YM461, a PAF antagonist, blocks antigen-induced late airway responses and airway hyperresponsiveness in allergic sheep.

We examined the effect of an orally active antagonist, YM461, of platelet activating factor (PAF) on antigen-induced early and late airway responses and on the development of airway hyperresponsiveness 24 h after challenge in allergic sheep. Early and late airway responses were determined by measuring specific lung resistance (SRL) before and periodically after challenge. Airway responsiveness was determined from the slopes of dose-response curves of SRL vs. increasing doses of carbachol aerosol. The sheep were challenged with Ascaris suum antigen once after vehicle treatment (control) and once 1 h after oral administration of 3 or 10 mg/kg YM461 (each trial was greater than or equal to 14 days apart). Airway responsiveness to carbachol was determined 1-3 days prior to and 24 h after antigen challenge. In control 1 and control 2 trials antigen challenge caused significant peak early (288 and 292%, respectively) and peak late (103 and 124%, respectively) increases over baseline in SRL. SRL returned to baseline 24 h after challenge but the sheep developed airway hyperresponsiveness as indicated by the 2.6-fold increases in the slopes of the carbachol dose-response curves in the control trials. YM461, 3 and 10 mg/kg p.o., significantly inhibited the late responses (66 and 82%, respectively) and blocked the development of airway hyperresponsiveness at 24 h. The early responses were not significantly reduced in either trial. These results suggest that PAF contributes to the antigen-induced late airway responses and associated airway hyperresponsiveness in allergic sheep.