title: Inhibitors of fibrinolytic components play different roles in the formation and removal of arterial thrombus in mice.
abstract: Plasminogen activator inhibitor-1 (PAI-1) and alpha2-anti-plasmin (alpha2-AP) may contribute to arterial thrombolysis resistance. The role of these components on thrombus evolution in vivo was investigated in mice deficient for PAI-1 (PAI-1(-/-)) or alpha2-AP (alpha2-AP(-/-)) or their wild-type counterparts (PAI-1(+/+), alpha2-AP(+/+)). Moreover, the influence of either PAI-1 or alpha2-AP deficiency on the results of pharmacologic inhibition of glycoprotein IIb/IIIa of platelets or thrombin was also investigated. A thrombus was induced in the murine carotid artery by endothelial injury. The alpha2-AP(-/-) mice were indistinguishable from wild-type, whereas the time to occlusion in PAI-1(-/-) was significantly prolonged to 24.9 +/- 3.7 min. Vascular patency was markedly increased in both PAI-1- and alpha2-AP-deficient mice. In separate animals, either a glycoprotein IIb/IIIa antagonist or a thrombin inhibitor was applied. The time required to occlusion was prolonged in a dose-dependent manner in all types of mice. When each compound was administered to PAI-1(-/-) mice, significant changes were observed. In conclusion, lack of PAI-1 prolongs the time to occlusion and accelerates clot lysis, whereas alpha2-AP only has an effect on spontaneous reperfusion. Consequently, the inhibition of PAI-1, but not of alpha2-AP, could enhance the effects of anti-thrombotic therapy.
authors.affiliation: Department of Pharmacology, Gifu University School of Medicine, Gifu, Japan. leuven@cc.gifu-u.ac.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsuno
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Okada
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ueshima
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsuo
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Uematsu
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D020212:Carotid Artery Injuries / Q000150:complications; D004730:Endothelium, Vascular / Q000293:injuries; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010875:Pipecolic Acids / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D015842:Serine Proteinase Inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors; D013918:Thrombin Time; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D014654:Vascular Patency / Q000187:drug effects; D000979:alpha-2-Antiplasmin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C090662:GR 144053; D010875:Pipecolic Acids; D010879:Piperazines; D010880:Piperidines; D017395:Plasminogen Activator Inhibitor 1; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D000979:alpha-2-Antiplasmin; D001120:Arginine; D013917:Thrombin; C031942:argatroban