Benzodiazepine analogues inhibit arachidonate-induced aggregation and thromboxane synthesis in human platelets.
1. Benzodiazepine analogues inhibit human platelet aggregation induced by arachidonate with an EC50 value of 0.68 microM for PK 11195, the most potent analogue used. 2. There was a highly significant correlation between the inhibition of arachidonate-induced aggregation and the affinity for the peripheral-type of benzodiazepine binding sites. 3. There was no significant correlation between the inhibition of the platelet activating factor (PAF)-induced aggregation and the binding to the peripheral-type of benzodiazepine binding sites. 4. The inhibition of platelet aggregation seems to result from the inhibition of arachidonic acid cyclo-oxygenation, since the synthesis of thromboxane and 12-hydroxy-heptadecatrienoic acid, both cyclo-oxygenase products, was reduced. 5. Our results suggest that peripheral-type of benzodiazepine binding sites on human platelets could be linked to cyclo-oxygenase.
Fonlupt
P
P
Unité INSERM 205-Laboratoire de Chimie Biologique, Villeurbanne, France.
Croset
M
M
Lagarde
M
M
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology*; D001779:Blood Coagulation Factors / Q000037:antagonists & inhibitors; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000378:metabolism; D007700:Kinetics; D010972:Platelet Activating Factor; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects; D013931:Thromboxanes / Q000096:biosynthesis*
D001095:Arachidonic Acids; D001779:Blood Coagulation Factors; D016861:Cyclooxygenase Inhibitors; D007546:Isoquinolines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011963:Receptors, GABA-A; D013931:Thromboxanes; D001569:Benzodiazepines; D016718:Arachidonic Acid; C037850:PK 11195