title: Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: A beneficial off-target effect?
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors: Mark A
authors: MA
authors: Birrell
authors: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors: Sara J
authors: SJ
authors: Bonvini
authors: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors: Eric
authors: E
authors: Dubuis
authors: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors: Sarah A
authors: SA
authors: Maher
authors: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors: Michael A
authors: MA
authors: Wortley
authors: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors: Megan S
authors: MS
authors: Grace
authors: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors: Kristof
authors: K
authors: Raemdonck
authors: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors: John J
authors: JJ
authors: Adcock
authors: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom. Electronic address: m.belvisi@imperial.ac.uk.
authors: Maria G
authors: MG
authors: Belvisi
mesh_terms: D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000294:innervation; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D003371:Cough / Q000503:physiopathology; D006224:Cricetinae; D057809:HEK293 Cells; D006801:Humans; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D012602:Scopolamine Derivatives / Q000494:pharmacology*; D011984:Sensory Receptor Cells / Q000502:physiology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D000069447:Tiotropium Bromide; D014630:Vagus Nerve / Q000502:physiology
chemical_list: D018727:Muscarinic Antagonists; D012602:Scopolamine Derivatives; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D002211:Capsaicin; D002118:Calcium; D000069447:Tiotropium Bromide
keywords: Sensory nerves; anticholinergics; capsaicin; cough; ion channels; vagus