The benzodiazepine receptor ligands RO 5-4864 and RO 15-1788 do not block the inhibition of PAF-induced platelet aggregation seen with the hetrazepine WEB2086.
The hypothesis was tested that the hetrazepine WEB 2086 acts as an inhibitor of PAF-induced platelet aggregation via interaction with the platelet benzodiazepine receptor(BDZR). WEB 2086 is a potent inhibitor of rabbit platelet aggregation and ATP secretion induced by 370 nM PAF. The two BDZR ligands RO 5-4864 and RO 15-1788 (7-96 microM) are inactive as PAF antagonists. When platelets were pretreated with either BDZR ligand, and then exposed to various concentrations of WEB 2086, there was no alteration of the dose-response relationship of the hetrazepine on PAF-induced aggregation, as reflected by threshold concentration, ED50, or maximum inhibition seen with WEB 2086. Pretreatment of platelets with the BDZR ligands also failed to block the inhibitory action of WEB 2086 on PAF-induced ATP release. The data are consistent with the notion that WEB 2086 acts as a PAF antagonist through its action at a specific PAF receptor, and is dissociated from, and independent of, interaction with the benzodiazepine receptor.
Griffin
K
K
Laboratory of Pharmacology and Experimental Therapeutics, Pacific Presbyterian Medical Center/MRI, San Francisco, CA 94115.
Hong
T
T
Levy
J V
JV
D000255:Adenosine Triphosphate / Q000097:blood; D000818:Animals; D001381:Azepines / Q000378:metabolism / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005442:Flumazenil / Q000494:pharmacology*; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D014227:Triazines / Q000378:metabolism / Q000494:pharmacology*; D014230:Triazoles
D001381:Azepines; D001570:Benzodiazepinones; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; D014227:Triazines; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086; C028513:4'-chlorodiazepam; D005442:Flumazenil; D000255:Adenosine Triphosphate