Relationship between endothelin and the pathophysiology of tissue factor-induced and lipopolysaccharide-induced disseminated intravascular coagulation in rats: a study examining the effect of an endothelin receptor antagonist.
We investigated the relationship between endothelin, a potent vasoconstrictor peptide, and the pathophysiology of disseminated intravascular coagulation (DIC), using two models of DIC. Experimental DIC was induced by sustained infusion of 50 mg/kg lipopolysaccharide (LPS), or 3.75 U/kg thromboplastin, for 4 h via the rat tail vein. The effect of administration of a non-selective endothelin receptor antagonist (TAK-044) (2, 10, or 50 mg/kg, from -0.5 to 4 h) on thromboplastin-induced DIC was not significant. However, LPS-induced elevation of alanine aminotransferase, creatinine and glomerular fibrin deposition was significantly suppressed by co-administration of TAK-044 in a dose-dependent manner, although no effect of TAK-044 was observed on the platelet count, fibrinogen concentration or the level of thrombin-antithrombin complex. Moreover, plasma levels of D-dimer, which reflect the grade of fibrinolysis of cross-linked fibrin, were significantly increased by co-administration of each dose of TAK-044 in the LPS-induced DIC model in rats. Our results suggest that vasoconstriction, as well as depressed fibrinolysis, contribute to severe organ dysfunction in LPS-induced, but not thromboplastin-induced, DIC, and that endothelin plays a role in the development of organ injury in LPS-induced DIC in rats.
Suga
Yukio
Y
Department of Hospital Pharmacy, Kanazawa University School of Medicine, Japan.
Asakura
Hidesaku
H
Yoshida
Tomotaka
T
Omote
Mika
M
Ontachi
Yasuo
Y
Mizutani
Tomoe
T
Yamazaki
Masahide
M
Morishita
Eriko
E
Nakao
Shinji
S
Miyamoto
Ken-ichi
K
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D003404:Creatinine / Q000097:blood; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism*; D005337:Fibrin / Q000032:analysis; D006490:Hemostatics / Q000008:administration & dosage*; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008297:Male; D010456:Peptides, Cyclic / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D013925:Thromboplastin / Q000008:administration & dosage*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D006490:Hemostatics; D008070:Lipopolysaccharides; D010456:Peptides, Cyclic; C482199:lipopolysaccharide, E coli O55-B5; C088196:TAK 044; D005337:Fibrin; D013925:Thromboplastin; D003404:Creatinine; D000410:Alanine Transaminase