Antagonism of Paf-induced oedema formation in rabbit skin: a comparison of different antagonists

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Abstract
Eight platelet activating factor (Paf) antagonists were evaluated as inhibitors of oedema formation in rabbit skin induced by intradermal injection of Paf plus prostaglandin E2 (PGE2). Antagonists were tested by both intradermal (i.d.) and intravenous (i.v.) routes. Intradermal injection of two antagonists structurally-related to Paf (SRI 63-675 and CV-3988) resulted in a partial inhibition of Paf-induced oedema formation but at high doses of antagonist, marked agonist activities were detected. CV-3988 administered i.v. inhibited Paf-induced plasma leakage by 73-80%; however, oedema responses to a range of other inflammatory mediators were also reduced, albeit to a lesser extent (40-60%). SRI 63-675 administered i.v. did not significantly inhibit Paf-induced oedema. The antagonist 48740 RP administered either i.d. showed partial, but selective, inhibition of Paf-induced oedema formation, although the doses required were high when compared with other antagonists. BN 52021 was a weak Paf antagonist when injected i.d., but following i.v. administration the responses to Paf were inhibited by 63-71%. Responses to all other mediators tested were unaffected. Kadsurenone and its synthetic derivatives, L-652,731 and L-659,989 all blocked responses to Paf in the skin. L-659,989 was the most potent, achieving almost total inhibition when injected i.d. and i.v.; moreover, it was selective for Paf. L-652,731 was more potent than kadsurenone. WEB 2086 given i.d. and i.v. showed similar activity to L-659,989 and it was also selective for Paf-induced oedema formation. These results illustrate that in rabbit skin not all Paf antagonists are selective for Paf, some showing agonist-like activity which can mask antagonist properties. It is suggested that before ascribing a role for endogenous Paf in an inflammatory reaction based on results with antagonists, the activity of the antagonists in the model under investigation should be rigorously established.