Effect of the selective thromboxane A 2 receptor antagonist, S-1452, on antigen-induced sustained bronchial hyperresponsiveness

Abstract

Long-lasting bronchial hyperresponsiveness to i.v. acetylcholine was observed in actively sensitized guinea-pigs after aerosol ovalbium exposure. The response became significant at 7 h post-challenge and persisted for at least 120 h compared to the response of unsensitized animals. Pretreatment of animals with the specific thromboxane A 2 receptor antagonist, S-1452 (calcium (1 R, 2 S, 3 S, 4 S)-(5 Z)-7-(((phenylsulfonyl)amino)bicyclo[2.2.1]hept-2-yl) hept-5-enoate dihydrate), almost completely inhibited the onset of bronchial hyperresponsiveness, as assessed at 24 and 120 h post-challenge. However, it was ineffective when administered at 1 h post-challenge or 2 h before assessment of bronchial responsiveness. Lung vascular injury occured transiently immediately after antigen challenge, the kinetics of injury being associated with those for the production of thromboxane B 2 in bronchoalveolar lavage fluid. The vascular injury was dramatically suppressed by pretreatment with S-1452. These findings suggest that acutely generated thromboxane A 2 plays an important role in the pathogenesis of antigen-induced long-lasting bronchial hyperresponsiveness, probably by producing vascular damage in the lungs.