Platelet-activating factor (PAF) receptor antagonists inhibit arachidonic acid induced platelet aggregation in rabbit whole blood.
The potency of several platelet-activating factor (PAF) receptor antagonists was measured by observing their inhibitory effects against PAF induced platelet aggregation. Their selectivity was assessed by monitoring their effect on platelet aggregation induced by arachidonic acid (AA) and adenosine diphosphate (ADP). The antagonists inhibited platelet aggregation induced at the PAF EC50 (0.023 microM) with the following rank order of potency: WEB 2086 greater than WEB 2170 greater than SRI 64-412 greater than SRI 63-675 greater than BN 52021 greater than kadsurenone greater than SRI 63-441 greater than alprazolam. While the antagonists had no inhibitory effect at the EC50 for ADP (10 microM), they did inhibit platelet aggregation induced at the EC50 for AA (55 microM). However, there was considerable variability in the slope of the inhibitory response and the relative potency of each antagonist against PAF induced platelet aggregation as compared to AA induced platelet aggregation. The antagonist IC50 (microM) against PAF and AA were as follows, with those that showed significantly different (p less than 0.01) slopes indicated by an asterisk: SRI 63-441* (3.8, 15.1); SRI 63-675 (1.4, 36.2); SRI 64-412 (0.5, 10.5); BN 52021* (2.4, 58.9); kadsurenone* (2.8, 28.3); alprazolam* (10, 25); WEB 2086 (0.055, 0.220), and WEB 2170 (0.107, 0.534). Therefore, in rabbit whole blood the antagonists were potent, although not completely selective, inhibitors of PAF induced platelet aggregation. These results suggest that the mode of action of PAF and AA induced platelet aggregation may share some common features. However, since the slope of the inhibitory response against PAF and AA for some antagonists differed, mechanistic differences in their action appear to exist.
Ammit
A J
AJ
Human Reproduction Unit, Royal North Shore Hospital of Sydney, St. Leonards, N.S.W., Australia.
O'Neill
C
C
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007700:Kinetics; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D043562:Receptors, G-Protein-Coupled; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate