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Interaction of the Paf antagonist WEB 2086 and its hetrazepine analogues with human platelets and endothelial cells
Author(s) -
Korth R.,
Hirafuji M.,
Keraly C. Lalau,
Delautier D.,
Bidault J.,
Benveniste J.
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb12640.x
Subject(s) - platelet activating factor , platelet , chemistry , bovine serum albumin , umbilical vein , antagonist , ic50 , medicine , biochemistry , endocrinology , in vitro , biology , receptor
1 Intact platelets and confluent human umbilical vein endothelial cells bound [ 3 H]‐Paf‐acether (platelet activating factor, [ 3 H]‐Paf) at 20°C in the presence of 0.25% (w/v) bovine serum albumin (BSA). 2 [ 3 H]‐Paf binding to platelets was inhibited in a concentration‐dependent manner by WEB 2086. An excess of WEB 2086 indicated the presence of specific, saturable Paf binding which reached a maximum of 28.3 ± 3.7 fmol [ 3 H]‐Paf per 5 × 10 7 platelets. In platelets, different hetrazepines (WEB 2098, 2105, but not 2118) also inhibited [ 3 H]‐Paf binding in a concentration‐dependent manner. 3 WEB 2086 partially displaced platelet‐bound [ 3 H]‐Paf in a concentration‐dependent manner reaching a plateau at 400 nM WEB 2086. No further displacement was observed when WEB 2086 and an excess of unlabelled Paf were added together. 4 The hetrazepines inhibited platelet aggregation. Platelet aggregation IC 50 values correlated well with the IC 50 values of the hetrazepines against [ 3 H]‐Paf binding ( r 2 = 0.99). WEB 2086 shifted the Paf dose‐response curve rightwards in a parallel manner. Tested against platelet aggregation the pA 2 obtained for WEB 2086 was 7.9. 5 WEB 2086 inhibited [ 3 H]‐Paf binding to endothelial cells in a concentration‐dependent manner. WEB 2086 also inhibited the Paf‐mediated cytosolic calcium increase in endothelial cells with an IC 50 value of 23.1 ± 10.4 nM as compared with an IC 50 of 21.6 ± 10.4 nM WEB 2086 for platelet aggregation. 6 These results demonstrate an inhibition of [ 3 H]‐Paf binding to platelets and endothelial cells by different hetrazepines, most probably at the Paf receptor level.