Prostaglandin E2 mediates cough via the EP3 receptor: implications for future disease therapy.
BACKGROUND
A significant population of patients with severe asthma and chronic obstructive pulmonary disease is less responsive to beta(2)-adrenoceptor agonists and corticosteroids, and there are possible safety issues concerning long-term use of these drugs. Inhaled prostaglandin E(2) (PGE(2)) is antiinflammatory and a bronchodilator in patients with asthma, but it also causes cough.


OBJECTIVE
We aimed to identify the receptor involved in PGE(2)-induced sensory nerve activation and cough using a range of in vitro and in vivo techniques.


METHODS
Depolarization of vagal sensory nerves (human, mouse, and guinea pig) was assessed as an indicator of sensory nerve acitivity. Cough was measured in a conscious guinea pig model.


RESULTS
Using an extensive range of pharmacological tools, we identified that the EP(3) receptor mediates PGE(2)-induced depolarization of sensory nerves in human, mouse, and guinea pig. Further supporting evidence comes from data showing that responses to PGE(2) are virtually abolished in isolated vagus nerves from EP(3)-deficient mice (Ptger3(-/-)). Finally, we demonstrated the role of the EP(3) receptor in vivo using a selective EP(3) antagonist to attenuate PGE(2)-induced cough.


CONCLUSIONS
Identification of the receptor mediating PGE(2)-induced cough represents a key step in developing a drug that is antiinflammatory and a bronchodilator but without unwanted side effects.
Maher
Sarah A
SA
Respiratory Pharmacology, Airways Diseases, Imperial College London, Faculty of Medicine, National Heart and Lung Institute, Sir Alexander Fleming Building, London, SW7 2AZ, UK.
Birrell
Mark A
MA
Belvisi
Maria G
MG
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D003371:Cough / Q000503:physiopathology*; D003517:Cyclopentanes / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D054833:Isoindoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011422:Propionates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000502:physiology*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D011984:Sensory Receptor Cells / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D014630:Vagus Nerve / Q000187:drug effects; D044004:Xanthones / Q000494:pharmacology
C518619:6-(2-(5-chloro-2-(((2,4-difluorophenyl)methyl)oxy)phenyl)-1-cyclopenten-1-yl)-2-pyridinecarboxylic acid; D001572:Benzofurans; D003517:Cyclopentanes; D054833:Isoindoles; C515270:N-(2-(4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo(f)isoindol-2-yl)phenyl)acetyl)benzene sulphonamide; C545647:PTGER3 protein, human; D011422:Propionates; C545648:Ptger3 protein, mouse; D011725:Pyridines; C515593:RO3244794; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013449:Sulfonamides; D044004:Xanthones; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D015232:Dinoprostone; D004121:Dimethyl Sulfoxide