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Hepatic morphological alterations, glycogen content and cytochrome P450 activities in rats treated chronically with Nω-nitro-L-arginine methyl ester (L-NAME)

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Abstract

Chronic treatment of rats with Nω-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension mediated partly by enhanced angiotensin-I-converting enzyme (ACE) activity. We examined the influence of L-NAME on rat liver morphology, on hepatic glycogen, cholesterol, and triglyceride content, and on the activities of the cytochrome P450 isoforms CYP1A1/2, CYP2B1/2, CYP2C11, and CYP2E1. Male Wistar rats were treated with L-NAME (20 mg/rat per day via drinking water) for 2, 4, and 8 weeks, and their livers were then removed for analysis. Enzymatic induction was produced by treating rats with phenobarbital (to induce CYP2B1/2), β-naphthoflavone (to induce CYP1A1/2), or pyrazole (to induce CYP2E1). L-NAME significantly elevated blood pressure; this was reversed by concomitant treatment with enalapril (ACE inhibitor) or losartan (angiotensin II AT1 receptor antagonist). L-NAME caused vascular hypertrophy in hepatic arteries, with perivascular and interstitial fibrosis involving collagen deposition. Hepatic glycogen content also significantly increased. L-NAME did not affect fasting glucose levels but significantly reduced insulin levels and increased the insulin sensitivity of rats, based on an intraperitoneal glucose tolerance test. Immunoblotting experiments indicated enhanced phosphorylation of protein kinase B and of glycogen synthase kinase 3. All these changes were reversed by concomitant treatment with enalapril or losartan. L-NAME had no effect on hepatic cholesterol or triglyceride content or on the basal or drug-induced activities and protein expression of the cytochrome P450 isoforms. Thus, the chronic inhibition of NO biosynthesis produced hepatic morphological alterations and changes in glycogen metabolism mediated by the renin-angiotensin system. The increase in hepatic glycogen content probably resulted from enhanced glycogen synthase activity following the inhibition of glycogen synthase kinase 3 by phosphorylation.

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Acknowledgments

The authors thank José Ilton dos Santos for technical assistance, Dr. Luzia Modolo (Department of Biochemistry, Institute of Biology, UNICAMP) for help with NOS activity assays, Dr. Patrick M. Dansete (Laboratoire de Chemie et de Biochime Pharmacologiques et Toxicologiques, Paris, France) for providing the tienilic acid, Dr. Aureo T. Yamada (Department of Histology and Embryology, Institute of Biology, UNICAMP) for use of the microscope and image analysis system, and Dr. José E. Belizário (Department of Pharmacology, Institute of Biochemical Sciences, University of São Paulo, São Paulo, Brazil) for use of the fluorometer.

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  1. Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), CP 6111, 13083-970, Campinas, SP, Brazil

    Christiane Aparecida Badin Tarsitano & Stephen Hyslop

  2. Departamento de Biologia Celular e Estrutural, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), CP 6109, 13083-970, Campinas, SP, Brazil

    Christiane Aparecida Badin Tarsitano

  3. Departamento de Histologia e Embriologia, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), CP 6109, 13083-970, Campinas, SP, Brazil

    Valdemar A. Paffaro Jr. & Maria Alice da Cruz-Höfling

  4. Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), CP 6111, 13083-970, Campinas, SP, Brazil

    José Rodrigo Pauli & Mario J. Saad

  5. Departamento de Anatomia Patológica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), CP 6111, 13083-970, Campinas, SP, Brazil

    Gustavo Henrique da Silva

  6. Departamento de Bioquímica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), CP 6109, 13083-970, Campinas, SP, Brazil

    Ione Salgado

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  1. Christiane Aparecida Badin Tarsitano
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  2. Valdemar A. Paffaro Jr.
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  3. José Rodrigo Pauli
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  7. Maria Alice da Cruz-Höfling
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  8. Stephen Hyslop
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Correspondence to Stephen Hyslop.

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C.A.B.T. was supported by a doctoral studentship from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grant no. 00/02083-0). I.S., M.A.C.H., M.J.A.S., and S.H. are supported by research fellowships from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

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Tarsitano, C.A.B., Paffaro, V.A., Pauli, J.R. et al. Hepatic morphological alterations, glycogen content and cytochrome P450 activities in rats treated chronically with Nω-nitro-L-arginine methyl ester (L-NAME). Cell Tissue Res 329, 45–58 (2007). https://doi.org/10.1007/s00441-007-0411-9

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