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Possibilities of manipulating nitric oxide biosynthesis in the treatment of portal hypertension: statins

  • Conference paper
Portal Hypertension in the 21st Century

Abstract

Statins are lipid-lowering agents that act by inhibiting the activity of the ratelimiting enzyme for cholesterol synthesis, the 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, Statins are among the most widely prescribed drug class in Western countries, and have been consistently shown to decrease the incidence of cardiovascular events and to improve survival in patients with ischemic heart disease1. Although the beneficial effects of statins were initially entirely attributed to their lipid-lowering effects, detailed analysis of randomized controlled trials suggested that some of their benefits were independent of their cholesterol-lowering capacity2, 3. This prompted further investigations that showed a variety of effects of statins beyond cholesterol reduction, which have been called the pleiotropic effects of statins4, Statins reduce oxidant stress and inflammation at the vessel wall, have anti thrombotic and anti proliferative properties and improve endothelial function, increasing nitric oxide (NO) production in endothelial cells5–11, Statins’ effects on angiogenesis are more controversial, but it seems that at clinically relevant doses statins are proangiogenic agents 7, 12, 13. Many of these effects have been demonstrated to occur as early as within 24 hours of statin administration, further reinforcing their independence from plasma cholesterol changes14–16.

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References

  1. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Stroke. 2002;33:2337–41.

    Article  PubMed  Google Scholar 

  2. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 1998;97:1440–5.

    Google Scholar 

  3. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet. 1995;20:1274–5.

    Google Scholar 

  4. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arteriosc1er Thromb Vasc Biol. 2001:21:1712–19.

    Article  CAS  Google Scholar 

  5. Dangas G, Smith DA, Unger AH et al. Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect. Thromb Haemost. 2000;83:688–92.

    PubMed  CAS  Google Scholar 

  6. Lefer DJ. Statins as potent antiinflammatory drugs. Circulation. 2002;106:2041–2.

    Article  PubMed  Google Scholar 

  7. Kureishi Y, Luo Z, Shiojima I et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000;6:1004–10.

    Article  PubMed  CAS  Google Scholar 

  8. McGirt MJ, Lynch JR, Parra A et al. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke. 2002;33:2950–6.

    Article  PubMed  CAS  Google Scholar 

  9. Bates K, Ruggeroli CE, Goldman S, Gaballa MA. Simvastatin restores endothelial NO-mediated vasorelaxation in large arteries after myocardial infarction. Am J Physiol Heart Circ Physiol. 2002;283:H768–75.

    PubMed  CAS  Google Scholar 

  10. Laufs U, Gertz K, Dirnagl U, Bohm M, Nickenig G, Endres M. Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain Res. 2002;942:23–30.

    Article  PubMed  CAS  Google Scholar 

  11. Kalinowski L, Dobrucki LW, Brovkovych V, Malinski T. Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin. Circulation. 2002;105:933–8.

    Article  PubMed  CAS  Google Scholar 

  12. Weis M, Heeschen C, Glassford AJ, Cooke JP. Statins have biphasic effects on angiogenesis. Circulation. 2002;105:739–45.

    Article  PubMed  CAS  Google Scholar 

  13. Dimmeler S, Aicher A, Vasa M et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/ Akt pathway. J Clin Invest. 2001;108:391–7.

    PubMed  CAS  Google Scholar 

  14. Omori H, Nagashima H, Tsurumi Y et al. Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects. Br J Clin Pharmacol. 2002;54:395–9.

    Article  PubMed  CAS  Google Scholar 

  15. Laufs U, Wassmann S, Hilgers S, Ribaudo N, Bohm M, Nickenig G. Rapid effects on vascular function after initiation and withdrawal of atorvastatin in healthy, normocholesterolemic men. Am J Cardiol. 2001;88:1306–7.

    Article  PubMed  CAS  Google Scholar 

  16. Sironi L, Cimino M, Guerrini U et al. Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. ArterioscIer Thromb Vasc Biol. 2003;23:322–7.

    Article  CAS  Google Scholar 

  17. Laufs U, La F, V, Plutzky J, Liao JK. Up-regulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97:1129–35.

    Article  PubMed  CAS  Google Scholar 

  18. Sessa WC. Can modulation of endothelial nitric oxide synthase explain the vasculoprotective actions of statins? Trends Mol Med. 2001;7:189–91.

    Article  PubMed  CAS  Google Scholar 

  19. Laufs U. Beyond lipid-lowering: effects of statins on endothelial nitric oxide. Eur J Clin Pharmacol. 2003;58:719–31.

    PubMed  CAS  Google Scholar 

  20. Endres M, Laufs U, Huang Z et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA. 1998;95:8880–5.

    Article  PubMed  CAS  Google Scholar 

  21. Wolfrum S, Grimm M, Heidbreder M et al. Acute reduction of myocardial infarct size by a hydroxymethyl glut aryl coenzyme A reductase inhibitor is mediated by endothelial nitric oxide synthase. J Cardiovasc Pharmacol. 2003;41:474–80.

    Article  PubMed  CAS  Google Scholar 

  22. Mukai Y, Shimokawa H, Matoba T et al. Acute vasodilator effects of HMG-CoA reductase inhibitors: involvement of PI3-kinase/Akt pathway and Kv channels. J Cardiovasc Pharmacol. 2003;42:118–24.

    Article  PubMed  CAS  Google Scholar 

  23. Fulton D, Gratton JP, McCabe TJ et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999;399:597–601.

    Article  PubMed  CAS  Google Scholar 

  24. Skaletz-Rorowski A, Lutchman M, Kureishi Y, Lefer DJ, Faust JR, Walsh K. HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells. Cardiovasc Res. 2003;57:253–64.

    Article  PubMed  CAS  Google Scholar 

  25. Feron O, Dessy C, Desager JP, Balligand JL. Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance. Circulation. 2001;103:113–18.

    Article  PubMed  CAS  Google Scholar 

  26. Pelat M, Dessy C, Massion P, Desager JP, Feron O, Balligand JL. Rosuvastatin decreases caveolin-l and improves nitric oxide-dependent heart rate and blood pressure variability in apolipoprotein E-/-mice in vivo. Circulation. 2003;20:2480–6.

    Article  Google Scholar 

  27. Hattori Y, Nakanishi N, Akimoto K, Yoshida M, Kasai K. HMG-CoA reductase inhibitor increases GTP cyclohydrolase I mRNA and tetrahydrobiopterin in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2003;23:176–82.

    Article  PubMed  CAS  Google Scholar 

  28. Laufs U, Liao JK. Targeting Rho in cardiovascular disease. Circ Res. 2000;87:526–8.

    Article  PubMed  CAS  Google Scholar 

  29. Vidal F, Colome C, Martinez-Gonzalez J, Badimon L. Atherogenic concentrations of native low-density lipoproteins down-regulate nitric-oxide-synthase mRNA and protein levels in endothelial cells. Eur J Biochem. 1998;252:378–84.

    Article  PubMed  CAS  Google Scholar 

  30. Wassmann S, Laufs U, Muller K et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2002;22:300–5.

    Article  PubMed  CAS  Google Scholar 

  31. Bosch J, D’Amico G, Garcia-Pagan JC. Portal hypertension. In: Schiff ER, Sorrell MF, Maddrey WC, editors. Diseases of the Liver, 9th edn. Philadelphia: Lippincott Williams & Wilkins, 2003:429–86.

    Google Scholar 

  32. Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology. 2002;35:478–91.

    Article  PubMed  CAS  Google Scholar 

  33. Bathal PS, Grossmann HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol. 1985;1:325–9.

    Article  Google Scholar 

  34. Gupta TK, Toruner M, Chung MK, Groszmann RJ. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology. 1998;28:926–31.

    Article  PubMed  CAS  Google Scholar 

  35. Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology. 1998;114:344–51.

    Article  PubMed  CAS  Google Scholar 

  36. Shah V, Toruner M, Haddad F et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology. 1999;117:1222–8.

    Article  PubMed  CAS  Google Scholar 

  37. Sarela AI, Mihaimeed FM, Batten JJ, Davidson BR, Mathie RT. Hepatic and splanchnic nitric oxide activity in patients with cirrhosis. Gut. 1999;44:749–53.

    Article  PubMed  CAS  Google Scholar 

  38. Bellis L, Berzigotti A, Abraldes JG et al. Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis. Hepatology. 2003; 37:378–84.

    Article  PubMed  CAS  Google Scholar 

  39. Lee SS, Hadengue A, Moreau R, Sayegh R, Hillon P, Lebrec D. Postprandial hemodynamic responses in patients with cirrhosis. Hepatology. 1988;8:647–51.

    Article  PubMed  CAS  Google Scholar 

  40. Tsunoda T, Ohnishi K, Tanaka H. Portal hemodynamic responses after oral intake of glucose in patients with cirrhosis. Am J Gastroenterol. 1988;83:398–403.

    PubMed  CAS  Google Scholar 

  41. O’Brien S, Keogan M, Patchett S, McCormick PA, Afdhal N, Hegarty JE. Postprandial changes in portal haemodynamics in patients with cirrhosis. Gut. 1992;33:364–7.

    Article  PubMed  Google Scholar 

  42. Albillos A, Rossi I, Iborra J et al. Octreotide prevents postprandial splanchnic hyperemia in patients with portal hypertension. J Hepatol. 1994;21:88–94.

    Article  PubMed  CAS  Google Scholar 

  43. Bendtsen F, Simonsen L, Henriksen JH. Effect on hemodynamics of a liquid meal alone and in combination with propranolol in cirrhosis. Gastroenterology. 1992;102:1017–23.

    PubMed  CAS  Google Scholar 

  44. Vorobioff JD, Gamen M, Kravetz O et al. Effects of long-term propranolol and octreotide on postprandial hemodynamics in cirrhosis: a randomized, controlled trial. Gastroenterology. 2002;122:916–22.

    Article  PubMed  CAS  Google Scholar 

  45. Navasa M, Chesta J, Bosch J, Rodes J. Reduction of portal pressure by isosorbide-5-mononitrate in patients with cirrhosis. Effects on splanchnic and systemic hemodynamics and liver function. Gastroenterology. 1989;96:1110–18.

    PubMed  CAS  Google Scholar 

  46. Garcia-Pagan JC, Feu F, Navasa M et al. Long-term haemodynamic effects of isosorbide 5-mononitrate in patients with cirrhosis and portal hypertension. J Hepatol. 1990;11:189–95.

    Article  PubMed  CAS  Google Scholar 

  47. Salmeron JM, Ruiz dA, Gines A et al. Renal effects of acute isosorbide-5-mononitrate administration in cirrhosis. Hepatology. 1993;17:800–6.

    PubMed  CAS  Google Scholar 

  48. Van de CM, Omasta A, Janssens S et al. In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats. Gut. 2002;51:440–5.

    Article  Google Scholar 

  49. Van De CM, Van Pelt JF, Nevens F, Fevery J, Reichen J. Low NO bioavailability in CCl4 cirrhotic rat livers might result from low NO synthesis combined with decreased superoxide dismutase activity allowing superoxide-mediated NO breakdown: a comparison of two portal hypertensive rat models with healthy controls. Comp Hepatol. 2003;2:2.

    Article  Google Scholar 

  50. Shah V, Cao S, Hendrickson H, Yao J, Katusic ZS. Regulation of hepatic eNOS by caveolin and calmodulin after bile duct ligation in rats. Am J Physiol Gastrointest Liver Physiol. 2001;280:G 1209–16.

    Google Scholar 

  51. Chatila R, Theise N, Shah V, West AB, Sessa RJ, Groszmann RJ. Caveolin-1 in normal and cirrhotic human liver. Gastroenterology. 2000;118:A979.

    Article  Google Scholar 

  52. Yokomori H, Oda M, Ogi M, Sakai K, Ishii H. Enhanced expression of endothelial nitric oxide synthase and caveolin-1 in human cirrhosis. Liver. 2002;22:150–8.

    Article  PubMed  CAS  Google Scholar 

  53. Morales-Ruiz M, Cejudo-Martin P, Fernandez-Varo G et al. Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats. Gastroenterology. 2003; 125:522–31.

    Article  PubMed  CAS  Google Scholar 

  54. Zafra C, Abraldes JG, Turnes J et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology. 2004;126:749–55.

    Article  PubMed  CAS  Google Scholar 

  55. Sikuler E, Groszmann RJ. Interaction of flow and resistance in maintenance of portal hypertension in a rat model. Am J Physiol. 1986;250:G205–12.

    PubMed  CAS  Google Scholar 

  56. Susic D, Varagic J, Ahn J, Slama M, Frohlich ED. Beneficial pleiotropic vascular effects of rosuvastatin in two hypertensive models. J Am Coli Cardiol. 2003;42: 1091–7.

    Article  CAS  Google Scholar 

  57. Polio J, Groszmann RJ. Hemodynamic factors involved in the development and rupture of esophageal varices: a pathophysiologic approach to treatment. Semin Liver Dis. 1986; 6:318–31.

    Article  PubMed  CAS  Google Scholar 

  58. Mallat A, Preaux AM, Blazejewski S, Dhumeaux D, Rosenbaum J, Mavier P. Effect of simvastatin, an inhibitor of hydroxy-methylglutaryl coenzyme A reductase, on the growth of human Ito cells. Hepatology. 1994;20:1589–94.

    Article  PubMed  CAS  Google Scholar 

  59. Rombouts K, Kisanga E, Hellemans K, Wielant A, Schuppan D, Geerts A. Effect of HMG-CoA reductase inhibitors on proliferation and protein synthesis by rat hepatic stellate cells. J Hepatol. 2003;38:564–72.

    Article  PubMed  CAS  Google Scholar 

  60. Chalasani N, Aljadhey H, Kesteron J, Murray MD, Hall SD. Patients with elevated liver enzymes may not be at higher risk for statin hepatotoxicity than those with normal enzymes. Gastroenterology. 2004;126:1287–92.

    Article  PubMed  CAS  Google Scholar 

  61. Ritzel U, Leonhardt U, Nather M, Schafer G, Armstrong VW, Ramadori G. Simvastatin in primary biliary cirrhosis: effects on serum lipids and distinct disease markers. J Hepatol. 2002;36:454–8.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Hepatic Hemodynamic Laboratory, Liver Unit Hospital Clinic, Villaroel 170, 08036, Barcelona, Spain

    J. Bosch

Authors
  1. Juan G. Abraldes
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  2. Carmen Zafra
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  3. J. Bosch
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Editor information

Editors and Affiliations

  1. Yale University School of Medicine, New Haven, CT, USA

    R. J. Groszmann

  2. Hepatic Hemodynamic Laboratory Liver Unit, Hospital Clinic, University of Barcelona, Spain

    J. Bosch

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Abraldes, J.G., Zafra, C., Bosch, J. (2004). Possibilities of manipulating nitric oxide biosynthesis in the treatment of portal hypertension: statins. In: Groszmann, R.J., Bosch, J. (eds) Portal Hypertension in the 21st Century. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-1042-9_13

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  • DOI: https://doi.org/10.1007/978-94-007-1042-9_13

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-010-3774-7

  • Online ISBN: 978-94-007-1042-9

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