TY - JOUR T1 - Functional Relevance of the Expression of Ligand-Induced Binding Sites in the Response to Platelet GP IIb/IIIa Antagonists <em>In Vivo</em>. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 945 LP - 951 VL - 286 IS - 2 AU - Natalie P. Murphy AU - Domenico Pratico AU - Desmond J. Fitzgerald Y1 - 1998/08/01 UR - http://jpet.aspetjournals.org/content/286/2/945.abstract N2 - RGD-containing peptides and other antagonists of the platelet glycoprotein (GP) IIb/IIIa may induce a high-affinity binding site for fibrinogen and the expression of novel epitopes, called ligand-induced binding sites (LIBS). The functional relevance of LIBS expression in a canine model of coronary thrombolysis induced by tissue-type plasminogen activator (t-PA) was examined. Ro43–5054 (N-[N-[N-(p-amidinobenzoyl)-b-alanyl]-l-a-aspartyl]-3-phenyl-l-alanine) and Ro44–9883 ([1-(N-(p-amidinobenzoyl)-l-tyrosyl)-4-piperidinyl)oxy]acetic acid), antagonists of the GP IIb/IIIa receptor, were administered in increasing doses of 2 to 10 μg/kg/min, beginning 30 min before the infusion of t-PA. LIBS expression was determined by the binding of the monoclonal antibody, D3GP3, to platelets on exposure to Ro43–5054, Ro44–9883 and t-PA. Ro43–5054 was shown to induce LIBS, whereas Ro44–9883 and t-PA did not. Both drugs abolished platelet aggregation in response to U46619 and ADP ex vivo. Reocclusion was prevented with both Ro43–5054 and Ro44–9883, but neither drug altered reperfusion times (49 ± 8 and 55 ± 39 min). Both drugs increased the rate of bleeding compared with t-PA alone, but there was no difference in hemostasis between the two drugs. To determine whether the drugs differed in their effect on platelet activation in vivo, urinary 2,3-dinor-thromboxane (TX) B2, a major metabolite of TXB2, was determined by gas chromatography-mass spectrometry. After reperfusion, the urinary 2,3-dinor-TXB2 increased in the Ro43–5054-treated group, similar to control groups (32 ± 8 and 37 ± 9 ng/mg creatinine). This increase was blunted in the Ro44–9883-treated group (9 ± 3 ng/mg creatinine). GP IIb/IIIa antagonists that do not induce LIBS result in a greater suppression of platelet activity but not in any discernible functional benefit in vivo. The American Society for Pharmacology and Experimental Therapeutics ER -