title: Theophylline inhibits the cough reflex through a novel mechanism of action.
abstract: BACKGROUND
  Theophylline has been used in the treatment of asthma and chronic obstructive pulmonary disease for more than 80 years. In addition to bronchodilator and anti-inflammatory activity, clinical studies have suggested that theophylline acts as an antitussive agent. Cough is the most frequent reason for consultation with a family doctor, and treatment options are limited. Determining how theophylline inhibits cough might lead to the development of optimized compounds.
  
  
  OBJECTIVE
  We sought to investigate the inhibitory activity of theophylline on vagal sensory nerve activity and the cough reflex.
  
  
  METHODS
  Using a range of techniques, we investigated the effect of theophylline on human and guinea pig vagal sensory nerve activity in vitro and on the cough reflex in guinea pig challenge models.
  
  
  RESULTS
  Theophylline was antitussive in a guinea pig model, inhibited activation of single C-fiber afferents in vivo and depolarization of human and guinea pig vagus in vitro, and inhibited calcium influx in airway-specific neurons in vitro. A sequence of pharmacological studies on the isolated vagus and patch clamp and single-channel inside-out experiments showed that the effect of theophylline was due to an increase in the open probability of calcium-activated potassium channels. Finally, we demonstrated the antitussive activity of theophylline in a cigarette smoke exposure model that exhibited enhanced tussive responses to capsaicin.
  
  
  CONCLUSIONS
  Theophylline inhibits capsaicin-induced cough under both normal and "disease" conditions by decreasing the excitability of sensory nerves through activation of small- and intermediate-conductance calcium-activated potassium channels. These findings could lead to the development of optimized antitussive compounds with a reduced side effect potential.
authors.affiliation: Respiratory Pharmacology, Pharmacology & Toxicology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Eric
authors.initials: E
authors.lastname: Dubuis
authors.affiliation: Respiratory Pharmacology, Pharmacology & Toxicology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Wortley
authors.affiliation: Respiratory Pharmacology, Pharmacology & Toxicology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Grace
authors.affiliation: Respiratory Pharmacology, Pharmacology & Toxicology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Maher
authors.affiliation: Respiratory Pharmacology, Pharmacology & Toxicology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: John J
authors.initials: JJ
authors.lastname: Adcock
authors.affiliation: Respiratory Pharmacology, Pharmacology & Toxicology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Birrell
authors.affiliation: Respiratory Pharmacology, Pharmacology & Toxicology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom. Electronic address: m.belvisi@imperial.ac.uk.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Belvisi
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000996:Antitussive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D003371:Cough / Q000188:drug therapy / Q000209:etiology*; D004195:Disease Models, Animal; D017950:Ganglia, Sensory / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D012018:Reflex / Q000187:drug effects* / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D013806:Theophylline / Q000008:administration & dosage / Q000494:pharmacology*; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
chemical_list: D000996:Antitussive Agents; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D051640:Small-Conductance Calcium-Activated Potassium Channels; D013806:Theophylline; D002211:Capsaicin; D002118:Calcium
keywords: Sensory nerves; capsaicin; cough; ion channels; vagus