INFLUENCE OF SK-AND-F-96148 ON THROMBOXANE-MEDIATED RESPONSES IN THE AIRWAYS OF THE CAT

The effects of SK&F 96148, a thromboxane receptor blocking agent, on bronchoconstrictor responses were investigated in paralyzed, anesthetized, mechanically ventilated cats. I.v. injections of the thromboxane A2 (TXA2) mimics, U-46619 and U-44069, produced dose-related increases in transpulmonary pressure and lung resistance (R(L)) and decreases in dynamic compliance (Cdyn). After administration of SK&F 96148, 5 mg/kg i.v., bronchoconstrictor responses to U-46619 and U-44069 were reduced markedly, whereas airway responses to prostaglandin (PG) F2-alpha, serotonin, PGD2, or the PGD2 metabolite, 9-alpha, 11-beta-PGF2, were not altered. The duration of action of SK&F 96148 was greater than 2 h, and the TXA2 receptor blockade was overcome when 10-fold larger doses of the TXA2 mimics were administered. Bronchoconstrictor responses to arachidonic acid, platelet-activating factor (PAF), endothelin-1, and E. coli endotoxin were blocked by SK&F 96148. The present data suggest that SK&F 96148 has selective thromboxane receptor blocking activity in the airways of the cat, and that bronchoconstrictor responses to endothelin-1, arachidonic acid, PAF, and E. coli endotoxin are mediated in part by the formation of TXA2.