196; G0800195; MR/K020293/1). S.J.B. and M.A.W. were supported by NHLI Trust and MRC studentships, respectively. E.D. was funded by a Wellcome Trust project grant (089301/Z/09/Z) and latterly by a research grant from Boehringer-Ingelheim. Consumables were funded by Boehringer-Ingelheim. The human tissue experiments in this study were undertaken with the support of the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.

Disclosure of potential conflict of interest: M. G. Belvisi has received research support from Boehringer Ingelheim; has received support for travel to the 2012 ERS meeting; is a Director of IR Pharma CRO; has received consultancy fees from Chiesi, Glenmark, Almirall, AstraZeneca, GlaxoSmithKline, SunPharma, Provesica, Ario, and Innosquared; and has received lecture fees from Chiesi. The rest of the authors declare that they have no relevant conflicts of interest.