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The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

2002; Lippincott Williams & Wilkins; Volume: 35; Issue: 2 Linguagem: Inglês

10.1053/jhep.2002.31432

1527-3350

Reiner Wiest, Roberto J. Groszmann,

Organ Transplantation Techniques and Outcomes

HepatologyVolume 35, Issue 2 p. 478-491 Special ArticleFree Access The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough Reiner Wiest, Reiner Wiest Hepatic Hemodynamic Laboratory, Veterans Administration Medical Center, West Haven, ConnecticutSearch for more papers by this authorRoberto J. Groszmann, Corresponding Author Roberto J. Groszmann [email protected] Department of Medicine, Yale University School of Medicine, New Haven, CTVA Medical Center, Hepatic Hemodynamic Laboratory/111J, 950 Campbell Avenue, West Haven, CT 06516. fax: 203-937-3873.===Search for more papers by this author Reiner Wiest, Reiner Wiest Hepatic Hemodynamic Laboratory, Veterans Administration Medical Center, West Haven, ConnecticutSearch for more papers by this authorRoberto J. Groszmann, Corresponding Author Roberto J. Groszmann [email protected] Department of Medicine, Yale University School of Medicine, New Haven, CTVA Medical Center, Hepatic Hemodynamic Laboratory/111J, 950 Campbell Avenue, West Haven, CT 06516. fax: 203-937-3873.===Search for more papers by this author First published: 30 December 2003 https://doi.org/10.1053/jhep.2002.31432Citations: 360AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Bhathal P, Grossman H. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1985; 1: 325–337. MEDLINE 2 Reichen J, Le M. Verapamil favourably influences hepatic microvascular exchange and function in rats with cirrhosis of the liver. J Clin Invest 1986; 78: 448. MEDLINE 3 Palmer R, Ferrige A, Moncada S. Nitric oxide accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327: 527–526. 4 Vane J, Anggard E, Botting R. Regulatory functions of vascular endothelium. New England Journal of Medicine 1990; 323: 27–36. 5 Sessa W. The nitric oxide synthase family of proteins. J Vasc Res 1994; 31: 131–143. MEDLINE 6 Ramis I, Bioque G, Lorente J, Jares P, Quesada P, Rosello-Catafau J, Gelpi E, Bulbena O. Constitutive nuclear factor-kappa B activity in human upper airway tissues and nasal epithelial cells. Eur Respir J 2000; 15: 582–589. MEDLINE 7 Takahashi M, Ishida T, Traub O, Corson M, Berk B. Mechanotransduction in endothelial cells: temporal signaling events in response to shear stress. J Vasc Res 1997; 34: 212–219. MEDLINE 8 Cadelina G, Shah V, Choo K, Sessa W, Groszmann R. Elevated portal pressure in mice with targeted disruptio of the gene for endothelial nitric oxide sythase. Hepatology 2000; 32: A1202. 9 Gupta T, Toruner M, Chung M. Endothelial dysfunction in the intrahepatic microcirculation of cirrhotic rats. Hepatology 1998; 28: 926–931. MEDLINE 10 Shah V, Toruner M, Haddad F, Cadelina G, Papapetropoulos A, Choo K, Sessa W, et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology 1999; 117: 1222–1228. MEDLINE 11 Sarela A, Mihaimeed F, Batten J, Davidson B, Mathie R. Hepatic and splanchnic nitric oxide activity in patients with cirrhosis. Gut 1999; 44: 749–753. MEDLINE 12 Rockey D, Chung J. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology 1998; 114: 344–351. MEDLINE 13 Esteban F, Pedrosa J, Jimenez A, Fernandez A, Bentura M, Martinez-Murillo R, Rodrigo J, et al. Distribution of neuronal nitric oxide synthase in the rat liver. Neuroscti Lett 1997; 226: 99–102. 14 Beckman J, Koppenol W. Nitric oxide, superoxide, and peroxynitrite: the good, the bad and the ugly. Am J Physiol 1996; 271: C1424–C1437. MEDLINE 15 Malinski T, Bailey F, Zhang Z, Chopp M. Nitric oxide release from a single cell measured in situ by a prophyrinic-based microsensor. Nature 1992; 358: 676–678. MEDLINE 16 Halbrügge T, Lütsch K, Thyen A, Graefe K. Role of nitric oxide formation in the regulation of haemodynamics and the release of noradrenaline and adrenaline. Naunyn Schmiedebergs Arch Pharmacol 1991; 344: 720–727. MEDLINE 17 Mittal M, Gupta T, Lee F, Sieber C, Groszmann R. Nitric oxide modulates vascular tone in normal rat liver. American Journal of Physiology 1994; 267: G416–G422. 18 Zhang B, Borderie D, Sogni P, Soubrane O, Houssin D, Calmus Y. NO-mediated vasodilation in the rat liver. Role of hepatocytes and liver endothelial cells. J Hepatol 1997; 26: 1348–1355. MEDLINE 19 Ming Z, Han C, Lautt W. Nitric oxide mediates hepatic arterial vacular escape from norepinephrine-induced constriction. Am J Physiol 1999; 277: G1200–G1206. MEDLINE 20 Loureiro-Silva M, Cadelina G, Groszmann R. Nitric oxide modulates both pre-sinusoidal and sinusoidal responses to phenylephrine in normal rat liver. Gastroenterology 2001; 120: A–9. 21 Loureiro-Silva M, Cadelina G, Groszmann R. Nitric oxide plays a greater role on the sinusoidal than pre-sinusoidal increased vascular resistance in cirrhotic rat liver. Hepatology 34: 4(2); Oct 2001, 257A. 22 Buga G, Gold M, Fukuto J, Ignarro L. Shear stress-induced release of nitric oxide from endothelial cells grown on beads. Hypertension 1991; 17: 187–193. MEDLINE 23 Ranjan V, Xiao Z, Diamond S. Constitutive NOS expression in cultured endothelial cells is elevated by fluid shear stress. Am J Physiol 1995; 269: H550–H555. MEDLINE 24 Shah V, Haddad F, Garcia-Cardena G, Frangos J, Mennone A, Groszmann R, Sessa W. Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids. J Clin Invest 1997; 100: 2923–2930. MEDLINE 25 Thiemermann C, Ruetten H, Wu C, Vane J. The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. Br J Pharmacol 1995; 116: 2845–2851. MEDLINE 26 Saetre T, Gundersen Y, Thiemermann C, Aasen A. Aminoethyl-isothiourea, a selective inhibitor of inducible nitric oxide synthase activity, improves liver circulation and oxygen metabolism in a porcine model of endotoxemia. Shock 1998; 9: 109–115. MEDLINE 27 Moller S, Gülberg V, Henriksen J, Gerbes A. Endothelin-1 and Endothelin-3 in cirrhosis: Relations to systemic and splanchnic haemodynamics. Journal of Hepatology 1995; 23: 135–144. MEDLINE 28 Groszmann R, de Franchis R. Portal Hypertension. Lippincott-Raven, 1998. 29 Zhang J, Pegoli W, Jr, Clemens M. Endothelin-1 induces direct constriction of hepatic sinusoids. Am J Physiol 1994; 266: G624–G632. MEDLINE 30 Rockey D, Weisiger R. Endothelin induced contractility of stellate cell from normal and cirrhotic rat liver: implication for regulation of portal pressure and resistance. Hepatology 1996; 24: 233–240. MEDLINE 31 Pinzani M, Milani S, De Franco R, Grappone C, Caligiuri A, Gentilini A, Tosti-Guerra C, et al. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 1996; 110: 534–548. MEDLINE 32 Leivas A, Jimenez W, Bruix J, Boix L, Bosch J, Arroyo V, Rivera F, et al. Gene expression of endothelin-1 and ETa and ETb receptors in human cirrhosis: Relationship with hepatic hemodynamics. J Vasc Res 1998; 35: 186–193. MEDLINE 33 Busse R, Fleming I. Endothelial dysfunction in atherosclerosis. J Vasc Res 1996; 33: 181–194. MEDLINE 34 Ludmer P, Selwyn A, Shook T, Wayne R, Mudge G, Alexander R, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986; 315: 1046–1051. MEDLINE 35 Böger R, Bode-Böger S, Frölich J. The L-arginine-nitric oxide pathway: role in atherosclerosis and therapeutic implications. Atherosclerosis 1996; 127(1): 1–11. MEDLINE 36 Wever R, Lüscher T, Cosentino F, Rabelink T. Atherosclerosis and the two faces of endothelial nitric oxide synthase. Circulation 1998; 97: 108–112. MEDLINE 37 Cayatte A, Palacino J, Horten K, Cohen R. Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Arterioscler Thromb 1994; 14: 753–759. MEDLINE 38 Radomski M, Palmer R, Moncada S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci U S A 1990; 87: 5193–5197. MEDLINE 39 Diodati J, Dakak N, Gilligan D, Quyyumi A. Effect of atherosclerosis on endothelium-dependent inhibition of platelet activation in humans. Circulation 1998; 98: 17–24. MEDLINE 40 Wanless I, Wong F, Blendis L, Greig P, Heathcote E, Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995; 21: 1238–1247. MEDLINE 41 Kubes P, Suzuki M, Ganger D. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 1991; 88: 4651–4655. MEDLINE 42 Keaney J, Vita J. Atherosclerosis, oxidative stress, and antioxidant protection in endothelium-derived relaxing factor action. Prog Cardiovasc Dis 1995: 129–154. 43 Rubbo H, Radi R, Trujillo M, Telleri R, Kalyanaraman B, Barnes S, Kirk M, et al. Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. J Biol Chem 1994; 269: 26066–26075. MEDLINE 44 Tsukamoto H, Rippe R, Niemela O, Lin M. Roles of oxidative stress in activation of kupffer and Ito cells. J Gastroenterol Hepatol 1995; 10: S53. 45 Parola M, Pinzani M, Casini A, Albano E, Poli G, Gentilini A, Gentilini P, Dianzani M. Stimulation of lipid peroxidation or 4-hydroxynoneal treatment increases procollagen alpha 1 (I) gene expression and synthesis in human fat-storing cells. Biochem Biophys Res Comm 1993; 194: 1044–1050. 46 Muriel P. Nitric oxide protection of rat liver from lipid peroxidation, collagen accumulation, and liver damage induced by carbon tetrachloride. J Vasc Res 1998; 33: 181–194. 47 Myers P, Tanner M. Vascular endothelial cell regulation of extracellular matrix collagen: role of nitric oxide. Arterioscler Thromb Vasc Biol 1998; 18: 717–722. MEDLINE 48 Casini A, Ceni E, Salzano R, Biondi P, Parola M, Galli A, Foschi M, et al. Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: role of nitric oxide. Hepatology 1997; 25: 361–367. MEDLINE 49 Deitch E. Multiple organ failure. Adv Surg 1993; 26: 333–356. MEDLINE 50 Deitch E. Pathophysiology and potential future therapy. Ann Surg 1992; 216: 117–134. MEDLINE 51 Wiest R, Groszmann R. Nitric oxide and portal hypertension: its role in the regulation of intrahepatic and splanchnic vascular resistance. Sem Liver Disease 1999; 19: 411–426. 52 Hess D, Matsumoto A, Nudelman R, Stamler J. S-nitrosylation: spectrum and specificity. Nature Cell Biology 2001; 3: E46–E49. MEDLINE 53 Grisham M, Jourd'heuil D, Wink D. Nitric oxide I: Physiological chemistry of nitric oxide and its metabolites: implications in inflammation. Am J Physiol 1999; 276: G315–G321. MEDLINE 54 Salvemini D, Misko T, Masferrer J, Seibert K, Currie M, Needleman P. Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci U S A 1993; 90: 7240–7244. MEDLINE 55 Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J 1992; 6: 3051–3064. MEDLINE 56 Stamler S, Singel D, Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms. Science 1992; 258: 1898–1902. MEDLINE 57 Omasta A, Roskams T, Vermaele P, Fevery J. In the CCl4 cirrhosis but not in pre-hepatic portal hypertension or biliary cirrhosis, a reduced expression of CENOS is found in rat liver. Gastroenterology 2000; 118(4): A963. 58 Zimmermann H, Kurzen P, Klossner W, Renner E, Marti U. Decreased constitutive hepatic nitric oxide synthase expression in secondary biliary fibrosis and its changes after Roux-en Y choledocho-jejunostromy in the rat. J Hepatol 1996; 25: 567–573. MEDLINE 59 Sessa W, Garcia-Cardena G, Liu J, Keh A, Pollock J, Bradley J, Thiru A, et al. The Golgi association of endothelial nitric oxide synthase is necessary for the efficient synthesis of nitric oxide. J Biol Chem 1995; 270: 17641–17644. MEDLINE 60 Garcia-Cardena G, Oh P, Liu J, Schnitzer J, Sessa W. Targeting of nitric oxide synthase to endothelial caveolae via palmitoylation: Implications for nitric oxide signaling. Proc Nat Acad Sci U S A 1996; 93: 6448–6453. 61 Garcia-Cardena G, Fan R, Stern D, Liu J, Sessa W. Endothelial nitric oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1. J Biol Chem 1996; 271: 27237–27240. MEDLINE 62 Michel T, Li G, Busconi L. Phosphorylation and subcellular translocation of endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 1993; 90: 6252–6256. MEDLINE 63 Papapetropoulos A, Rudic R, Sessa W. Molecular control of nitric oxide synthases in the cardiovascular system. Cardiovasc. Res. 1999; 43: 509–520. 64 Michel J, Feron O, Sase K, Prabhakar P, Michel T. Caveolin versus calmodulin. Counterbalancing allosteric modulators of endothelial nitric oxide synthase. J Biol Chem 1997; 272: 25907. MEDLINE 65 Garcia-Cardena G, Martasek P, Masters B, Skidd PM, Couet J, Li S, Lisanti M, Sessa W. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. J Biol Chem 1997; 41: 25437–25440. 66 Michel J, Feron O, Sacks D, Michel T. Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin. J Biol Chem 1997; 272: 15583–15586. MEDLINE 67 Chatila R, Thiese N, Shah V, West A, Sessa W, Groszmann R. Caveolin-1 in normal and cirrhotic human liver. Gastroenterology 2000; 111: 4(Suppl 2, Part 1): A979. 68 Laufs U, La Fata V, Plutzky J, Liao J. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998; 97: 1129–1135. MEDLINE 69 Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, Sanchez-Pascuala R, Hernandez G, Diaz C, Lumas S. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998; 101: 2711–2719. MEDLINE 70 Dueland S, Reichen J, Everson G, Davis R. Regulation of cholesterol and bile acid homeostasis in bile-obstructed rats. Biochem J 1991; 280: 373–377. MEDLINE 71 Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Thodorou I, Khalil L, et al. Liver fibrosis in overweight patients. Gastroenterology 2000; 118: 1117–1123. MEDLINE 72 Bist A, Fielding P, Fielding C. Two sterol regulatory element-like sequences mediate up-regulation of caveolin gene transcription in response to low density lipoprotein free cholesterol. Proc Natl Acad Sci U S A 1997; 94: 10693–10698. MEDLINE 73 Stroess E, Koomans H, Rabelink T. Vascular function in the forearm of hypercholesterolemic patients off and on lipid-lowering medication. Lancet 1980; 346: 467–471. 74 Wagner A, Köhler T, Ruckschloss U, Just I, Hecker M. Improvement of nitric-oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 2000; 20: 61–69. MEDLINE 75 Creager M, Gallagher S, Girerd X, Coleman S, Dzau V, Cooke J. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 1992; 90: 1248–1253. MEDLINE 76 Gupta T, Groszmann R. Administration of L-arginine, the physiological precursor of nitric oxide, reduces portal perfusion pressure and ameliorates hepatic vascular hyperreactivity in experimental cirrhosis. Hepatology 1994; 20: 200A. 77 Kakumitsu S, Shijo H, Yokoyama M, Kim T, Akiyoshi N, Ota K, Kubara K, Okumura M, et al. Effects of L-arginine on the systemic, mesenteric, and hepatic circulation in patients with cirrhosis. Hepatology 1998; 27: 377–382. MEDLINE 78 Werner E, Werner-Felmayer G, Wachter H, Mayer B. Biosynthesis of nitric oxide: dependence on pteridine metabolism. Rev Physiol Biochem Pharmacol 1996; 127: 97–135. MEDLINE 79 Stroes E, Van Faasen E, Londen G, Rabelink T. Oxygen radical stress in vascular disease: the role of endothelial nitric oxide synthase. J Cardiovasc Pharm 1998: S14–21. 80 Jiang J, Valen G, Tokuno S, Thoren P, Pernow J. Endothelial dysfunction in atherosclerotic mice: improved relaxation by combined supplementation with L-arginine-tetrahydrobiopterin and enhanced vasoconstriction by endothelin. Br J Pharmacol 2000; 131: 1255–1261. MEDLINE 81 Higman D, Strachan A, Buttery L, RCJ H, Springall D, Greenhalgh R, Powell J. Smoking impairs the activity of endothelial nitric oxide synthase in saphenous vein. Arterioscler Thromb Vasc Biol 1996; 16(4): 546–552. MEDLINE 82 Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Luscher T, Rabelink T. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. Journal of Clinical Investigation 1997; 99: 41–46. MEDLINE 83 Cosentino F, Patton S, d'Uscio L, Werner E, Werner-Felmayer G, Moreau P, Malinski T, et al. Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats. J Clin Invest 1998; 101(7): 1530–1537. MEDLINE 84 Wever R, Van Dam T, Van Rijn H, DeGroot F, Rabelink T. Tetrahydrobiopterin regulates superoxide and nitric oxide generation by recombinant endothelial nitric oxide synthase. Biochem Biophys Res Commun 1997; 237: 340–344. MEDLINE 85 Bult H, Herman A, Matthys K. Antiatherosclerotic activity of drugs in relation to nitric oxide function. Eur J Pharmacol 1999; 375: 157–176. MEDLINE 86 May J. How does ascorbic acid prevent endothelial dysfunction? Free Radic. Biol. Med. 2000; 28: 1421–1429. 87 Groszmann R, Kravetz D, Bosch J, Glickman M, Bruix J, Bredfeldt J, Conn H, Rodes J, et al. Nitroglycerin improves the hemodynamic response to vasopressin in portal hypertension. Hepatology 1982; 2: 757–762. MEDLINE 88 Harrison D, Bates J. The nitrovasodilators: new ideas about old drugs. Circulation 1993; 87(1461): 1467. 89 Dudenhoefer A, Toruner M, Cadelina G, Groszmann R. Bioactivation of nitroglycerin and vasomotor response to nitric oxide is impaired in cirrhotic rat livers. Hepatology 1999; 30(4 Pt 2): 279. 90 Groszmann R. β-Adrenergic Blockers and Nitrovasodilators for the Treatment of Portal Hypertension: The Good, the Bad, the Ugly. Gastroenterology 1997; 113: 1794–1797. MEDLINE 91 Saavedra J, Billiar T, Williams D, Kim Y, Watkins S, Keefer L. Targeting nitric oxide delivery in vivo. Design of a liver-selective NO donor prodrug that blocks tumor necrosis-alpha-induced apoptosis and toxicity in the liver. J Med Chem 1997; 40: 1947–1954. MEDLINE 92 Moal F, Vuillemin E, Wang J, Veal N, Oberti F, Cales P. Chronic Hemodynamic Effects Of A New Liver Specific No Donor (V-PYRRO/NO) In Bile Duct Ligated (BDL) Rats. Gastroenterology 2000; 118(4): A978. 93 Yu Q, Shao R, Qian H, George S, Rockey D. Gene transfer of the neuronal NO synthase isoform to cirrhotic rat liver ameliorates portal hypertension. J Clin Invest 2000; 105: 741–748. MEDLINE 94 Omasta A, Nevens F, Vermaelen P, Fevery J. CENOS Gene Transfer Enhances NO Production And NOS Protein Expression In The CCl4 Cirrhotic Rat Liver Resulting In Prolonged Decrease Of Portal Pressure. Gastroenterology 2000; 118(4): A905. 95 Groszmann R. Hyperdynamic circulation of liver diseases forty years later: Pathophysiology and clinical consequences. Hepatology 1994; 20: 1359–1363. MEDLINE 96 Vorobioff J, Bredfeldt J, Groszmann R. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Am J Physiol 1983; 244: G52. MEDLINE 97 Sikuler E, Kravetz D, Groszmann R. Evolution of portal hypertension and mechanisms involved in its maintenance in a rat model. Am J Physiol 1985; 248: G618. MEDLINE 98 Pizcueta P, Pique J, Fernandez M, Bosch J, Rodes J, Whittle B, Moncada S. Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition. Gastroenterology 1992; 103: 1909–1915. MEDLINE 99 Casadevall M, Pique J, Cirera I, Goldin E, Elizalde I, Panes J, Martinez-Cuesta M, et al. Increased blood hemoglobin attenuates splanchnic vasodilation in portal-hypertensive rats by nitric oxide inactivation. Gastroenterology 1996; 110: 1156–1165. MEDLINE 100 Lee R, Albillos A, Colombato L, Groszmann R. The role of nitric oxide in the vascular hyporesponsiveness to methoxamine in portal hypertensive rats. Hepatology 1992; 16: 1043–1048. MEDLINE 101 Niederberger M, Martin P, Gines P, Morris K, Tsai P, Xu D, McMurty I, Schrier R. Normalization of nitric oxide production corrects arterial vasodilation and hyperdynamic circulation in cirrhotic rats. Gastroenterology 1995; 109: 1624–1630. MEDLINE 102 Kiel J, Pitts V, Benoit J, Granger D, Shepherd A. Reduced vascular sensitivity to norepinephrine in portal hypertensive rats. Am J Physiol 1985; 248: G192. MEDLINE 103 Hartleb M, Moreau R, Cailmail S, Gaudin C, Lebrec D. Vascular hyporesponsiveness to endothelin 1 in rats with cirrhosis. Gastroenterology 1994; 107: 1085–1093. MEDLINE 104 Sieber C, Lopez-Talavera J, Groszmann R. Role of nitric oxide in the in vitro splanchnic vascular hyporeactivity in ascitic cirrhotic rats. Gastroenterology 1993; 104: 1750–1754. MEDLINE 105 Sieber C, Sumanovski L, Moll-Kaufmann C, Stalder G. Hyposensitivity to nerve stimulation in portal hypertensive rats: role of nitric oxide. Eur J Clin Invest 1997; 27: 902–907. MEDLINE 106 Atucha N, Shah V, Garcia-Cardena G, Sessa W, Groszmann R. Role of endothelium in the abnormal response of mesenteric vessels in rats with portal hypertension and liver cirrhosis. Gastroenterology 1996; 111: 1627–1632. MEDLINE 107 Wiest R, Hori N, Cadelina G, Das S, Groszmann R. Increased nitric oxide release in response to vasoconstrictors in the superior mesenteric arterial bed of cirrhotic rats. Hepatology 1997; 26: A390. 108 Martin P, Ohara M, Gines P, Xu D, St. John J, Niederberger M, Schrier R. Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites. J Clin Invest 1998; 101: 235–242. MEDLINE 109 Martin P, Xu D, Niederberger M, Weigert A, Tsai P, St John J, Gines P, Schrier R. Upregulation of endothelial constitutive NOS: a major role in the increased NO production in cirrhotic rats. Am J Physiol 1996; 270: F494–F499. MEDLINE 110 Niederberger M, Gines P, Martin P, Tsai P, Morris K, McMurtry I, Schrier R. Comparison of vascular nitric oxide production and systemic hemodynamics in cirrhosis versus prehepatic portal hypertension in rats. Hepatology 1996; 24: 947–951. MEDLINE 111 Cahill P, Redmond E, Hodges R, Zhang S, Sitzmann J. Increased endothelial nitric oxide synthase activity in the hyperemic vessels of portal hypertensive rats. J Hepatology 1996; 25: 370–378. 112 Cahill P, Foster C, Redmond E, Gingalewski C, Wu Y, Sitzmann J. Enhanced nitric oxide synthase activity in portal hypertensive rabbits. Hepatology 1995; 22: 598–606. MEDLINE 113 Hori N, Wiest R, Groszmann R. Enhanced Release of Nitric Oxide in Response to Changes in Flow and Shear Stress in the Superior Mesenteric Arteries of Portal Hypertensive Rats. Hepatology 1998; 28: 1467–1473. MEDLINE 114 Nadaub S, Philippe M, Arnal J, Michel J, Soubrier F. Sustained increase in aortic endothelial nitric oxide synthase expression in vivo in a model of chronic high blood flow. Circ Res 1996; 79: 857–863. MEDLINE 115 Wiest R, Shah V, Sessa W, Groszmann R. Nitric oxide overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive rats. American Journal of Physiology 1999; 276(39): G1043–G1051. MEDLINE 116 Garcia-Cardena G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, Sessa WC. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 1998; 392: 821–824. MEDLINE 117 Shah V, Wiest R, Garcia-Cardena G, Cadelina G, Sessa W, Groszmann R. HSP 90 regulation of endothelial nitric oxide synthase contributes to vascular control in portal hypertension. Am J Physiol 1999; 277: G463–G468. MEDLINE 118 Fleming I, Busse R. Signal transduction of eNOS activity. Cardiovasc. Res. 1999; 43: 532–541. 119 Iwakiri Y, Tsai M-H, Sessa W, Groszmann R. The phosphorylation of endothelial nitric oxide synthase by Akt increases nitric oxide production in early portal hypertension. Gastroenterology 2001; 120: A–9. 120 Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet 1991; I: 776. 121 Morales-Ruiz M, Jimenez W, Perez-Sala D, Ros J, Leivas A, Lamas S, Rivera F, et al. Increased nitric oxide synthase expression in arterial vessels of cirrhotic rats with ascites. Hepatology 1996; 24: 1481–1486. MEDLINE 122 Fernandez M, Garcia-Pagan J, Casadevall M, Bernadich C, Piera C, Whittle B, Pique J, Bosch J, Rodes J. Evidence against a role for inducible nitric oxide synthase in the hyperdyamic circulation of portal-hypertensive rats. Gastroenterology 1995; 108: 1487–1495. MEDLINE 123 Heinemann A, Stauber R. The role of inducible nitric oxide synthase in vascular hyporeactivity of endotoxin-treated and portal hypertensive rats. Eur J Pharmacol 1995; 278: 87–90. MEDLINE 124 Griscavage J, Hobbs A, Ignarro L. Negative modulation of nitric oxide synthase by nitric oxide and nitroso compounds. Adv Pharmacol 1995; 34: 215–234. MEDLINE 125 Griscavage J, Rogers N, Sherman N, Ignarro L. Inducible nitric oxide synthase from rat alveolar cell line is inhibited by nitric oxide. J Immunol 1993; 151: 6329–6337. MEDLINE 126 Heller J, Sogni P, Tazi K, Chagneau C, Poirel O, Moreau R, Lebrec D. Abnormal regulation of aortic NOS2 and NOS3 activity and expression from portal vein-stenosed rats after lipopolysaccharide administration. Hepatology 1999; 30: 698–704. MEDLINE 127 Guarner C, Soriano G, Tomas A, Bulbena O, Novella M, Balanzo J, Vilardell F, et al. Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia. Hepatology 1993; 18: 1139–1143. MEDLINE 128 Chu C, Lee F, Wang S, Lu R, Tsai Y, Lin H, Hou M, et al. Hyperdynamic circulation of cirrhotic rats with ascites: role of endotoxin, tumour necrosis factor and nitric oxide. Clinical Science 1997; 93: 219–225. MEDLINE 129 Garcia JN, Mirshahi F, Jarai Z, Kunos G, Sanyal A. The endogenous cannabinoid system: A novel and potent regulator of systemic and portal hemodynamics in normal and cirrhotic rats. Hepatology 2000; 32: 4(2): 220A. 130 Ros J, Jimenez W, Claria J, To-Figueras J, Cejudo P, Fernandez G, Planaguma A, Arroyo V, et al. Endogenous cannabinoids: A new system involved in the homeostasis of arterial pressure in cirrhosis. Hepatology 2000; 32: 4(2): 460A. 131 Wiest R, Garcia-Tsao G, Cadelina G, Das S, Shah V, Groszmann R. Bacterial translocation to mesenteric lymph nodes enhances eNOS-derived NO overproduction in mesenteric vasculature of cirrhotic rats: role for impairment in vascular contractility. J Clin Invest 1999; 104: 1223–1233. MEDLINE 132 Lopez-Talavera J, Cadelina G, Olchowski J, Merrill W, Groszmann R. Thalidomide inhibits tumor necrosis factor-α, decreases nitric oxide synthesis and ameliorates the hyperdynamic circulatory syndrome in portal hypertensive rats. Hepatology 1996; 23: 1616–1621. MEDLINE 133 Kilbourn R, Belloni P. Endothelial cell production of nitrogen oxides in response to interferon gamma in combination with tumor necrosis factor, interleukin-1, or endotoxin. J Natl Cancer Inst 1990; 82: 772–77. MEDLINE 134 Lopez-Talavera J, Merrill W, Groszmann R. Tumor necrosis factor a: A major contributor to the hyperdynamic circulation in prehepatic portal-hypertensive rats. Gastroenterology 1995; 108: 761–767. MEDLINE 135 Rosenkranz-Weiss P, Sessa W, Milstien S, Kaufman S, Watson C, Pober J. Regulation of nitric oxide synthesis by proinflammatory cytokines in human umbilical vein endothelial cells. Elevations in tetrahydrobiopterin levels enhance endothelial nitric oxide synthase specific activity. J Clin Invest 1994; 93: 2236–2243. MEDLINE 136 Katusic Z, Stelter A, Milstien S. Cytokines stimulate GTP cyclohydrolase I gene expression in cultured human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol 1998; 18: 27–32. MEDLINE 137 Bhagat K, Hingorani A, Palacios M, Charles I, Vallance P. Cytokine-induced venodilatation in humans in vivo: eNOS masquerading as iNOS. Cardiovasc Res 1999; 41: 754–764. MEDLINE 138 Wiest R, Tsai M-H, Garcia-Tsao G, McCuskey R, Milstien S, Groszmann R. Bacterial Translocation to mesenteric lymph nodes induces endotoxemia and stimulates GTP-Cyclohydrolase I in mesenteric vasculature of cirrhotic rats. Hepatology 2000; 32: A1206. 139 Battista S, Bar F, Mengozzo G, Zanon E, Grosso M, Molino G. Hyperdynamic circulation in patients with cirrhosis: direct measurement of nitric oxide levels in hepatic and portal veins. Journal of Hepatology 1997; 26: 75–80. MEDLINE 140 Fernandez-Seara J, Prieto J, Quiroga J, Zozaya J, Cobos M, Rodriguez-Eire J, Garcia-Plaza A, et al. Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure. Gastroenterology 1989; 97: 1304–1312. MEDLINE 141 Bernardi M, Trevisani F. Systemic and regional hemodynamics in pre-ascitic cirrhosis. J Hepatol 1997; 27: 588–591. MEDLINE 142 Gadano A, Sogni P, Yang S, Cailmail S, Moreau R, Nepveux P, Couturier D, Lebrec D. Endothelial calcium-calmodulin dependent nitric oxide synthase in the in vitro vascular hyporeactivity of portal hypertensive rats. J Hepatol 1997; 26: 678–686. MEDLINE 143 Weigert A, Martin P, Niederberger M, Higa E, McMurtry I, Gines P, Schrier R. Endothelium-dependent vascular hyporesponsiveness without detection of nitric oxide synthase induction in aortas of cirrhotic rats. Hepatology 1995; 22: 1856–1862. MEDLINE 144 Ortiz M, Fortepiani L, Martinez C, Atucha N, Garcia-Estan J. Vascular hyporesponsiveness in aortic rings from cirrhotic rats: role of nitric oxide and endothelium. Clin Sci (Colch) 1996; 91: 733–738. MEDLINE 145 Claria J, Jimenez W, Ros J, Rigol M, Angeli P, Arroyo V, Rivera F, et al. Increased nitric oxide-dependent vasorelaxation in aortic rings of cirrhotic rats with ascites. Hepatology 1994; 20: 1615–1621. MEDLINE 146 Albillos A, Rossi I, Cacho G, Martinez M, Millan I, Abreu L, Barrios C, et al. Enhanced endothelium-dependent vasodilation in patients with cirrhosis. Am J Physiol 1995; 268: G459–G464. MEDLINE 147 Schlant R, Tsagaris T, Robertson R. Studies on the acute cardiovascular effects of intravenous sodium nitroprusside. American Journal of Cardiology 1962; 9: 51–59. 148 Colombato L, Albillos A, Groszmann R. Temporal relationship of peripheral vasodilatation, plasma volume expansion and the hyperdynamic circulatory state in portal hypertensive rats. Hepatology 1992; 15: 323–328. MEDLINE 149 Schrier R, Arroyo V, Bernardi M, Epstein M, Henriksen J, Rodes J. Peripheral arterial vasodilatation hypothesis: a proposal for the initiation of renal sodium and water retention. Hepatology 1988; 8: 1151–1157. MEDLINE 150 Atucha N, Garcia-Estan J, Ramirez A, Perez M, Quesada T, Romero J. Renal effects of nitric oxide synthesis inhibition in cirrhotic rats. Am J Physiol 1994; 267: R1454–R1460. MEDLINE 151 Claria J, Jimenez W, Ros J, Asbert M, Castro A, Arroyo V, Rivera F, et al. Pathogenesis of arterial hypotension in cirrhotic rats with ascites: role of endogenous nitric oxide. Hepatology 1992; 15: 343–349. MEDLINE 152 Lee F-Y, Colombato L, Albillos A, Groszmann R. Nω-nitro-L-arginine administration corrects vasodilatation and systemic capillary hypotension, and ameliorates plasma volume expansion and sodium retention in portal hypertensive rats. Hepatology 1993; 17: 84–90. MEDLINE 153 Mosca P, Lee F, Kaumann A, Groszmann R. Pharmacology of portal-systemic collaterals in portal hypertensive rats: role of endothelium. Am J Physiol 1992; 263: G544–G550. MEDLINE 154 Lee F, Colombato L, Albillos A, Groszmann R. Administration of Nω-nitro-L-arginine ameliorates portal-systemic shunting in portal hypertensive rats. Gastroenterology 1993; 105: 1464–1470. MEDLINE 155 Halvorsen J, Myking A. The porto-systemic collateral pattern in the rat: an angiographic and anatomic study after partial occlusion of the portal vein. Eur Surg Res 1974; 6: 183. MEDLINE 156 Ziche M, Morbidelli L, Masini E, Amerini S, Granger H, Maggi C, Geppetti P, et al. Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance. J Clin Invest 1994; 94: 2036–44. MEDLINE 157 Rudic R, Shesely E, Maeda N, Smithies O, Segal S, Sessa W. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 1998; 101: 731–736. MEDLINE 158 Awolesi M, Sessa W, Sumpio B. Cyclic strain upregulates nitric oxide synthase in cultured bovine aortic endothelial cells. J Clin Invest 1995; 96: 1449–1454. MEDLINE 159 Geraghty J, Angerson W, Carter D. Portal venous pressure and portasystemic shunting in experimental portal hypertension. Am J Physiol 1989; 257: G52–7. MEDLINE 160 Kelly D, Summerfield J. Hemostasis in liver disease. Semin Liver Dis 1987; 7(3): 182–191. MEDLINE 161 Albornoz L, Bandi J, Otaso J, Laudanno O, Mastai R. A Prolonged bleeding time in experimental cirrhosis: role of nitric oxide. J Hepatol 1999; 30: 460. 162 Chester A, O'Niell G, Moncada S, Tadjkarimi S, Yacoub M. Low basal and stimulated release of nitric oxide in atherosclerotic epicardial coronary arteries. Lancet 1990; 336: 897–900. MEDLINE 163 Foerstermann U, Muegge A, Alheid U, Frolich J. Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries. Circ Res 1988; 62: 185–190. MEDLINE 164 Gupta T, Chung M, Toruner M, Groszmann R. Endothelial dysfunction in the intrahepatic microcirculation of the cirrhotic rat. Hepatology 1998; 28: 926–931. MEDLINE 165 Zieher A, Drexler H, Wollschlager H, Just H. Modulation of coronary vasomotor tone in humans: Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991; 83: 391–401. MEDLINE 166 Friedman S. Cytokines and fibrogenesis. Sem Liv Dis 1999; 19: 129–140. 167 Montovani A, Bussolino F, Dejana E. Cytokine regulation of endothelial cells function. FASEB J 1992; 6: 2591–2599. MEDLINE 168 Mallat A. Hepatic stellate cells and intrahepatic modulation of portal pressure. Digestion 1998; 59: 416–419. MEDLINE 169 Boeger R, Bode-Boeger S, Froelich J. The L-arginine-nitric oxide pathway: role in atherosclerosis and therapeutic implications. Atherosclerosis 1996: 1–11. 170 Katsuda S, Coltrera M, Ross R, Gown A. Human atherosclerosis. Immunocytochemical analysis of cell activation and proliferation in lesions of young adults. Am J Pathol 1993; 142: 1787–1793. MEDLINE 171 Ohara Y, Peterson T, Harrison D. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest 1993; 91: 2546–2551. MEDLINE 172 Ma X, Lopez B, Liu G. Hypercholesterolemia impairs a detoxification mechanism against peroxynitrite and renders the vascular tissue more susceptible to oxidative injury. Circ Res 1997; 80: 894–901. MEDLINE 173 Muegge A, Elwell J, Peterson T, Hofmeyer T, Heistad D, Harrison D. Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res 1991; 69: 1293–1300. MEDLINE 174 Poli G. Pathogenesis of liver fibrosis: role of oxidative stress. Molecular Aspects of Medicine 2000; 21: 49–89. MEDLINE 175 Whalen R, Rockey D, Friedman S, Boyer T. Activation of rat hepatic stellate cells leads to loss of glutathione S-transferases and their enzymatic activity against products of oxidative stress. Hepatology 1999; 30: 927–933. MEDLINE 176 Henning B, Chow C. Lipid peroxidation and endothelial cell injury: implications in atherosclerosis. Free Radic Biol Med 1988; 4: 99–106. MEDLINE 177 Muriel P. Peroxidation of lipids and liver damage. In: S Baskin, H Salem, eds. Antioxidants, Oxidants, and Free Radicals. Washington, DC: Taylor and Francis, 1997: 237–257. Citing Literature Volume35, Issue2February 2002Pages 478-491 ReferencesRelatedInformation