Beneficial effects of urokinase on lipopolysaccharide-induced disseminated intravascular coagulation in rats: focus on organ function and endothelin levels.
In a rat model of lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC), we used urokinase (UK) in an attempt to clarify the role of fibrinolysis and to investigate changes in plasma endothelin levels. Two kinds of experiment were performed. The first one: experimental DIC was induced by sustained infusion of 30 mg/kg LPS for 4 h via the tail vein, and two doses of UK (2.0 or 10.0 IU/g/4.5 h) were administered to rats 30 min before infusion of LPS, after which UK infusion was continued for a further 4 h. The second one: experimental DIC was induced by sustained infusion of 1 mg/kg/10 min LPS for 10 min, and two doses of UK (2.0 or 10.0 IU/g/4 h) were administered to rats at 30 min after LPS infusion. The parameters described below were determined at 4 h in the first experiment, at 4 h and 8 h in the second one. The similar results were observed in both kinds of experiment. There were no significant differences in plasma thrombin-antithrombin complex, fibrinogen or platelet number among the three DIC groups, in both kinds of experiment. Plasma levels of D-dimer were significantly increased in the LPS + higher dose of UK group when compared with the LPS group. The increased plasma plasminogen activator inhibitor (PAI) activity seen in the LPS group was significantly suppressed in the groups receiving UK (especially higher dose of UK). In addition, the increased plasma levels of creatinine and alanine aminotransferase seen in the LPS group were significantly suppressed in the groups receiving UK (especially higher dose of UK). Plasma levels of endothelin, known to be a potent vasoconstrictive agent, were markedly elevated by LPS infusion, and were significantly suppressed in the groups receiving UK of both kinds of experiment, in a dose-dependent fashion compared with LPS group. Glomerular fibrin deposition was significantly suppressed in the groups receiving UK when compared with the LPS group. No manifestations of bleeding were observed in any of the groups. Enhanced fibrinolysis and depressed endothelin induced by UK thus appear to play an important role in preventing the development of organ failure in the LPS-induced DIC model.
Asakura
Hidesaku
H
Department of Internal Medicine, Kanazawa, Ishikawa 920-8641, Japan. hasakura@med3.m.kanazawa-u.ac.jp
Asamura
Risa
R
Ontachi
Yasuo
Y
Hayashi
Tomoe
T
Omote
Mika
M
Arahata
Masahisa
M
Kadohira
Yasuko
Y
Maekawa
Mio
M
Yamazaki
Masahide
M
Morishita
Eriko
E
Yoshida
Tomotaka
T
Miyamoto
Ken-Ichi
K
Nakao
Shinji
S
D000818:Animals; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000097:blood; D005342:Fibrinolysis / Q000187:drug effects; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008297:Male; D009102:Multiple Organ Failure / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D015912:Thrombolytic Therapy / Q000379:methods; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*
D015415:Biomarkers; D016232:Endothelins; D008070:Lipopolysaccharides; D014568:Urokinase-Type Plasminogen Activator