Endotoxin treatment causes all upregulation of the endothelin system in the liver: Amelioration of increased portal resistance by endothelin receptorantagonism

Background: Mechanisms underlying hepatic microcirculatory failure during e ndotoxemia are incompletely understood. Because endothelin-1 (ET-1) has bee n implicated in endotoxin-induced liver injury, we investigated the hepatic ET-1 system in endotoxin-treated rats. Methods: Rats were treated with endotoxin (Escherichia coli lipopolysacchar ide; 3 mg/kg, i.p.), and various determinations were made 24 h later. Results: Endotoxin treatment caused 11.2+/-1.6% weight loss, a decrease in mean arterial pressure (MAP; 96+/-5 mmHg vs 108+/-3 mmHg; P<0.05) and an in crease in portal pressure (11.6+/-1.3 mmHg vs 7.4+/-1 mmHg; P<0.02). No sig nificant changes in the serum levels of liver enzymes or hepatocellular nec rosis were observed. Endotoxin caused increases in hepatic ET-1 (from 345+/ -31 to 565+/-38 pg/g; P<0.01), ET-1 receptor density (from 179+/-16 to 340/-26 fmol/mg; P<0.02), and mRNA expression of preproendothelin-1, and ETA a nd ETB receptors. While the serum nitric oxide (nitrite + nitrate) concentr ation was increased in endotoxin-treated rats, that of ET-1 remained unchan ged. A mixed ETA/ETB receptor antagonist, TAK-044 (10 mg/kg, i.v.), reduced the weight loss from 11.2+/-1.6% to 5.9+/-2.9% (P<0.05) and the portal pre ssure from 11.6+/-1.3 mmHg to 8.6+/-0.7 mmHg (P<0.05) in endotoxin-treated rats. The mixed ETA/ETB receptor antagonist also caused an increase in seru m ET-1 concentration, but did not affect serum nitric oxide and MAP in endo toxin-treated rats. Conclusions: These results suggest that the upregulated hepatic ET-1 system is an important mechanism of increased portal resistance and related compl ications of endotoxemia. (C) 2001 Blackwell Science Asia Pty Ltd.