Thromboxane A2 mediated bronchoconstriction in the anesthetized guinea pig.

Arachidonic acid-induced platelet aggregation has been shown to be selectively antagonized by the thromboxane A2 synthetase inhibitor SQ 80,338 or by the thromboxane A2 receptor antagonist SQ 24,775. Experiments were done to see what effect these two compounds would have on the bronchoconstrictor response to various agents in the anesthetized guinea pig. Increases in pulmonary resistance and decreases in dynamic compliance were taken as an index of bronchoconstriction. Both SQ 80,338 (0.3-10.0 mg/kg) and SQ 24,775 (0.1-1.0 mg/kg) administered i.v. caused dose-related inhibitions of arachidonate-induced bronchoconstriction. SQ 80,338 (3.0 and 10.0 mg/kg) also inhibited bradykinin-induced bronchoconstriction in the presence of beta-adrenergic blockade. These same doses of SQ 80,338 and SQ 24,775 did not alter either histamine- or antigen-induced bronchoconstriction. SQ 80,338 (10.0 micrograms/ml) prevented arachidonate-induced release of TXA2 from the isolated perfused guinea pig lung while SQ 24,775 (1.0 microgram/ml) antagonized the contraction of the isolated rat aorta induced by 9,11,AZO-PGH2. These results suggest that both arachidonate and bradykinin-induced bronchoconstriction are mediated through the generation of TXA2, while histamine- and antigen-induced bronchoconstriction are not.