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Effects of the PAF antagonist WEB 2086 on PAF-induced physiologic alterations and on IgE anaphylaxis in the rabbit
1Division of Respiratory Sciences, College of Medicine, University of Arizona, Tucson 85724.
Abstract:
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 micrograms/kg) given 5 min before challenge with 0.6 micrograms/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.
Insights
Platelet-activating factor (PAF) antagonist WEB 2086 effectively blocked PAF-induced respiratory and circulatory issues in rabbits. However, its effects on IgE anaphylaxis were limited, though it did prevent anaphylactic death.
Area of Science:
- Pharmacology
- Immunology
- Respiratory Physiology
Background:
- Platelet-activating factor (PAF) is implicated in inflammatory responses.
- Understanding PAF's role in anaphylaxis is crucial for therapeutic development.
Purpose of the Study:
- To investigate the in vivo effects of PAF antagonist WEB 2086 on PAF- and antigen-induced physiological changes in rabbits.
- To determine the extent of WEB 2086's inhibitory action on anaphylactic responses.
Main Methods:
- Administration of PAF antagonist WEB 2086 to rabbits prior to challenge with PAF or antigen.
- Monitoring of respiratory, circulatory, and hematologic parameters.
- Assessment of anaphylactic lethality.
Main Results:
- WEB 2086 completely inhibited PAF-induced bronchoconstriction, altered breathing patterns, bradycardia, increased right ventricular pressure, and hypotension.
- PAF-induced thrombocytopenia, leukopenia, and basopenia were prevented by WEB 2086.
- WEB 2086 showed limited inhibition of IgE anaphylaxis, except for a significant reduction in total pulmonary resistance and prevention of anaphylactic lethality.
Conclusions:
- PAF is a key mediator of PAF-induced physiological alterations.
- PAF plays a role in anaphylactic lethality and increased pulmonary resistance but not other major anaphylactic responses.