SK&F 88046: inhibition of thromboxane-induced bronchoconstriction in anesthetized dogs

In addition to its well-described pro-aggregatory action, thromboxane A2 (TxA2) has been shown to be a potent bronchoconstrictor. The present study was designed to evaluate whether SK&F 88046 [N,N'-bis-7-(3-chlorobenzeneaminosulfonyl)-1,2,3,4- tetrahydroisoquinolyl disulfonylimide] had any inhibitory effects against canine bronchoconstriction induced by U-44069, a functional TxA2 mimic. Bronchopulmonary responses were measured by computer analyses in spontaneously breathing, pentobarbital-anesthetized mongrel dogs. In a dose range of 0.3-3.0 micrograms/kg i.v., U-44069 produced potent, dose-related increases in pulmonary airway resistance (RL) and decreases in dynamic lung compliance (CDYN), which were indicative of severe bronchoconstriction. The onset of agonist activity was prompt (1-2 min) and recovery usually occurred within 5-10 min. Pretreatment with varying doses of SK&F 88046 (1, 3 and 5 mg/kg) as a 10 min i.v. infusion, produced a significant inhibition of the RL and CDYN effects of U-44069. In addition, SK&F 88046, as well as UK 37248 (dazoxiben), a thromboxane synthetase inhibitor, was effective vs. arachidonic acid-induced decreases in CDYN; however, SK&F 88046 failed to alter significantly bronchopulmonary effects induced by other known bronchoconstrictors, e.g., PGF2 alpha, PGD2, histamine or acetylcholine. Therefore, SK&F 88046 represents an antagonist of TxA2-mediated changes in airway mechanics in the anesthetized dog.