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.

Abstract

Platelet-activating factor (PAF) is a potent lipid mediator of inflammation and asthma. Using a receptor preparation of rabbit platelet membranes, we identified a novel antagonist of PAF in the methylene chloride extract of a Chinese herbal plant, haifenteng (Piper futokadsura). 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 K; of 5.8x 10-8 M vs. a K; of 6.3 x 10-9 M for PAF itself. It inhibits PAF-induced aggregation of rabbit platelets and human neutrophils at 2.4-24 guM, without showing any PAF agonistic activity. It potently inhibits PAF-induced degranulation of human neutrophils at 2.5-50 #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 three related structures isolated from the same haifenteng extract.

Kadsurenone distinguishes between different platelet activating factor receptor subtypes on macrophages and polymorphonuclear leucocytes

“…Discussion Shen et al (1985) have reported pA2 values for kadsurenone of 6.28 with Paf-induced rabbit platelet aggregation and 6.32 with Paf-induced human p.m.n.l. aggregation.…”

“…The binding of Paf to platelet receptors and its human p.m.n.l. aggregating and degranulating actions have recently been shown to be antagonized by the plant-derived compound, kadsurenone (Shen et al, 1985). We have shown that Paf also stimulates the oxidative burst in guinea-pig macrophages (Hartung et al, 1983;Parnham & Leyck, 1983) and initiated the present study on the effects of kadsurenone on pig p.m.n.l.…”

Binding and metabolism of platelet-activating factor by human neutrophils.

“…Based on the phospholipids striking biological potency, its stereospecificity, and its ability to desensitize target cells, we suggested that cellular receptors were involved in transducing bioactivity (30)(31)(32). Subsequent studies have indeed demonstrated specific binding sites for PAF in or on platelets, PMN, and smooth muscle-containing tissues (33)(34)(35)(36) while other studies have identified compounds that competitively inhibit PAF binding and bioactions (37)(38)(39). In this report, we examine PAF metabolism concurrently with binding, track the subcellular movement of PAF and its metabolites, and characterize the location of PAF receptors.…”

Effectiveness and tolerability of CV‐3988, a selective PAF antagonist, after intravenous administration to man.

“…Although several specific PAF-receptor antagonists, chemically related (Terahsita et al, 1983;Steiner et al, 1985) and unrelated to PAF (Braquet et al, 1985;Komecki et al, 1984;Hwang et al, 1985;Shen et al, 1985), have recently been reported, human pharmacology is very limited (Chung etal., 1987). Here we report that (RS)-2-methoxy-3-(octadecylcarbamoyloxy)-propyl 2-(3-thiazolio) ethylphosphate (CV-3988) (Terashita et al, 1983), when administered intravenously to human volunteers, inhibits PAF induced platelet aggregation ex vivo.…”