Hepatic sinusoidal fibrosis induced by cholesterol and stilbestrol in the rabbit: 2. Hemodynamic and drug disposition studies

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Abstract

We assessed hepatic functions and systemic and splanchnic hemodynamics in a new model of hepatic sinusoidal fibrosis. Fibrosis was induced by the simultaneous administration for 8 weeks of diethyl-stilbestrol (DES) (10 mg twice weekly, subcutaneously) and cholesterol-supplemented diet (1%) in rabbits. A marked and progressive impairment of hepatic function was observed during the 8 weeks of treatment with a significant decrease in indocyanine green (ICG) systemic clearance (- 89%; P < .001) and aminopyrine elimination (-69%; P < .001). In fibrotic animals, hyperdynamic circulation was found with an increased cardiac output (+73%, P < 0.01) and a decreased peripheral vascular resistance (-50%; P < .005), as evaluated by the microsphere technique in animals that were awake. The total portal venous inflow was not significantly modified in fibrotic rabbits. However, since there was a marked increase in the liver weight, the portal venous inflow was significantly decreased when expressed per gram of liver weight (-30%; P < .05). In contrast, the hepatic artery blood flow was markedly increased, even when expressed per gram of liver weight (+95%; P < .01). Portal pressure was significantly increased in treated rabbits (from 7.4 ± .4 to 14.4 ± .6 mm Hg, P < .01). This new experimental model could prove useful to evaluate the influence of extensive perisinusoidal fibrosis on exchanges between plasma and hepatocytes, particularly of protein-bound substances.

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