Platelet GPIIb/IIIa receptor inhibition by SC-49992 prevents thrombosis and rethrombosis in the canine carotid artery.

Abstract

OBJECTIVE:

Platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptors represent the final common pathway for aggregation. GPIIb/IIIa inhibition with antibodies or RGD peptides prevents arterial thrombosis. The present study examined the ability of SC-49992 (SC), a GPIIb/IIIa receptor antagonist, to prevent thrombosis in a canine model of carotid artery thrombosis.

METHODS:

Both carotid arteries of anaesthetised dogs were instrumented with Doppler probes. A 300 microA current was applied to the intimal surface of the right carotid artery via an intraluminal electrode; time to occlusive thrombus formation was noted. SC (30 and 60 micrograms/.kg-1 x min-1, intravenously) or saline was infused for 240 min. The procedure for thrombus formation was repeated after 60 min of drug infusion for the left carotid artery.

RESULTS:

SC did not alter heart rate or blood pressure. Frequency of occlusive thrombus formation was reduced or prevented in a dose dependent manner (control = 100%, n = 12; SC 30 micrograms = 50%, n = 6; SC 60 micrograms = 0%, n = 6; p < 0.05). SC resulted in a reduction in thrombus weight (p < 0.05) v control. Ex vivo platelet aggregation to ADP and arachidonic acid was inhibited. Platelet reactivity remained inhibited 60 min after cessation of SC infusion. In a second group of animals, a carotid artery thrombus was formed and lysed with administration of anisoylated plasminogen streptokinase activator complex (0.05 U.kg-1). SC (60 micrograms.kg-1 x min-1, intravenously, n = 6) or saline (n = 6) was infused for 240 min. In dogs receiving saline there was an 83% rate of rethrombosis; none of the SC treated animals had reocclusion after recanalisation (p < 0.05).

CONCLUSIONS:

SC-49992 inhibits ex vivo platelet aggregation, prevents occlusive thrombus formation in a canine model of arterial thrombosis, and prevents rethrombosis after thrombolysis. The data are consistent with results obtained with murine monoclonal antibodies directed against the platelet GPIIb/IIIa receptor.

• Authors: W E Rote, S W Werns, J H Davis, L P Feigen, K S Kilgore, B R Lucchesi
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 27 Issue 3 Pg. 500-7 (Mar 1993) ISSN: 0008-6363 [Print] England
• PMID: 8490951 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 8-guanidino-octanoyl-Asp-Phe
• Dipeptides
• Platelet Aggregation Inhibitors
• Platelet Glycoprotein GPIb-IX Complex
• Platelet Membrane Glycoproteins
• Receptors, Immunologic
• glycoprotein receptor GPIb-IX

Topics

• Animals
• Blood Pressure (drug effects)
• Carotid Artery Thrombosis (prevention & control)
• Dipeptides (therapeutic use)
• Dogs
• Dose-Response Relationship, Drug
• Heart Rate (drug effects)
• Male
• Platelet Aggregation Inhibitors (therapeutic use)
• Platelet Glycoprotein GPIb-IX Complex
• Platelet Membrane Glycoproteins
• Receptors, Immunologic (drug effects)
• Recurrence