Effect of the selective thromboxane A2 receptor antagonist, S-1452, on antigen-induced sustained bronchial hyperresponsiveness.
Long-lasting bronchial hyperresponsiveness to i.v. acetylcholine was observed in actively sensitized guinea-pigs after aerosol ovalbumin 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 A2 receptor antagonist, S-1452 (calcium (1R,2S,3S,4S)-(5Z)-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 occurred transiently immediately after antigen challenge, the kinetics of injury being associated with those for the production of thromboxane B2 in bronchoalveolar lavage fluid. The vascular injury was dramatically suppressed by pretreatment with S-1452. These findings suggest that acutely generated thromboxane A2 plays an important role in the pathogenesis of antigen-induced long-lasting bronchial hyperresponsiveness, probably by producing vascular damage in the lungs.
Arimura
A
A
Discovery Research Laboratories II, Shionogi & Co., Ltd. Osaka, Japan.
Asanuma
F
F
Matsumoto
Y
Y
Kurosawa
A
A
Jyoyama
H
H
Nagai
H
H
D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006168:Guinea Pigs; D007114:Immunization; D007275:Injections, Intravenous; D008168:Lung / Q000098:blood supply / Q000473:pathology; D008297:Male; D010047:Ovalbumin / Q000008:administration & dosage / Q000633:toxicity; D011453:Prostaglandins / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013928:Thromboxane A2 / Q000378:metabolism
D000336:Aerosols; D001643:Bridged Bicyclo Compounds; D005229:Fatty Acids, Monounsaturated; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; C056566:S 145; D013928:Thromboxane A2; D010047:Ovalbumin; D000109:Acetylcholine