Hepatic fibrosis or increased liver collagen contents drive functional abnormalities that, when extensive, may be life threatening. The purpose of this study was to assess the effects of the chronic stimulation or inhibition of nitric oxide synthesis in rats with hepatic fibrosis induced by permanent common bile duct ligation (3 weeks) and the role of expression of the different nitric oxide synthase isoforms. Bile duct ligation led to an important accumulation of collagen in the hepatic parenchyma, as shown both histologically and by the hydroxyproline contents of livers. Bilirubin and serum enzyme activities (measured as markers of cholestasis) increased several-fold after bile duct ligation. The area of fibrotic tissue, liver hydroxyproline content and serum markers of cholestasis were clearly related in obstructed rats. The absence of modifications in haemodynamic parameters excludes circulatory changes from being responsible for the development of liver alterations. In animals treated with NG-nitro-L-arginine methyl ester (L-NAME) the area of fibrosis was similar to that of untreated animals, the signs of cholestasis and cellular injury being more evident. In rats treated with L-arginine the area of fibrosis was almost three times larger than that found in bile duct ligated rats and in L-NAME-treated bile duct ligated rats, although the observed biochemical changes were similar to those seen in rats treated with L-NAME. Our results with inducible nitric oxide synthase, obtained by Western blots and immunohistochemistry, indicate a greater expression of the inducible enzyme in bile duct ligated and L-arginine-treated animals and a lower expression in the L-NAME and control groups. Constitutive nitric oxide synthase expression, obtained by Western blots, was very similar in all groups, except for the L-arginine-treated rats in which it was lower. These results suggest that nitric oxide production may be a key factor in the development of fibrosis in bile duct ligated rats. They also support the hypothesis of a dual role for nitric oxide; one beneficial, mediated by its circulatory effects, and the second negative, through its local toxic effects.
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March 01 1999
Effects of chronic nitric oxide activation or inhibition on early hepatic fibrosis in rats with bile duct ligation
Paula MAYORAL;
Paula MAYORAL
1Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain
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Manuela CRIADO;
Manuela CRIADO
1Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain
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Froilan HIDALGO;
Froilan HIDALGO
1Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain
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Olga FLORES;
Olga FLORES
*Departamento de Anatomía e Histología Humanas, Universidad de Salamanca, 37007 Salamanca, Spain, and
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Miguel A. ARÉVALO;
Miguel A. ARÉVALO
*Departamento de Anatomía e Histología Humanas, Universidad de Salamanca, 37007 Salamanca, Spain, and
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Nélida ELENO;
Nélida ELENO
1Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain
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Angel SÁNCHEZ-RODRÍGUEZ;
Angel SÁNCHEZ-RODRÍGUEZ
†Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
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Jose M. LÓPEZ-NOVOA;
Jose M. LÓPEZ-NOVOA
1Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain
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Alejandro ESTELLER
1Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain
Correspondence: Professor A. Esteller.
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Publisher: Portland Press Ltd
Received:
July 09 1998
Revision Received:
October 01 1998
Accepted:
November 05 1998
Online ISSN: 1470-8736
Print ISSN: 0143-5221
The Biochemical Society and the Medical Research Society © 1999
1999
Clin Sci (Lond) (1999) 96 (3): 297–305.
Article history
Received:
July 09 1998
Revision Received:
October 01 1998
Accepted:
November 05 1998
Citation
Paula MAYORAL, Manuela CRIADO, Froilan HIDALGO, Olga FLORES, Miguel A. ARÉVALO, Nélida ELENO, Angel SÁNCHEZ-RODRÍGUEZ, Jose M. LÓPEZ-NOVOA, Alejandro ESTELLER; Effects of chronic nitric oxide activation or inhibition on early hepatic fibrosis in rats with bile duct ligation. Clin Sci (Lond) 1 March 1999; 96 (3): 297–305. doi: https://doi.org/10.1042/cs0960297
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