Endotoxin treatment causes an upregulation of the endothelin system in the liver: amelioration of increased portal resistance by endothelin receptor antagonism.
BACKGROUND
Mechanisms underlying hepatic microcirculatory failure during endotoxemia are incompletely understood. Because endothelin-1 (ET-1) has been 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 lipopolysaccharide; 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 increase in portal pressure (11.6 +/- 1.3 mmHg vs 7.4 +/- 1 mmHg; P < 0.02). No significant changes in the serum levels of liver enzymes or hepatocellular necrosis 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 ET(A) and ET(B) receptors. While the serum nitric oxide (nitrite +/- nitrate) concentration was increased in endotoxin-treated rats, that of ET-1 remained unchanged. A mixed ET(A)/ET(B) 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 pressure from 11.6 +/- 1.3 mmHg to 8.6 +/- 0.7 mmHg (P < 0.05) in endotoxin-treated rats. The mixed ET(A)/ET(B) receptor antagonist also caused an increase in serum ET-1 concentration, but did not affect serum nitric oxide and MAP in endotoxin-treated rats.


CONCLUSIONS
These results suggest that the upregulated hepatic ET-1 system is an important mechanism of increased portal resistance and related complications of endotoxemia.
Gandhi
C R
CR
Thomas E Starzl Transplantation Institute University of Pittsburgh and Veterans Administration Medical Center Pittsburgh, Pennsylvania 15213, USA. Gandhics@msx.upmc.edu
Kuddus
R H
RH
Nemoto
E M
EM
Murase
N
N
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism; D019446:Endotoxemia / Q000503:physiopathology*; D004731:Endotoxins / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D010456:Peptides, Cyclic / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D019332:Endothelin-1; D004731:Endotoxins; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D017466:Receptors, Endothelin; C088196:TAK 044; D009569:Nitric Oxide