Inhibitory effect of new PAF antagonists on PAF-induced rabbit platelet aggregation in vitro and ex vivo.
The effect of BN 50739, a recently developed PAF antagonist, on PAF-induced rabbit platelet aggregation in vitro and ex vivo was investigated. BN 50739 caused a right shift in PAF dose-response curves of platelet aggregation both in vitro and ex vivo. The amplitude of maximum aggregation, however, did not change as the concentration of PAF was increased indicating that BN 50739 is a competitive inhibitor. In vitro, in the presence of 10, 33 and 66 nM of BN 50739, the EC50 of PAF inducing aggregation increased 3.7, 11.1 and 50 times, respectively, and platelet disaggregation was promoted. The IC50 of BN 50739 for 2.5 nM PAF-induced platelet aggregation was 13.8 nM. Under the same condition, the IC50s of BN 50741, BN 50730, BN 50726, SRI 63-441 and BN 52021 were 18.3, 33.1, 63.4, 712 and 24,600 nM, respectively. BN 50739 given i.p. at 1, 3 or 10 mg/kg increased the concentration of PAF inducing 50% maximal platelet-rich plasma aggregation 3.4, 28 and 134 times, respectively. The apparent biological half-life of BN 50739 at 3 and 10 mg/kg i.p. was 2.5 and 5.4 h, respectively. BN 50739 had no effect on arachidonic acid (AA)- or collagen-induced platelet aggregation at concentrations effectively inhibiting PAF-induced platelet aggregation; however, moderate inhibition on AA- and collagen-induced aggregation was observed as the concentration of BN 50739 exceeded 100 nM. The results indicate that BN 50739 is the most potent and competitive PAF antagonist.
Yue
T L
TL
Department of Pharmacology, SmithKline Beecham, King of Prussia, PA 19406-0939.
Rabinovici
R
R
Farhat
M
M
Feuerstein
G
G
D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors; D001381:Azepines / Q000494:pharmacology*; D003094:Collagen / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D015394:Molecular Structure; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; C064509:BN 50739; D016718:Arachidonic Acid; D003094:Collagen