Effect of GR144053, a fibrinogen-receptor antagonist, on thrombus formation and vascular patency after thrombolysis by tPA in the injured carotid artery of the hamster.
The antithrombotic effect of GR144053, which inhibits platelet aggregation by binding to the fibrinogen receptor (glycoprotein IIb/IIIa), was investigated in vitro and in vivo by using hamsters. This compound inhibited the platelet aggregation induced by adenosine diphosphate (ADP; 2.5 microM) with a mean inhibitory concentration (IC50) value of 2.2 +/- 0.4 x 10(-5) M. Vascular injury was inflicted in one carotid artery by using a modified catheter to produce endothelial denudation. In the control group, arterial blood flow was interrupted 4.4 +/- 2.3 min (n = 12) after the injury. When GR144053 continuously infused intravenously at doses of 0 (saline) 0.1, 0.3, and 1.0 mg/kg/h (n = 8, each), the time that elapsed before the vessel became completely obstructed was prolonged in a dose-dependent manner. In separate experiments, reperfusion could be obtained by continuous infusion of tissue-type plasminogen activator (tPA; 0.52 mg/kg) starting 30 min after the initiation of thrombus formation. When GR144053 (0.3 and 1.0 mg/kg/h) was infused in addition to tPA, the incidence of reperfusion and the later patency of the reperfused artery were much improved as compared with tPA alone. The bleeding time at the end of tPA infusion was significantly prolonged in the presence of the highest dose of GR144053. Next, neointima formation was evaluated 2 weeks after the vascular injury. When GR144053 (0.3 mg/kg/h) was continuously infused i.v. by an implanted osmotic pump for 14 days, the neointimal area was significantly reduced. In separate hamsters, the proliferating index of smooth muscle cells (SMCs) by using bromodeoxyuridine (BrdU) was investigated, and treatment with both tPA and GR144053 significantly decreased the SMC proliferation index in vivo. However, in the in vitro experiments using a hamster SMC line, GR144053 did not have an inhibitory effect on SMC proliferation. These findings suggest that GR144053 inhibits platelet activation on the injured artery and improves vascular patency after thrombolysis with tPA, which furthermore results in suppression of neointima formation.
Department of Pharmacology, Gifu University School of Medicine, Japan.
H
H
Matsuno
O
O
Kozawa
M
M
Niwa
T
T
Ito
K
K
Tanabe
M
M
Nishida
H
H
Hayashi
T
T
Uematsu
D000818:Animals; D001760:Bleeding Time; D002341:Carotid Artery Thrombosis / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004195:Disease Models, Animal; D004347:Drug Interactions; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D014654:Vascular Patency / Q000187:drug effects*
D005343:Fibrinolytic Agents; C090662:GR 144053; D010455:Peptides; D010879:Piperazines; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen; D010959:Tissue Plasminogen Activator