Contribution of prostaglandin D2 via prostanoid DP receptor to nasal hyperresponsiveness in guinea pigs repeatedly exposed to antigen.
We examined the role of prostanoid DP receptor in nasal blockage in an experimental allergic rhinitis model in guinea pigs. Local inhalation of prostaglandin D(2) (PGD(2)) to the nasal cavity resulted in an increase in intranasal pressure in guinea pigs actively sensitized by repeated antigen exposure but not in non-sensitized guinea pigs. Nasal hyperresponsiveness was observed when the guinea pigs were exposed to histamine and U-46619 (11alpha, 9alpha-epoxymethano-PGH(2); a thromboxane (TX) A(2) mimetic) after repeated antigen exposure. S-5751 ((Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5-enoic acid), a prostanoid DP receptor antagonist, inhibited not only PGD(2)-induced nasal blockage but also nasal hyperresponsiveness to histamine and U-46619 in sensitized guinea pigs. Combined exposure of the nasal cavity of guinea pigs to an aerosol of PGD(2) with histamine or U-46619 at sub-threshold concentrations synergistically caused a marked increase in intranasal pressure. These responses were significantly suppressed by S-5751. These results suggest that PGD(2) plays a critical role in the increase in intranasal pressure via prostanoid DP receptor, probably through synergistically enhancing the nasal response with other chemical mediators released from mast cells and other inflammatory cells activated by allergens.
Yasui
Kiyoshi
K
Frontier Drug Discovery, Discovery Research Laboratories, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. kiyoshi.yasui@shionogi.co.jp
Asanuma
Fujio
F
Hirano
Yosuke
Y
Shichijo
Michitaka
M
Deguchi
Masashi
M
Arimura
Akinori
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000281:Administration, Intranasal; D000485:Allergens; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006168:Guinea Pigs; D006632:Histamine / Q000378:metabolism; D008297:Male; D009297:Nasal Mucosa / Q000378:metabolism*; D015508:Nasal Obstruction / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D009666:Nose / Q000187:drug effects / Q000503:physiopathology; D010047:Ovalbumin; D011312:Pressure; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012221:Rhinitis, Allergic, Perennial / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
C432167:7(2-(5-hydroxybenzo(b)thiophen-3-ylcarbonylamino)-10-norpinan-3-yl)hept-5-enoic acid; D000485:Allergens; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013876:Thiophenes; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006632:Histamine; D010047:Ovalbumin; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor