A stable model of cirrhotic portal hypertension in the rat: thioacetamide revisited.
BACKGROUND
Cirrhotic animal models are vital to investigate complications of chronic liver disease. We chronologically characterized the effect of thioacetamide, administrated orally and adapted weekly to weight changes, focusing on the optimal moment to obtain all typical features of portal hypertension and cirrhosis.


METHODS
Male Wistar rats, 200-250 g, were intoxicated for 6, 12 or 18 weeks (n = 8 per group), respectively, and compared with age-matched controls (n = 4 per group). An in-situ perfusion model was used to evaluate intrahepatic resistance and endothelial function. Splanchnic blood flow and portosystemic shunting were assessed by a perivascular flow probe.


RESULTS
Rats intoxicated for 6 or 12 weeks had no mortality and histologically showed hepatitis and advanced fibrosis, respectively. At 18 weeks, mortality was 16% (on a total of 56 animals) and only at that moment all animals showed homogenous macronodular cirrhosis with signs of high-grade hepatocellular dysplasia. Portal hypertension was present at 12 weeks (11 +/- 0.4 vs. 5.9 +/- 0.4 mmHg, P < 0.001), but was not associated with the hyperdynamic state until 18 weeks (12.1 +/- 0.8 vs. 5.6 +/- 0.5 mmHg, P < 0.001). At this latter time-point, we also observed increased intrahepatic resistance associated with endothelial dysfunction, hyperresponsiveness to vasoconstrictors, splanchnic hyperaemia and portosystemic shunting. These alterations were associated with increased systemic levels of nitrate/nitrite and thromboxane A(2).


CONCLUSIONS
Thioacetamide, adapted to weekly weight changes, leads to a homogenous, reproducible model of cirrhosis in the rat in 18 weeks, which is associated with all the typical characteristics of portal hypertension, including endothelial dysfunction.
Laleman
W
W
Department pf Hepatology, University Hospital Gasthuisberg, Leuven, Belgium.
Vander Elst
I
I
Zeegers
M
M
Servaes
R
R
Libbrecht
L
L
Roskams
T
T
Fevery
J
J
Nevens
F
F
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage*; D006439:Hemodynamics / Q000187:drug effects; D006975:Hypertension, Portal / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D023421:Models, Animal; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide / Q000008:administration & dosage*; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000097:blood
D002273:Carcinogens; D009566:Nitrates; D013853:Thioacetamide; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; D019001:Nitric Oxide Synthase