Tezosentan, an endothelin receptor antagonist, limits liver injury in endotoxin challenged cirrhotic rats.
OBJECTIVE
Lipopolysaccharide (LPS) induces liver injury which is associated with upregulated endothelin (ET)-1 production. The aim of this study was to investigate the effects of tezosentan, a non-selective ETA and ETB receptor antagonist, in LPS challenged rats with cirrhosis.


METHODS
Rats with cirrhosis received LPS and then tezosentan or placebo one hour later. Four hours after LPS administration, rats were killed to measure serum transaminase activity and plasma tumour necrosis factor alpha (TNF-alpha) levels. Hepatic inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), a marker of neutrophil infiltration, and cyclooxygenase (COX)-2 expression were also measured.


RESULTS
LPS administration significantly decreased arterial pressure and significantly increased plasma endothelin levels. Following LPS and tezosentan administration, serum aspartate aminotransferase and alanine aminotransferase activities were similar to those in the control group while they were increased by more than 700% with LPS alone. Plasma TNF-alpha levels were significantly lower in rats receiving LPS and tezosentan (182 (38) pg/ml) compared with those receiving LPS alone (821 (212) pg/ml). Tezosentan significantly decreased hepatic MPO activity and hepatic neutrophils but had no effect on LPS induced iNOS or COX-2. Survival rate was significantly higher in rats receiving LPS plus tezosentan (80%) than in rats receiving LPS alone (50%).


CONCLUSIONS
In LPS challenged cirrhotic rats, tezosentan administration prevents LPS induced liver injury by decreasing intrahepatic neutrophil infiltration. In addition, tezosentan increases survival in these rats.
Urbanowicz
W
W
INSERM U-481, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92118 Clichy, France.
Sogni
P
P
Moreau
R
R
Tazi
K A
KA
Barriere
E
E
Poirel
O
O
Martin
A
A
Guimont
M C
MC
Cazals-Hatem
D
D
Lebrec
D
D
D000818:Animals; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood; D019446:Endotoxemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000201:enzymology; D008103:Liver Cirrhosis / Q000150:complications* / Q000378:metabolism; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009195:Peroxidase / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000627:therapeutic use*; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014665:Vasodilator Agents / Q000627:therapeutic use*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D008070:Lipopolysaccharides; D011725:Pyridines; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C120582:tezosentan; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000637:Transaminases