Interference by the novel PAF-acether antagonist WEB 2086 with the bronchopulmonary responses to PAF-acether and to active and passive anaphylactic shock in guinea-pigs.
The interaction between the triazolothienodiazepine WEB 2086 and the in vitro and in vivo bronchopulmonary effects of PAF-acether and active/passive anaphylaxis in the guinea-pig was studied. WEB 2086 (1-100 nM) inhibited PAF-acether (10-100 ng)-induced bronchoconstriction and TXB2 release from isolated and perfused guinea-pig lungs without affecting the response to 100 micrograms arachidonic acid. In addition, 1-10 microM WEB 2086 significantly reduced antigen-induced TXB2 and histamine release from lungs from actively and passively sensitized guinea-pigs. In the presence of the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA), mepyramine, methysergide, indomethacin and atropine, WEB 2086 (20-50 microM) inhibited by 30-40% the residual contraction of lung parenchyma strips from guinea-pigs actively sensitized by 0.1-10 micrograms antigen. In vivo, WEB 2086 (0.1-1 mg/kg) reversed or abolished the bronchoconstriction, hypotension, thrombocytopenia and leukopenia evoked by perfusion of PAF-acether (3 or 44 ng/kg per min). At 3 mg/kg, WEB 2086 also markedly decreased the bronchoconstriction and leukopenia induced by 100 micrograms/kg antigen in mepyramine (5 micrograms/kg)-treated passively sensitized guinea-pigs. In contrast, WEB 2086 was ineffective against active anaphylaxis in vivo. These results demonstrate that WEB 2086 antagonizes the bronchopulmonary effects due to PAF-acether and to anaphylactic shock in the guinea-pig.
D000707:Anaphylaxis / Q000503:physiopathology*; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011863:Radioimmunoassay; D012137:Respiratory System / Q000187:drug effects* / Q000503:physiopathology; D013050:Spectrometry, Fluorescence; D013921:Thrombocytopenia / Q000139:chemically induced; D013929:Thromboxane B2 / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology*; D014230:Triazoles
D001381:Azepines; D007202:Indicators and Reagents; D010972:Platelet Activating Factor; D014227:Triazines; D014230:Triazoles; C052518:WEB 2086; D013929:Thromboxane B2; D006632:Histamine