Yangambin: A New Naturally-Occurring Platelet-Activating Factor Receptor Antagonist: Binding and In Vitro Functional Studies

Abstract

The effects of the furofuran lignan yangambin on rabbit platelet aggregation and binding of [³ H]-PAF to rabbit platelet plasma membranes were studied. Log concentration-response curves to PAF were obtained in the presence or absence of increasing concentrations of yangambin. This lignan dose-dependently inhibited PAF-induced platelet aggregation in platelet-rich plasma (PRP) and shifted PAF curves to the right without decreasing the maximal response. The Schild plot constructed from these data showed a slope of 1.17 and a pA₂ of 6.45. Moreover, yangambin at 10^-5 M did not inhibit the platelet aggregation induced by ADP (5 × 10^-7 M), collagen (0.1 µg ml^-1), or thrombin (0.05 U ml^-1). Biochemical studies showed that [³ H]-PAF labelled in a saturable manner a single class of binding sites on platelet membranes with a K_d of 1.25 ± 0.24 nM and a maximal binding capacity (B_max) of 14.9 ± 2.4 pmol mg protein^-1. Both unlabelled PAF and yangambin competitively displaced [³ H]-PAF binding with an IC₅₀ of 1.54 ± 0.37 nM and 1.93 ± 0.53 µM, respectively. The incubation of rabbit blood neutrophils with yangambin at 10^-5 M did not prevent PAF-induced in vitro chemotaxis in conditions where the PAF antagonist SR 27417 at 10^-5 A M abolished the phenomenon. These results indicate that yangambin is an antagonist that selectively blocks PAF receptors on platelets.

Key words

PAF antagonists - (+)-yangambin - Ocotea duckei Vattimo - Lauraceae - PAF - PAF receptors