Identification of the thromboxane A2 receptor in hepatic sinusoidal endothelial cells and its role in endotoxin-induced liver injury in rats.
The presence of the thromboxane A2 receptor in sinusoidal endothelial cells was investigated and its pathogenic role in endotoxin-induced liver injury examined. The receptor was measured with a binding assay using a specific thromboxane A2 receptor antagonist, [3H]S-145. Scatchard analysis of the binding indicated the presence of a single class of high-affinity binding sites with a dissociation constant of 5.00 +/- 0.96 nmol/L, a maximal binding of 22.85 +/- 2.71 fmol/10(6) cells and 13.80 +/- 1.60 x 10(3) binding sites per cell. The addition of a cyclooxygenase inhibitor, indomethacin, during the cell preparation increased the maximal binding value and the number of binding sites of 37.34 +/- 3.01 and 22.50 +/- 1.80 x 10(3) sites/cell, respectively. The binding was displaced by various thromboxane A2 analogs such as ONO-3708 and STA2 but was not effectively competed for by other prostaglandins. Endotoxin injection reduced dissociation constant, maximal binding and the number of binding sites in sinusoidal endothelial cells to 3.49 +/- 0.87 nmol/L, 6.03 +/- 0.64 fmol/10(6) cells and 3.65 +/- 0.39 x 10(3) sites/cell, respectively. A cyclooxygenase inhibitor and a Kupffer cell inhibitor added before endotoxin treatment significantly prevented the reduction in the number of thromboxane A2 receptors. It is possible that these effects were due to a reduction in the agonist-induced internalization of the thromboxane A2 receptor brought about by the prevention of thromboxane A2 production. Preadministration of both a cyclooxygenase inhibitor and a thromboxane A2 receptor antagonist attenuated the degree of endotoxin-induced liver injury.(ABSTRACT TRUNCATED AT 250 WORDS)
Ishiguro
S
S
First Department of Surgery, Faculty of Medicine, Kyoto University, Japan.
Arii
S
S
Monden
K
K
Adachi
Y
Y
Funaki
N
N
Higashitsuji
H
H
Fujita
S
S
Furutani
M
M
Mise
M
M
Kitao
T
T
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004731:Endotoxins; D005682:Gadolinium / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects; D008070:Lipopolysaccharides; D008102:Liver Circulation; D008107:Liver Diseases / Q000517:prevention & control; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins; D008070:Lipopolysaccharides; D017482:Receptors, Thromboxane; D005682:Gadolinium