Hepatic and mesenteric nitric oxide synthase expression in a rat model of CCl(4)-induced cirrhosis.
BACKGROUND
Cirrhosis and portal hypertension are frequently linked with changes in expression of nitric oxide synthase (NOS) and/or endotoxaemia.


OBJECTIVE
This study tested the following hypothesis: that inducible (i)NOS activity is increased within the visceral circulation concurrently with decreased constitutive (c)NOS activity in the hepatic sinusoids and that the concentration of NO metabolites in portal blood is consequent on endotoxin concentration.


METHODS
Plasma concentrations of (nitrite + nitrate) and endotoxin, together with hepatic and mesenteric NOS activity (arginine/citrulline method) and protein expression (histochemistry) plus portal and arterial blood pressure, were determined in rats made severely cirrhotic by intragastric CCl(4) over 14 weeks (n = 6) compared with age-matched controls (n = 5). The concentrations of [nitrite + nitrate] and endotoxin in portal plasma were also directly compared in rats made cirrhotic for a period of 8-14 weeks (n = 10).


RESULTS
In rats with advanced cirrhosis, arterial [nitrite + nitrate] was 93.1 (22.4) micromol/L (mean, SEM) compared with 29.1 (6.1) micromol/L in controls (P < 0.05); portal plasma [NO(2)(-) + NO3(-)] was 127.1 (27.2) compared with 24.7 (4.7) micromol/L in controls (P < 0.05). Cirrhotic rats had higher endotoxin concentration in plasma compared with controls (systemic: 85.0 (24.5) versus 1.7 (0.2) EU/ml, P < 0.05; portal: 180.3 (47.9) versus 1.7 (0.2) EU/ml, P < 0.05). The same severely cirrhotic rats possessed decreased cNOS activity in liver (2.95 [0.40] versus 5.29 [0.85] pmol/min/g; P < 0.05) and increased iNOS activity in mesentery (4.83 [1.23] versus 1.47 [0.15] pmol/min/g; P < 0.05) compared with controls. Histochemical observations confirmed these findings. Rats given CCl(4) for a period of 8-14 weeks possessed high endotoxin concentration in portal plasma, with correspondingly high [nitrite + nitrate] (r(2) = 0.954; P < 0.001).


CONCLUSIONS
An endotoxin-induced increase in mesenteric iNOS activity and a decrease in hepatic cNOS activity may account for, respectively, the hyperdynamic visceral circulation and the increased intrahepatic resistance of cirrhosis.
Bhimani
E K
EK
Department of Gastrointestinal Surgery, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, UK.
Serracino-Inglott
F
F
Sarela
A I
AI
Batten
J J
JJ
Mathie
R T
RT
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D004731:Endotoxins / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008102:Liver Circulation / Q000502:physiology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008643:Mesentery / Q000098:blood supply / Q000378:metabolism*; D023421:Models, Animal; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D013152:Splanchnic Circulation / Q000502:physiology
D004731:Endotoxins; D009569:Nitric Oxide; D002251:Carbon Tetrachloride; D019001:Nitric Oxide Synthase