Functional relevance of the expression of ligand-induced binding sites in the response to platelet GP IIb/IIIa antagonists in vivo.
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 microg/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.
Murphy
N P
NP
Centre for Cardiovascular Science, Department of Clinical Pharmacology Royal College of Surgeons in Ireland, St. Stephens Green, Dublin, Ireland.
Pratico
D
D
Fitzgerald
D J
DJ
D000085:Acetates / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D003328:Coronary Thrombosis / Q000503:physiopathology; D004285:Dogs; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006470:Hemorrhage / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D000085:Acetates; D005343:Fibrinolytic Agents; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C078174:Ro 43-5054; D014443:Tyrosine; D013929:Thromboxane B2; C028965:2,3-dinor-thromboxane B2; C084062:lamifiban; D010959:Tissue Plasminogen Activator