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

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 3; pp. 679 - 687.e9
• Main Authors: Birrell, Mark A., PhD, Bonvini, Sara J., BSc, Dubuis, Eric, PhD, Maher, Sarah A., PhD, Wortley, Michael A., PhD, Grace, Megan S., PhD, Raemdonck, Kristof, PhD, Adcock, John J., PhD, Belvisi, Maria G., PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.03.2014; Elsevier; Elsevier Limited; Mosby
• Subjects: Allergy and Immunology; Animals; anticholinergics; Asthma and Lower Airway Disease; Biological and medical sciences; Bronchi - drug effects; Bronchi - innervation; Calcium - metabolism; capsaicin; Capsaicin - pharmacology; Chronic obstructive pulmonary disease; cough; Cough - physiopathology; Cricetinae; Experiments; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Glucose; HEK293 Cells; Humans; Immunopathology; ion channels; Medical sciences; Muscarinic Antagonists - pharmacology; Nerve Fibers, Unmyelinated - drug effects; Nerve Fibers, Unmyelinated - physiology; Pneumology; Respiratory system : syndromes and miscellaneous diseases; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Scopolamine Derivatives - pharmacology; Sensory nerves; Sensory Receptor Cells - physiology; Smooth muscle; Studies; Tiotropium Bromide; TRPV Cation Channels - antagonists & inhibitors; vagus; Vagus Nerve - physiology; Intracellular calcium; DiI; DMSO; Upper respiratory tract infection; PGE 2; Enhanced pause; cough; URI; MCh; Resiniferatoxin; TRP; vagus; Methacholine; capsaicin; RTX; Chronic obstructive pulmonary disease; Sensory nerves; [Ca 2+] i; LAMA; Penh; ion channels; Transient receptor potential; K 50; ECS; DilC18-1,1′-dioctacetyl-3,3,3′,3′-tetramethyl-indocarbocyanine perchlorate; Dimethyl sulfoxide; Extracellular solution; 50 mmol/L potassium chloride extracellular solution; Long-acting muscarinic receptor antagonist; anticholinergics; Prostaglandin E 2; COPD; PGE2; [Ca2+]i; K50; Immunopathology; Targeting; Capsaicin; Tiotropium bromide; Ionic channel; Respiratory system; Cough; Transitory; Respiratory tract; Anticholinergic agent; Immunology; Sensory nerve; Anticholinesterase agent; Biological receptor
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.12.003

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.