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.