Artículos de revistas
Hepatic Morphological Alterations, Glycogen Content And Cytochrome P450 Activities In Rats Treated Chronically With Nω-nitro-l-arginine Methyl Ester (l-name)
Cell And Tissue Research. , v. 329, n. 1, p. 45 - 58, 2007.
Paffaro Jr. V.A.
Da Silva G.H.
Da Cruz-Hofling M.A.
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 AT 1 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. © 2007 Springer-Verlag.32914558Aitken, A.E., Richardson, T.A., Morgan, E.T., Regulation of drug metabolizing enzymes and transporters in inflammation (2005) Annu Rev Pharmacol Toxicol, 46, pp. 123-149Alexander, B., The role of nitric oxide in hepatic metabolism (1998) Nutrition, 14, pp. 376-390Bernhardt, R., Cytochrome P450: Structure, function, and generation of reactive oxygen species (1996) Rev Physiol Biochem Pharmacol, 127, pp. 137-221Borgs, M., Bollen, M., Keppens, S., Yap, S.H., Stalmans, W., Vanstapel, F., Modulation of basal hepatic glycogenolysis by nitric oxide (1996) Hepatology, 23, pp. 1564-1571Borzychowski, A.M., Chantakru, S., Minhas, K., Paffaro, V.A., Yamada, A.T., He, H., Korach, K.S., Croy, B.A., Functional analysis of murine uterine natural killer cells genetically devoid of oestrogen receptors (2003) Placenta, 24, pp. 403-411Brass, E.P., Vetter, W.H., Inhibition of glucagon-stimulated glycogenolysis by S-nitroso-N-acetylpenicillamine (1993) Pharmacol Toxicol, 72, pp. 369-372Burke, M.D., Mayer, R.T., Differential effects of phenobarbitone and 3-methylcholanthrene induction on the hepatic microsomal metabolism and cytochrome P540 binding of phenoxazone and a homologous series of its n-alkyl esters (alkoxyresorufins) (1983) Chem Biol Interact, 45, pp. 243-258Burke, M.D., Thompson, S., Elcombe, C.R., Halpert, J., Haaparanta, T., Mayer, R.T., Ethoxy-, pentoxy- and benzyloxyphenoxazones and homologues: A series of substrates to distinguish between different induced cytochromes P-450 (1985) Biochem Pharmacol, 34, pp. 3337-3345Carlson, T.J., Billings, R.E., Role of nitric oxide in the cytokine-mediated regulation of cytochrome P-450 (1996) Mol Pharmacol, 49, pp. 796-801Casada, M., Díaz-Guerra, M.J., Bosca, L., Martin-Sanz, P., Characterization of nitric oxide dependent changes in carbohydrate hepatic metabolism during septic shock (1996) Life Sci, 58, pp. 561-572Chrysselis, M.C., Rekka, E.A., Siskou, I.C., Kourounakis, P.N., Nitric oxide releasing morpholine derivatives as hypolipidemic and antioxidant agents (2002) J Med Chem, 45, pp. 5406-5409Clejan, L.A., Cederbaum, A.I., Role of cytochrome P450 in the oxidation of glycerol by reconstituted systems and microsomes (1992) FASEB J, 6, pp. 765-770Clemens, M.G., Nitric oxide in liver injury (1999) Hepatology, 30, pp. 1-5Donato, M.T., Guillén, M.I., Jover, R., Castel, J.V., Gómez- Lechón, M.J., Nitric oxide-mediated inhibition of cytochrome P450 by interferon-γ in human hepatocytes (1997) J Pharmacol Exp Ther, 281, pp. 484-490Donato, M.T., Ponsoda, X., O'Connor, E., Casteli, J.V., Gómez-Lechón, J., Role of endogenous nitric oxide in liver-specific functions and survival of cultured rat hepatocytes (2001) Xenobiotica, 31, pp. 249-264Dupuis, M., Soubrier, F., Brocheriou, I., Raoux, S., Haloui, M., Louedec, L., Michel, J.B., Nadaud, S., Profiling of aortic smooth muscle cell gene expression in response to chronic inhibition of nitric oxide synthase in rats (2004) Circulation, 110, pp. 867-873Ebel, R.E., O'Keefe, D.H., Peterson, J.A., Nitric oxide complexes of cytochrome P450 (1975) FEBS Lett, 55, pp. 198-201Folch, J., Lees, M., Stanley, G.H.S., A simple method for the isolation and purification of total lipids from animal tissues (1957) J Biol Chem, 226, pp. 497-509Garcia-Villafranca, J., Guillen, A., Castro, J., Involvement of nitric oxide/cyclic GMP signaling pathway in the regulation of fatty acid metabolism in rat hepatocytes (2003) Biochem Pharmacol, 65, pp. 807-812Gergel, D., Misík, V., Riesz, P., Cederbaum, A.I., Inhibition of rat and human cytochrome P450 2E1 catalytic activity and reactive oxygen radical formation by nitric oxide (1997) Arch Biochem Biophys, 337, pp. 239-250Gonzalez, W., Fontaine, V., Pueyo, M.E., Laquay, N., Messika-Zeitoun, D., Philippe, M., Arnal, J.-F., Michel, J.B., Molecular plasticity of vascular wall during NG-nitro-L-arginine methyl ester-induced hypertension - modulation of proinflammatory signals (2000) Hypertension, 36, pp. 103-109Gurusamy, N., Watanabe, K., Ma, M., Prakash, P., Hirabayashi, K., Zhang, S., Muslin, A.J., Aizawa, Y., Glycogen synthase kinase 3β together with 14-3-3 protein regulates diabetic cardiomyopathy: Effect of losartan and tempol (2006) FEBS Lett, 580, pp. 1932-1940Haugen, D.A., Coon, M.J., Properties of electrophoretically homogenous phenobarbital-inducible forms of liver microsomal cytochrome P-450 (1976) J Biol Chem, 251, pp. 7929-7939Henriksen, E.J., Jacob, S., Modulation of metabolic control by angiotensin converting enzyme (ACE) inhibition (2003) J Cell Physiol, 196, pp. 171-179Hodgson, P.D., Renton, K.W., The role of nitric oxide generation in interferon-evoked cytochrome P450 down-regulation (1995) Int J Immunopharmacol, 17, pp. 995-1000Horiuchi, M., Mogi, M., Iwai, M., Signaling crosstalk angiotensin II receptor subtypes and insulin (2006) Endocrine J, 53, pp. 1-5Hropot, M., Grötsch, H., Klaus, E., Langer, K.H., Linz, W., Wiemer, G., Scholkens, B.A., Ramipril prevents the detrimental sequels of chronic NO synthase inhibition in rats: Hypertension, cardiac hypertrophy and renal insufficiency (1994) Naunyn-Schmiedeberg's Arch Pharmacol, 350, pp. 646-652Hropot M, Langer KH, Wiemer G, Grötsch H, Linz W (2003) Angiotensin II subtype AT1 receptor blockade prevents hypertension and renal insufficiency induced by chronic NO-synthase inhibition in rats. Naunyn-Schmiedeberg's Arch Pharmacol 367:312-317Hsieh, N.K., Wang, J.Y., Liu, J.C., Lee, W.H., Chen, H.I., Structural changes in cerebral arteries following nitric oxide deprivation: A comparison between normotensive and hypertensive rats (2004) Thromb Haemost, 92, pp. 162-170Jones, B.E., Czaja, M.J., Mechanisms of hepatic toxicity. III. Intracellular signaling in response to toxic liver injury (1998) Am J Physiol, 275, pp. G874-G878Jover, B., Mimran, A., Nitric oxide inhibition and renal alterations (2001) J Cardiovasc Pharmacol, 38 (SUPPL. 2), pp. S65-S70Kaplowitz, N., Mechanisms of liver cell injury (2000) J Hepatol, 32 (SUPPL. 1), pp. 39-47Kataoka, C., Egashira, K., Inoue, S., Takemoto, M., Ni, W., Koyanagi, M., Kitamoto, S., Takeshita, A., Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats (2002) Hypertension, 39, pp. 245-250Katoh, M., Egashira, K., Usui, M., Ichiki, T., Tomita, H., Shimokawa, H., Rakugi, H., Takeshita, A., Cardiac angiotensin II receptors are upregulated by long-term inhibition of nitric oxide synthesis in rats (1998) Circ Res, 83, pp. 743-751Khatsenko, O., Kikkawa, Y., Nitric oxide differentially affects constitutive cytochrome P450 isoforms in rat liver (1997) J Pharmacol Exp Ther, 280, pp. 1463-1470Khedara, A., Kawai, Y., Kayashita, J., Kato, N., Feeding rats the nitric oxide synthase inhibitor, L-N(omega)nitroarginine, elevates serum triglyceride and cholesterol and lowers hepatic fatty acid oxidation (1996) J Nutr, 126, pp. 2563-2567Khedara, A., Goto, T., Morishima, M., Kayashita, J., Kato, N., Elevated body fat in rats by the dietary nitric oxide synthase inhibitor, L-N omega nitroarginine (1999) Biosci Biotechnol Biochem, 63, pp. 698-702Kitano, T., Okumura, T., Nishizawa, M., Liew, S.Y., Seki, T., Inoue, K., Ito, S., Altered response to inflammatory cytokines in hepatic energy metabolism in inducible nitric oxide synthase knockout mice (2002) J Hepatol, 36, pp. 759-765Koop, D.R., Hydroxylation of p-nitrophenol by rabbit ethanol-inducible cytochrome P-450 isozyme 3a (1986) Mol Pharmacol, 29, pp. 399-404Kurowska, E.M., Carroll, K.K., Hypercholesterolemic properties of nitric oxide. In vivo and in vitro studies using nitric oxide donors (1998) Biochim Biophys Acta, 1392, pp. 41-50Laemmli, U.K., Cleavage of structural proteins during assembly of the head of bacteriophage T4 (1970) Nature, 222, pp. 680-685Li-Masters, T., Morgan, E.T., Down-regulation of phenobarbital-induce cytochrome P4502B mRNAs and proteins by endotoxin in mice independent from nitric oxide production by inducible nitric oxide synthase (2002) Biochem Pharmacol, 64, pp. 1703-1711Lo, S., Russel, J.C., Taylor, A.W., Determination of glycogen in small tissue samples (1970) J Appl Physiol, 28, pp. 234-236López-García, M.P., Endogenous nitric oxide is responsible for the early loss of P450 in cultured rat hepatocytes (1998) FEBS Lett, 438, pp. 145-149Lowry, O.H., Rosebrough, N.J., Farr, A.L., Randall, R.J., Protein measurement with the Folin phenol reagent (1951) J Biol Chem, 193, pp. 265-275Machado, L.J., Mihessen-Neto, I., Marubayashi, U., Reis, A.M., Coimbra, C.C., Hyperglycemic action of angiotensin II in freely moving rats (1995) Peptides, 16, pp. 479-483Martens, F.M.A.C., Demeilliers, B., Girardot, D., Daigle, C., Dao, H.H., deBlois, D., Moreau, P., Vessel-specific stimulation of protein synthesis by nitric oxide synthase inhibition. Role of extracellular signal-regulated kinases 1/2 (2002) Hypertension, 39, pp. 16-21Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C., Homeostasis model assessment, insulin resistance and beta-cell function from lasting plasma glucose and insulin concentrations in man (1985) Diabetologia, 28, pp. 412-418Minamino, T., Kitakaze, M., Papst, P.J., Ueda, Y., Sakata, Y., Asanuma, H., Ogai, A., Hori, M., Inhibition of nitric oxide synthesis induced coronary vascular remodeling and cardiac hypertrophy associated with the activation of p70 S6 kinase in rats (2000) Cardiovasc Drugs Ther, 14, pp. 533-542Moncada, S., Palmer, R.M.J., Higgs, E.A., Nitric oxide: Physiology, pathophysiology and pharmacology (1991) Pharmacol Rev, 43, pp. 100-142Monshouwer M, Witkamp RF, Nijmeijer SM, Van Amsterdam JG, Van Miert ASJPAM (1996) Suppression of cytochrome P450- and UDP glucuronosyl transferase-dependent enzyme activities by proinflammatory cytokines and possible role of nitric oxide in primary cultures of pig hepatocytes. Toxicol Appl Pharmacol 137:237-244Moreno H Jr, Metze K, Bento AC, Antunes E, Zatz R, Nucci G de (1996) Chronic nitric oxide inhibition as a model of hypertensive heart muscle disease. Basic Res Cardiol 91:248-255Moreno H Jr, Nathan LP, Metze K, Costa SKP, Antunes E, Hyslop S, Zatz R, Nucci G de (1997) Non-specific inhibitors of nitric oxide synthase cause myocardial necrosis in the rat. Clin Exp Pharmacol Physiol 24:349-352Müller, C.M., Scierka, A., Stiller, R.L., Kim, Y.-M., Cook, D.R., Lancaster Jr, J.R., Buffington, C.W., Watkins, W.D., Nitric oxide mediates hepatic cytochrome P450 dysfunction induced by endotoxin (1996) Anesthesiology, 84, pp. 1435-1442Muriel, P., Regulation of nitric oxide synthesis in the liver (2000) J Appl Toxicol, 20, pp. 89-195Neau, E., Dansette, P.M., Andronik, V., Mansuy, D., Hydroxylation of the thiophene ring by hepatic monooxygenases. Evidence for 5-hydroxylation of 2-aroylthiophenes as a general metabolic pathway using a simple UV-visible assay (1990) Biochem Pharmacol, 39, pp. 1101-1107Ogihara, T., Asano, T., Ando, K., Chiba, Y., Sakoda, H., Anai, M., Shojima, N., Fujita, T., Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling (2002) Hypertension, 40, pp. 872-879Okruhlicová, L., Tribulová, N., Bernátová, I., Pechánová, O., Induction of angiogenesis in NO-deficient rat heart (2000) Physiol Res, 49, pp. 71-76Omura, T., Sato, R., The carbon monoxide-binding pigment of liver microsomes. 1. Evidence for its hemoprotein nature (1964) J Biol Chem, 239, pp. 2370-2378Pfeilschifter, J., Eberhardt, W., Beck, K.F., Regulation of gene expression by nitric oxide (2001) Pflügers Arch Eur J Physiol, 442, pp. 479-486Pilz, R.B., Casteel, D.E., Regulation of gene expression by cyclic GMP (2003) Circ Res, 93, pp. 1034-1046Ribeiro M, Antunes E, Nucci G de, Lovisolo SM, Zatz R (1992) Chronic inhibition of nitric oxide synthesis: a new model of arterial hypertension. Hypertension 20:298-303Ribeiro Jr, E.A., Cunha, F.Q., Tamashiro, W.M., Martins, I.S., Growth phase-dependent subcellular localization of nitric oxide synthase in maize cells (1999) FEBS Lett, 445, pp. 283-286Rockey, D.C., Hepatic blood flow regulation by stellate cells in normal and injured liver (2001) Semin Liver Dis, 21, pp. 337-349Saad, M.J., Araki, E., Miralpeix, M., Rothenberg, P.I., White, M.F., Kahn, C.R., Regulation of insulin receptor substrate 1 in liver and muscle of animal models of insulin resistance (1992) J Clin Invest, 90, pp. 1839-1849Saltiel, A.R., Kahn, C.R., Insulin signalling and the regulation of glucose and lipid metabolism (2001) Nature, 414, pp. 799-806Sanada S, Kitakaze M, Node K, Takashima S, Ogai A, Asanuma H, Sakata Y, Asakura M, Ogita H, Liao Y, Fukushima T, Yamada J, Minamino T, Kuzuya T, Hori M (2001) Differential subcellular actions of ACE inhibitors and AT1 receptor antagonists on cardiac remodeling induced by chronic inhibition of NO synthesis in rats. Hypertension 38:404-411Scott, A.M., Atwater, I., Rojas, E., A method for the simultaneous measurement of insulin release and B cell membrane potential in single mouse islets of Langerhans (1981) Diabetologia, 21, pp. 470-475Sewer, M.B., Morgan, E.T., Nitric oxide-independent suppression of P-450 2C 11 expression by interleukin-1β and endotoxin in primary rat hepatocytes (1997) Biochem Pharmacol, 54, pp. 729-737Sewer, M.B., Morgan, E.T., Down-regulation of the expression of three major rat liver cytochrome P450s by endotoxin in vivo occurs independently of nitric oxide production (1998) J Pharmacol Exp Ther, 287, pp. 352-358Sewer, M.B., Barclay, T.B., Morgan, E.T., Down-regulation of cytochrome P450 mRNAs and proteins in mice lacking a functional NOS2 gene (1998) Mol Pharmacol, 54, pp. 273-279Sprangers F, Sauerwein HP, Romijn JA, Woerkom GM van, Meijer AJ (1998) Nitric oxide inhibits glycogen synthesis in isolated rat hepatocytes. Biochem J 330:1045-1049Stadler, J., Trockfeld, J., Schmalix, W.A., Brill, T., Siewert, J.R., Greim, H., Doehmer, J., Inhibition of cytochrome P4501A by nitric oxide (1994) Proc Natl Acad Sci USA, 91, pp. 3559-3563Suzuki, T., Fujita, S., Narimatsu, S., Masubuchi, Y., Tachibana, M., Ohata, S., Hirobe, M., Cytochrome P450 isozymes catalyzing 4-hydroxylation of Parkinsonism-related compound 1,2,3,4-tetrahydroisoquinoline in rat liver microsomes (1992) FASEB J, 6, pp. 771-776Takemoto, M., Egashira, K., Tomita, H., Usui, M., Okamoto, H., Kitabatake, A., Shimokawa, H., Takeshita, A., Chronic angiotensin-converting enzyme inhibition and angiotensin II type-1 receptor blockade: Effects on cardiovascular remodeling in rats induced by the long-term blockade of nitric oxide synthesis (1997) Hypertension, 30, pp. 1621-1627Takemoto, M., Egashira, K., Usui, M., Numaguchi, K., Tomita, H., Tsutsui, H., Shimokawa, H., Takeshita, A., Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats (1997) J Clin Invest, 99, pp. 278-287Takemura, S., Minamiyama, Y., Imaoka, S., Funae, Y., Hirohashi, K., Inoue, M., Kinoshita, H., Hepatic cytochrome P-450 is directly inactivated by nitric oxide, not by inflammatory cytokines, in the early phase of endotoxemia (1999) J Hepatol, 30, pp. 1035-1044Towbin, H., Staehelin, T., Gordon, J., Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: Procedure and some applications (1979) Proc Natl Acad Sci USA, 76, pp. 4350-4354Trinder, P., Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen (1969) J Clin Invest, 22, pp. 158-161Velloso, L.A., Folli, F., Perego, L., Saad, M.J.A., The multi-faceted cross-talk between the insulin and angiotensin II signaling systems (2006) Diabetes Metab Res Rev, 22, pp. 98-107Wiest, R., Groszmann, R.J., Nitric oxide and portal hypertension: Its role in the regulation of intrahepatic and splanchnic vascular resistance (1999) Semin Liver Dis, 19, pp. 411-426Young, H.M., O'Brien, A.J., Furness, J.B., Ciampoli, D., Hardwick, J.P., McCabe, T.J., Narayanasami, R., Tracey, W.R., Relationships between NADPH diaphorase staining and neuronal, endothelial and inducible nitric oxide synthase and cytochrome P450 reductase immunoreactivities in guinea-pig tissues (1997) Histochem Cell Biol, 107, pp. 19-29Zatz, R., Baylis, C., Chronic nitric oxide inhibition model six years on (1998) Hypertension, 32, pp. 958-964Zheng, J.F., Wang, H.D., Liang, L.J., Protective effects of nitric oxide on hepatic steatosis induced by total parenteral nutrition in rats (2002) Acta Pharmacol Sin, 23, pp. 824-828