Effects of DP-1904, a thromboxane synthetase inhibitor, on the antigen-induced airway hyperresponsiveness and infiltration of inflammatory cells in guinea-pigs.
The effect of DP-1904, a novel thromboxane (TX) synthetase inhibitor, on airway hyperresponsiveness was studied in actively sensitized guinea-pigs. Airway hyperresponsiveness to intravenous ACh was observed at 3 and 7 h after aerosolized antigen challenge. In the model, a significant correlation between increases of respiratory resistance and microvascular leakage was observed, corresponding to the elevation of TXB2 in bronchoalveolar lavage fluid (BALF) in the early phase. DP-1904, at doses of 3 mg/kg or higher given orally one hour prior to the antigen challenge, inhibited the TXB2 production and the development of airway hyperresponsiveness in the early phase. Further, DP-1904 significantly suppressed the accumulation of lymphocytes in BALF and airway hyperresponsiveness in the late phase, although it only slightly decreased the mobilization of eosinophils and neutrophils. The results suggest that TXA2 is possibly involved in the development of airway hyperresponsiveness, and DP-1904 prevented the airway hyperresponsiveness via inhibition of TXA2 production and regulation of inflammatory cells.
Takami
M
M
Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan.
Tsukada
W
W
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D018893:Bronchoalveolar Lavage; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000517:prevention & control*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013997:Time Factors
D004791:Enzyme Inhibitors; D007093:Imidazoles; D013764:Tetrahydronaphthalenes; D013929:Thromboxane B2; D013928:Thromboxane A2; C056295:nafagrel; D013930:Thromboxane-A Synthase; D015232:Dinoprostone; D000109:Acetylcholine