Characterization of a platelet-activating factor receptor antagonist isolated from haifenteng (Piper futokadsura): specific inhibition of in vitro and in vivo platelet-activating factor-induced effects.

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Abstract
Platelet-activating factor (PAF) is a potent lipid mediator of inflammation and asthma. Using a receptor preparation of rabbit platelet membranes, a novel antagonist of PAF was identified in the methylene chloride extract of a Chinese herbal plant, haifenteng (P. futokadzura). The active antagonist, kadsurenone, was isolated and characterized in several in vitro and in vivo assays. It is a specific and competitive inhibitor of PAF binding to its receptor with a Ki of 5.8 .times. 10-8 M vs. a Ki of 6.3 .times. 10-9 M for PAF itself. It inhibits PAF-induced aggregation of rabbit platelets and human neutrophils at 2.4-24 .mu.M, without showing any PAF agonistic activity. It potently inhibits PAF-induced degranulation of human neutrophils at 2.5-50 .mu.M, also without any agonist activity. Kadsurenone is active orally at 25-50 mg/kg of body weight in blocking PAF-induced cutaneous permeability in the guinea pig. It also inhibits PAF-induced increases of hematocrit and circulating N-acetylglucosaminidase in the rat at > 10 mg/kg i.p. in a dose-dependent manner. Kadsurenone does not interfere with the function of several pharmacological mediators and receptors tested. Its structural specificity is evidenced by the poor PAF-antagonistic activities of 3 related structures isolated from the same haifenteng extract.