The effect of thrombin inhibition in a rat arterial thrombosis model.
The effect of heparin and the synthetic irreversible antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone (FPRCH2Cl) was studied on FeCl3-induced thrombotic occlusion of rat carotid arteries. Thrombocytopenia prevented occlusion in five of 7 rats for the 60 min observation period after FeCl3 injury demonstrating platelet dependence in this model of thrombosis. Intravenous injection of heparin (250 units/kg) followed by continuous infusion (250 units/kg/hr) failed to prevent occlusion in four of 6 rats whereas intravenous FPRCH2Cl infusion prevented occlusion at a dose of 200 nmol/kg/min during infusion in 6/6 rats. These findings indicate that thrombin plays a principle role in the platelet-dependent process of arterial thrombosis in FeCl3-damaged rat carotid arteries. Neutralization of the thrombogenic stimulus in this model by the thrombin inhibitor FPRCH2Cl suggests selective thrombin inhibition may be useful in the treatment of arterial thrombosis.
Broersma
R J
RJ
Marion Merrell Dow Research Institute, Indianapolis, IN 46268.
Kutcher
L W
LW
Heminger
E F
EF
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000517:prevention & control*; D004195:Disease Models, Animal; D005296:Ferrous Compounds / Q000633:toxicity; D005337:Fibrin / Q000502:physiology; D006493:Heparin / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013921:Thrombocytopenia / Q000097:blood
D000590:Amino Acid Chloromethyl Ketones; D005296:Ferrous Compounds; D005337:Fibrin; D006493:Heparin; D013917:Thrombin; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone; C029451:ferrous chloride