Demonstration of Ac-Arg-Gly-Asp-Ser-NH2 as an Antiaggregatory Agent in the Dog by Intracoronary Administration

Abstract

SummaryThis study compared the anti-platelet effect of Ac-RGDS-NH2 which is a peptide fragment from fibrinogen to Ac-RGES-NH2 in which the aspartic acid (D) of Ac-RGDS-NH2 has been replaced by glutamic acid (E). When Ac-RGDS-NH2 was infused intracoronary at concentrations of 100–400 mM, acute platelet dependent thrombus formation in the dog coronary artery was inhibited. However, infusion of Ac-RGES-NH2 intracoronary at similar concentrations to Ac-RGDS-NH2 failed to inhibit platelet dependent thrombus formation in the dog. Ac-RGDS-NH2 and Ac-RGES-NH2 were also tested for their ability to inhibit collagen-induced platelet aggregation in vitro. Ac-RGDS-NH2 elicited concentration-dependent inhibition of collagen-induced aggregation with no effect of Ac-RGES-NHz otr collagen-induced platelet aggregation. Thus, Ac-RGDS-NH2 is an effective antiplatelet agent after intracoronary administration in the dog and also inhibits collagen-induced platelet aggregation in vitro. Ac-RGDS-NH2 is a specific inhibitor of platelet aggregation as replacement of the aspartic acid in Ac-RGDS-NH2 with glutamic acid results in complete loss of biological activity.

Aurintricarboxylic acid in a canine model of coronary artery thrombosis.

“…Conditioned dogs of both sexes weighing [20][21][22][23][24][25] kg were used in this study. The trisodium salt of aurintricarboxylic acid ( Figure 1) …”

Acceleration of recombinant tissue-type plasminogen activator-induced thrombolysis and prevention of reocclusion by the combination of heparin and the Arg-Gly-Asp-containing peptide bitistatin in a canine model of coronary thrombosis.

“…Bitistatin was derived from the venom of the viper Bitis arietans and purified to greater than 90% homogeneity. 25 The other 10% of the bitistatin preparation was N-2 bitistatin, representing an 81-amino acid species. Bitistatin was lyophilized and reconstituted daily in sterile saline at a concentration of 1 mg/ml.…”

Kistrin, a polypeptide platelet GPIIb/IIIa receptor antagonist, enhances and sustains coronary arterial thrombolysis with recombinant tissue-type plasminogen activator in a canine preparation.

“…The GPI1b/IIIa receptor may be inhibited by several compounds, including monoclonal antibodies28 that exhibit potent antithrombotic effects in vivo29-32 but also by peptides derived from the gamma chain of fibrinogen33 or Arg-Gly-Asp-containing (RGD) peptides34'35 that prevent thrombosis in vivo. [36][37][38][39][40] Kistrin is a polypeptide (Mr, 7,334) composed of 68 amino acids, isolated from the venom of the Malayan pit viper Agkistrodon rhodostoma, which contains the typical RGD recognition sequence.41 It belongs to a family of proteins from pit viper venoms that are specific human platelet GPIIb/IIIa receptor antagonists that inhibit platelet aggregation. [42][43][44][45] Kistrin is 100-1,000 times more potent than the pentapeptide GRGDS for the inhibition of fibrinogen binding to platelets and for platelet aggregation, and its binding to platelets is both rapid and fully reversible.…”