Inhibition of airway hyper-responsiveness by TRPV1 antagonists (SB-705498 and PF-04065463) in the unanaesthetized, ovalbumin-sensitized guinea pig.
BACKGROUND AND PURPOSE Airway sensory nerves play a key role in respiratory cough, dyspnoea, airway hyper-responsiveness (AHR), all fundamental features of airway diseases [asthma and chronic obstructive pulmonary disease (COPD)]. Vagally mediated airway reflexes such as cough, bronchoconstriction and chest tightness originate from stimulation of airway sensory nerve endings. The transient receptor potential vanilloid 1 receptor (TRPV1) is present on peripheral terminals of airway sensory nerves and modulation of its activity represents a potential target for the pharmacological therapy of AHR in airway disease. EXPERIMENTAL APPROACH As guinea pig models can provide some of the essential features of asthma, including AHR, we have established the model with some classical pharmacological agents and examined the effect of the TRPV1 antagonists, SB-705498 and PF-04065463 on AHR to histamine evoked by ovalbumin (OA) in unanaesthetized sensitized guinea pigs restrained in a double chamber plethysmograph. Specific airway conductance (sGaw) derived from the airflow was calculated as a percentage of change from baseline. KEY RESULTS Cetirizine and salbutamol significantly inhibited OA-evoked bronchoconstriction [sGaw area under the curve (AUC): 70 and 78%, respectively]. Atropine, SB-705498 and PF-04065463 significantly inhibited OA-evoked AHR to histamine in unanaesthetized, OA-sensitized guinea pigs (sGaw AUC: 94%, 57% and 73%, respectively). Furthermore, this effect was not related to antagonism of histamine's activity. CONCLUSION AND IMPLICATIONS These data suggest that TRPV1 receptors located on airway sensory nerves are important in the development of AHR and that modulation of TRPV1-receptor activity represents a potential target for the pharmacological therapy of AHR in airway disease.
Allergy & Respiratory Biology, Pfizer Global R&D, Sandwich, UK.
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Delescluse
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Mace
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Adcock
D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects; D017332:Cetirizine / Q000494:pharmacology; D003521:Cyclopropanes / Q000627:therapeutic use*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010047:Ovalbumin / Q000008:administration & dosage; D011759:Pyrrolidines / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D014508:Urea / Q000031:analogs & derivatives* / Q000627:therapeutic use
D058666:Adrenergic beta-2 Receptor Agonists; D000485:Allergens; D003521:Cyclopropanes; D039563:Histamine H1 Antagonists, Non-Sedating; D018727:Muscarinic Antagonists; C576037:N-(1-(3,5-difluoro-4-((methylsulfonyl)amino)phenyl)ethyl)-2-methyl-2-(4-(trifluoromethyl)phenyl)cyclopropanecarboxamide; D011759:Pyrrolidines; C512301:SB 705498; D013449:Sulfonamides; D050916:TRPV Cation Channels; D001285:Atropine; D006632:Histamine; D014508:Urea; D010047:Ovalbumin; D000420:Albuterol; D017332:Cetirizine