Immunopharmacology, 10 (1985) 69-75 Elsevier 69 IMO 00287 Inhibition of the Vascular Actions of IgG Aggregates by BN 52021, a Highly Specific Antagonist of Paf-acether Mariano Sfinchez-Crespo 1, Sagrario Fernfindez-Gallardo ~, Maria-Luisa Nieto 1, JoElle Baran6s 2 and Pierre Braquet 2 1Laboratory of Experimental Nephrology, Fundacion Jimenez Diaz, 28040 Madrid, Spain and 21HB_IPSEN Institute for Therapeutic Research, F-92350 Le Plessis Robinson, France (Received 26 March 1985; accepted 20 May 1985) Abstract: The effect of BN 52021, a selective antagonist of paf-acether (Braquet GB patent 8, 418, 424 July 19, 1984), was studied in normotensive rats challenged with different doses of paf-acether. Sudden death was observed in animals receiving an i.v. dose of 10 #g/kg of paf-acether and this was prevented by prior treatment with BN 52021 (5 mg/kg, i.v.). Animals receiving 2.5 #g/kg of paf- acether had a fall of mean arterial pressure of 92.5 + 4.7 mmHg which recovered to the prechaUengelevel 20.5 q- 0.2 min thereafter. Previous treatment with BN 52021 (5 mg/kg, i.v.) reduced the mean arterial pressure fall to 47 + 0.9 mmHg and the time of recovery to 5.7 q- 1.7 min. The extravasation of 12SI-bovine serum albumin under the above conditions was reduced by BN 52021 from 36 + 3 to 18 + 3%. A lower dose of BN 52021 (1 mg/kg, i.v.) was also effective in reducing later extravasation, but was unable to prevent the extravasation which appears up to 10 min after the injection of paf-acether. To extend these findings to a model of endogenous production of paf-acether, other animals were challenged with soluble aggregates of human IgG (40 mg/kg, i.v.; Ifiarrea et al., Immu- nopharmacology 6:7, 1983). In these experiments, the development of hypotension and extravasation was more protracted than in the case of paf-acether-treated animals, which is consistent with the requirement of a time lag to generate the endogenous mediator; but BN 52021 (5 mg/kg, i.v.) was at least as effective in preventing hypotension and extravasation as in the case of paf-acether-treated animals. When BN 52021 (5 mg/kg, i.v.) was injected after the challenge with either paf-acether or IgG aggregates, arterial pressure rapidly recovered, which indicates that BN 52021 not only prevents, but also may reverse the action of paf-acether. In summary, the present data extend to in vivo models the pharmacological properties of BN 52021 and provide additional evidenceas to the involvement of paf-acether in shock states initiated by immunological challenge. Key words: Platelet-activating factor; BN 52021; Hypotension; Immunogiobulin G Introduction Platelet-activating factor (paf-acether) is a phos- pholipid mediator with a wide spectrum of biolog- ical activities (for review see Snyder, 1982; Benven- iste and Arnoux, 1983) on platelets, polymorphon- uclear leukocytes, heart, ileum, bronchial tree, kid- ney, liver and arterial and venous vessels. In the last years, the involvement of paf-acether in the reac- tions mediated by immune complexes and in the pathogenesis of the shock state has been docu- mented by the accumulation of direct and indirect data from various groups. For instance, Pinckard et al. (1977) have demonstrated a central role for paf-acether in anaphylaxis in rabbits and Camussi et al. (1982) have been able to detect this mediator in the peripheral blood of rabbits with serum sick- ness. Sanchez-Crespo et al. (1982) and Bessin et al. (1983a; 1983b) have shown that systemic infusion 0162-3109/85/$03.30 © 1985 Elsevier Science Publishers B.V. (Biomedical Division)