Effect of inhibition of thromboxane production on the leukotriene D 4-mediated bronchoconstriction in the guinea pig

Abstract

Leukotriene D 4 (LTD 4) administered intravenously to anesthetized, spontaneously breathing guinea pigs elicited decreases in dynamic lung compliance (C dyn) and airway conductance (G AW) with a maximal response achieved at 0.5 min. Simultaneously, plasma levels of thromboxane metabolite, TxB 2, and the prostacyclin metabolite, 6-keto-PGF 1α, increased 10-fold over pre-LTD 4 levels. Pretreatment of the guinea pigs with meclofenamic acid delayed the onset of the LTD 4-induced bronchoconstriction, antagonized the magnitude of the decreases in C dyn and G AW, and blocked the increase in plasma TxB 2 and 6-keto-PGF 1α levels. The thromboxane synthetase inhibitor, UK 37,248, suppressed the LTD 4-induced bronchoconstriction, while it completely blocked TxB 2 production without significantly affecting 6-keto-PGF 1α. The SRS-A end organ antagonist, FPL 55712, blocked both the LTD 4-induced bronchoconstriction and the production of the arachidonic acid metabolites. These results suggest that thromboxane A 2 plays an important role in mediating part of the bronchoconstriction elicited by intravenously administered LTD 4 in the guinea pig.