Effects of fibrinogen receptor antagonists GR144053F and aurintricarboxylic acid on platelet activation and degranulation

Activated blood platelets play crucial role in restenosis due to their fund amental significance in thrombus formation. Therefore, platelets are attrac tive targets for the inhibition with a variety of antagonists. In this stud y, we present direct evidence that GR144053F [non-peptide antagonist of gly coprotein IIb-IIIa complex (GPIIb-IIIa)] inhibits activation and degranulat ion of human platelets, and opposes the action of aurintricarboxylic acid ( ATA), the antagonist of von Willebrand factor, which augments platelet secr etion. The effects of both drugs on platelet function were monitored by usi ng various instrumental methods. Platelet-rich plasma and whole-blood aggre gation was measured by using ADP and collagen as agonists. Platelet degranu lation was assessed based on the expression of surface membrane activation markers: P-selectin, glycoprotein lb, and activated GPIIb-IIIa complex. Mea surements of closure time with platelet function analyzer PFA-100 (TM) enab led us to reason on primary hemostatic capacity and reflected both aggregab ility and adhesiveness. GR144053F markedly reduced primary hemostatic plate let response (IC50 = 114.0 +/- 9.6 nM) under conditions that closely mimick ed natural blood flow in circulation, and inhibited aggregation in platelet -rich plasma (IC50 = 17.7 +/- 7.0 nM). It was equally potent inhibitor of p latelet activation, degranulation, fibrinogen binding, platelet consumption , and aggregate formation. Also, ATA was efficient in inhibition of platele t aggregation and adhesion (by up to 50% at 100 muM), but the combined acti on of both drugs on primary haemostatic capacity was not additive. GR144053 F suppressed the activating effects of ATA on platelet degranulation and se cretion. Overall, our data indicate that GR144053F is not only the efficien t blocker of fibrinogen binding to GPIIb-IIIa, but also hampers platelet de granulation and may attenuate the activating effects of ATA. (C) 2001 Elsev ier Science Inc. All rights reserved.