EFFECTS OF THE PAF ANTAGONIST WEB-2086 ON PAF-INDUCED PHYSIOLOGICAL ALTERATIONS AND ON IGE ANAPHYLAXIS IN THE RABBIT

The inhibitory effects of the specific platelet-activating factor (PAF) antagonist WEB 2086 on the in vivo PAF- and antigen-induced respiratory, circulatory, and hematologic alterations in the rabbit were investigated. WEB 2086 (600 μg/kg) given 5 min before challenge with 0.6 μg/kg of PAF completely inhibited the PAF-induced bronchoconstriction, period of rapid, shallow breathing, bradycardia, increase in right ventricular pressure, and hypotension. The PAF-induced thrombocytopenia, leukopenia, and basopenia were also prevented by WEB 2086 pretreatment. In contrast, the inhibitory effects of WEB 2086 on IgE anaphylaxis were much more limited. No significant inhibition of the responses in tidal volume, breathing frequency, hypotension, or bradycardia was observed in sensitized rabbits pretreated with 1 or 6 mg/kg of WEB 2086. However, WEB 2086 significantly inhibited the increase in total pulmonary resistance. Although the peak changes in dynamic lung compliance and right ventricular pressure were not or were only slightly inhibited by WEB 2086, a more rapid recovery to baseline was observed in rabbits receiving the PAF antagonist. No significant inhibition of the thrombocytopenia, leukopenia, and basopenia accompanying antigen challenge was observed in WEB 2086-pretreated rabbits. Pretreatment with the PAF antagonist prevented anaphylactic lethality. Thus, PAF appears to play a role in the lethality and the maximum increase in total pulmonary resistance of IgE systemic anaphylaxis but does not appear to be a major mediator of the other physiologic alterations, including systemic hypotension.