BAY-U3405 AN ANTAGONIST OF THROMBOXANE-A2-INDUCED AND PROSTAGLANDIN-D2-INDUCED BRONCHOCONSTRICTION IN THE GUINEA-PIG

1 The novel thromboxane (TX) antagonist, BAY u3405, has been evaluated against bronchoconstriction induced by the TXA2 mimetic U-46619, prostaglandin D2 (PGD2), 5-hydroxytryptamine (5-HT), leukotriene D4 (LTD4) and histamine in the guinea-pig in vivo by use of a modification of the model described by Konzett & Rossler. 2 When given intravenously (i.v.) at 30 or 100-mu-g kg-1, U-46619 caused 80% maximal bronchoconstriction in most animals. In contrast, PGD2 caused a smaller 40%-50% maximal bronchoconstriction at the highest dose tested (300-mu-g kg-1, i.v.). 3 BAY u3405, given intravenously, orally (p.o.) or by aerosol antagonized U-46619-induced bronchoconstriction in a dose-related manner. The approximate ID50 values were 600-mu-g kg-1, i.v., 1.7mg kg-1 p.o. and 0.1% w/v 20 breaths by aerosol. 4 BAY u3405 had similar inhibitory activities against U-46619-induced bronchoconstriction and hypertension suggesting that it had no preferential activity on the airways. 5 When given intravenously BAY u3405 antagonized the bronchoconstrictor effect of intravenous PGD2 with ID50 values between 30-100-mu-g kg-1. 6 The action of BAY u3405 (10 mg kg-1, p.o.) was long lasting causing significant inhibition of U-46619-induced bronchoconstriction 7 h after dosing. 7 At 1 mg kg-1, i.v., a dose that abolished the response to U-46619 and PGD2, BAY u3405 had no effect on histamine-, 5-HT- or LTD4-induced bronchoconstriction. 8 BAY u3405 potently and selectively antagonized U-46619- or PGD2-induced bronchoconstriction in the Konzett-Rossler model of guinea-pig lung function. It should therefore prove to be a useful tool for defining the role of TXA2 and PGD2 in airway diseases such as asthma.