The role of platelet‐activating factor and peptidoleukotrienes in the vascular changes of rat passive anaphylaxis

The role of platelet‐activating factor (PAF) and peptidoleukotrienes as putative mediators of some of the vascular changes triggered by antigen was investigated in rats passively sensitized with monoclonal anti‐DNP (2,4‐dinitrophenyl) IgE. Lethal anaphylaxis with respiratory distress, systemic hypotension, detachment of the intestinal mucosa, leukopenia and extravasation of protein‐rich plasma was observed after antigen challenge of rats sensitized with partially purified monoclonal IgE at concentrations of 15 mg protein kg⁻¹. Analysis of the peritoneal fluid obtained after i.v. challenge with DNP‐BSA (bovine serum albumin) showed the presence of significant amounts of PAF (101 ± 8 pg/rat), whereas this mediator was undetectable in control animals. Leukotriene D₄ was the predominant peptidoleukotriene that could be recovered after antigen challenge, and showed an extremely high concentration (92 ± 15 ng/rat) as compared to PAF levels. Extravasation of protein‐rich plasma was observed shortly after challenge and reached a maximum at 30 min. Treatment of animals with i.v. PCA 4248 (1–2 mg kg⁻¹) and WEB 2086 (1 mg kg⁻¹), two chemically unrelated compounds which are antagonists of the PAF‐receptor, produced a significant reduction of the extravasation of protein‐rich plasma. The same degree of protection could be afforded by MK‐886, an inhibitor of leukotriene biosynthesis. Combined treatment with WEB 2086 and MK‐886 provided greater inhibition of protein‐rich plasma extravasation than either compound alone. PCA 4248 was also found to inhibit in a dose‐dependent manner the systemic hypotension observed upon DNP‐BSA challenge. These data indicate that the lipid mediators PAF and peptidoleukotrienes are major effectors of the vascular disturbances observed in rat passive IgE‐mediated anaphylaxis. 1992 British Pharmacological Society