Structure-function relationship in secondary biliary cirrhosis in the rat. Stereologic and hemodynamic characterization of a model.
Secondary biliary cirrhosis in the rat is an attractive model since unlike other models it does not rely on exogenous toxic compounds to induce cirrhosis. However, because little is known about the microcirculatory abnormalities of this model, this study investigated hemodynamics in rats with predefined functional impairment and related them to different aspects of stereologically quantified structure. All animals with at least 50% reduction in microsomal function, assessed by the aminopyrine breath test, had portal hypertension. The sinusoidal space, as assessed by multiple indicator dilution in the perfused liver, was reduced whereas large vessel space was increased. This reduction in sinusoidal space could contribute to increased portal resistance. The degree of intrahepatic shunting varied as assessed by a microsphere technique (13.9 vs. 0.5% in controls). These alterations were confirmed by stereological analysis. Numerically, there was excellent agreement between functional indicator dilution data and anatomic quantitation. Microvascular exchange was impaired as in other models of cirrhosis as shown by a reduced extravascular albumin space (4.5 vs. 2.2%, p < 0.01). In contrast to alterations in vascular space, this functional impairment was not reflected in the stereologically assessed space of Disse which averaged 5% of liver volume in both groups. Finally, in spite of reduced microsomal function in vivo (aminopyrine breath test) and in vitro (aminopyrine N-demethylase activity), the smooth endoplasmic reticulum was maintained (4.3 vs. 3.5 m2/ml cytosol, n.s.), which demonstrates that microsomal function in this model is reduced per unit hepatocyte. This suggests that the sick-cell hypothesis applies to secondary biliary cirrhosis in the rat.
Ohara
N
N
Department of Clinical Pharmacology, University of Berne, Switzerland.
Schaffner
T
T
Reichen
J
J
D000632:Aminopyrine / Q000032:analysis; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D001944:Breath Tests; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000502:physiology*; D006975:Hypertension, Portal / Q000209:etiology; D008105:Liver Cirrhosis, Biliary / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000632:Aminopyrine; D000633:Aminopyrine N-Demethylase