Antithrombotic properties of L-cysteine, N-(mercaptoacetyl)-D-Tyr-Arg-
Gly-Asp-sulfoxide (G4120) in a hamster platelet-rich femoral vein
thrombosis model
Y Imura, JM Stassen, S Bunting, F Stockmans and D Collen
Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
Platelet aggregation plays an important role in the pathogenesis in
arterial thrombotic disorders. The binding of fibrinogen via the Arg-
Gly-Asp (RGD) recognition sequence to the platelet glycoprotein IIb/IIIa
(GPIIb/IIIa) receptor is an essential step of platelet aggregation induced
by various physiologic agonists, and RGD-containing peptides that bind to
the GPIIb/IIIa receptor inhibit thrombus formation in vivo. L-cysteine,
N-(mercaptoacetyl)D-tyrosyl-L- arginylglycyl-L alpha-aspartyl-cyclic
(1----5)-sulfide, 5-oxide (G4120), a cyclic RGD-containing synthetic
pentapeptide, inhibits adenosine diphosphate (ADP)-induced platelet
aggregation with 50% inhibition (IC50) at a concentration of 0.05
microgram/mL in human plasma, 0.12 microgram/mL in hamster plasma, and 11
micrograms/mL in rat plasma. Corresponding values for the linear
tetrapeptide Arg-Gly- Asp-Phe (RGDF) were 7 and 100 micrograms/mL in human
and hamster plasma. The antithrombotic effects of G4120 and RGDF were
evaluated in a hamster model consisting of a mural platelet-rich femoral
vein thrombus induced by standardized endothelial cell damage. Bolus
intravenous injection of G4120 was followed by a biphasic disappearance of
G4120 from plasma with t1/2 alpha of 3.7 minutes and t1/2 beta of 63
minutes, corresponding to a plasma clearance of 5.2 +/- 0.68 mL/min. Bolus
intravenous injection of G4120 inhibited ex vivo platelet aggregation with
0.5 mumol/L ADP and in vivo thrombus formation in a dose-dependent manner,
with ID50 of 11 and 11 micrograms/kg, respectively. Bolus injection of RGDF
inhibited in vivo thrombus formation; 43% inhibition was obtained at a dose
of 30 mg/kg. Thus, this hamster platelet-rich femoral vein thrombosis model
may be useful for the investigation of the antithrombotic properties of
platelet GPIIb/IIIa antagonistic peptides. The cyclic synthetic peptide
G4120 appears to have a very potent antithrombotic activity in vivo.
Volume 80,
Issue 5,
pp. 1247-1253,
09/01/1992
Copyright © 1992 by The American Society of Hematology
