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A stable model of cirrhotic portal hypertension in the rat: thioacetamide revisited

Authors


  • Financial support: This study was supported by a grant from FWO Vlaanderen G.0111·98 (F. Nevens). W. Laleman was supported by a grant from the Fund for Scientific Research (Aspirant Mandaat – FWO Vlaanderen).

  • Department of Hepatology (W. Laleman, I. Vander Elst, M. Zeegers, R. Servaes, J. Fevery, F. Nevens) and Pathology (L. Libbrecht, T. Roskams), University Hospital Gasthuisberg, Leuven, Belgium.

Frederik Nevens, MD, PhD, Hepatology, University Hospital Gasthuisberg, K.U. Leuven, B-3000 Leuven, Belgium. Tel.: +32 16 344299; fax: +32 16 344387; e-mail: frederik.nevens@uz.kuleuven.ac.be

Abstract

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.

Materials and 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 A2.

Conclusion  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.

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