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 ug] 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 ug) resulted in only a 220±50% increase in SRL (p<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<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 response p<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.
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