The effect of an orally active leukotriene (LT) D4 antagonist WY-48, 252 on LTD4 and antigen-induced bronchoconstrictions in allergic sheep.

In this study we examined the effects of a new orally active leukotriene (LT) D4 receptor antagonist, WY-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]methanesulfonamide), on LTD4-induced bronchoconstriction and antigen-induced early and late responses in allergic sheep. For all studies WY-48,252 10 mg/kg, was administered via intragastric tube 1 h prior to airway challenge. In seven sheep, airway challenge with LTD4 [delivered dose mean +/- SE, 53 +/- 2 micrograms] resulted in an immediate increase in SRL to 600 +/- 18% over baseline. When these same sheep were treated with WY-48,252, airway challenge with LTD4 (delivered dose, 61 +/- 5 micrograms) resulted in only a 220 +/- 50% increase in SRL (p less than 0.05 vs placebo). The drug had no effect on baseline SRL. WY-48,252 was also effective in reducing early responses and blocking late responses to inhaled antigen in allergic sheep (n = 7). In the control trial, airway challenge with Ascaris suum antigen resulted in immediate and late (i.e. 6-8 h) increases in SRL of 499% and 138% over baseline (both responses, p less than 0.05). When these same sheep were pretreated with WY-48,252 the immediate antigen-induced increase in SRL was 171% and the late response was 49% over baseline (both responses p less than 0.05 vs control). These results indicate that WY-48,252 is a LTD4 antagonist in allergic sheep. The ability of this compound to modify antigen-induced early responses and to block antigen-induced late responses suggests that the generation of LTD4 during airway anaphylaxis contributes to both responses.