Cirrhotic portal hypertension: Current and future medical therapy for primary and secondary prevention of variceal bleeding

Minerva Medica

Volumn 97, Issue 4, 2006, Pages 325-345

  Laleman, W ^a   Nevens, F ^a  

^a UNIVERSITY HOSPITALS LEUVEN   (Belgium)

Author keywords

Intrahepatic vascular resistance; Portal hypertension, drug therapy; Portal hypertension, physiopathology

Indexed keywords

2 [[2 [[2 [[(HEXAHYDRO 1H AZEPIN 1 YL)CARBONYL]AMINO] 4 METHYLPENTANOYL]AMINO] 3 (1 METHYL 1H INDOL 3 YL)PROPIONYL]AMINO] 3 (2 PYRIDYL)PROPIONIC ACID; 2 PYRIDYLCARBAMIC ACID 2 [[5 (2 METHOXYPHENOXY) 6 [[(4 ISOPROPYLPHENYL)SULFONYL]AMINO] 2 MORPHOLINO 4 PYRIMIDINYL]OXY]ETHYL ESTER; ALPHA 1 ADRENERGIC RECEPTOR BLOCKING AGENT; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; BOSENTAN; CARVEDILOL; DARUSENTAN; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ENDOTHELIAL NITRIC OXIDE SYNTHASE; ENDOTHELIN A RECEPTOR ANTAGONIST; ENDOTHELIN B RECEPTOR ANTAGONIST; IRBESARTAN; ISOSORBIDE 5 NITRATE; LOSARTAN; NADOLOL; NEURONAL NITRIC OXIDE SYNTHASE; NITRATE; PLACEBO; PRAZOSIN; PROPRANOLOL DERIVATIVE; SOMATOSTATIN; THROMBOXANE A2 RECEPTOR BLOCKING AGENT; VASOCONSTRICTOR AGENT; VASODILATOR AGENT; VASOPRESSIN;

BETA ADRENERGIC RECEPTOR BLOCKING; BLOOD VESSEL TONE; CHRONIC LIVER DISEASE; CLINICAL TRIAL; DISEASE ASSOCIATION; DISEASE EXACERBATION; DRUG MECHANISM; ENDOSCOPIC THERAPY; ESOPHAGUS VARICES; ESOPHAGUS VARICES BLEEDING; GENE THERAPY; HUMAN; HYPOTENSION; LIVER CIRRHOSIS; NONHUMAN; PATHOPHYSIOLOGY; PORTAL HYPERTENSION; PORTAL VEIN; PRACTICE GUIDELINE; PRIMARY PREVENTION; REVIEW; RISK FACTOR; SECONDARY PREVENTION; SHUNTING; SURVIVAL TIME; VASCULAR RESISTANCE; VASOCONSTRICTION; VASODILATATION; VEIN LIGATION;

ADRENERGIC BETA-ANTAGONISTS; ANIMALS; DRUG THERAPY, COMBINATION; ENDOSCOPY; ESOPHAGEAL AND GASTRIC VARICES; FOLLOW-UP STUDIES; FORECASTING; GASTROINTESTINAL HEMORRHAGE; HUMANS; HYPERTENSION, PORTAL; ISOSORBIDE DINITRATE; LIGATION; LIVER CIRRHOSIS; LIVER CIRRHOSIS, ALCOHOLIC; MIDDLE AGED; NADOLOL; PORTASYSTEMIC SHUNT, SURGICAL; PORTASYSTEMIC SHUNT, TRANSJUGULAR INTRAHEPATIC; PRACTICE GUIDELINES; PROPRANOLOL; RANDOMIZED CONTROLLED TRIALS; RATS; RISK FACTORS; RISK REDUCTION BEHAVIOR; SPLANCHNIC CIRCULATION; STENTS; TIME FACTORS; VASCULAR RESISTANCE; VASODILATOR AGENTS;

EID: 33750600895     PISSN: 00264806     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (154)

1. Herrick FC. Experimental study into cause of increased portal pressure in portal cirrhosis. J Exp Med 1907;9:93.
2. Laleman W, Landeghem L, Wilmer A, Fevery J, Nevens F. Portal hypertension: from pathophysiology to clinical practice. Liv Int 2005;25:1079-90.
3. Bosch J, Garcia-Pagan JC. Complications of cirrhosis. I. Portal hypertension. J Hepatol 2000;32 Suppl 1:141-56.
4. Stewart SF, Day CP. The management of alcoholic liver disease. J Hepatol 2003;38 Suppl:2-13.
5. Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985;5:419-24.
6. Viallet A, Marleau D, Huet M, Martin F, Farley A, Villeneuve JP et al. Hemodynamic evaluation of patients with intrahepatic portal hypertension. Relationship between bleeding varices and the portohepatic gradient. Gastroenterology 1975;69:1297-300.
7. El Atti EA, Nevens F, Bogaerts K, Verbeke G, Fevery J. Variceal pressure is a strong predictor of variceal haemorrhage in patients with cirrhosis as well as in patients with non-cirrhotic portal hypertension. Gut 1999;45:6l8-21.
8. D'Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology 1995;22:332-54.
9. Casado M, Bosch J, Garcia-Pagan JC, Bru C, Banares R, Bandi JC et al. Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings. Gastroenterology 1998;114:1296-303.
10. Vorobioff J, Groszmann RJ, Picabea E, Gamen M, Villavicencio R, Bordato J et al. Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study. Gastroenterology 1996;11:701-9.
11. Fevery J, Nevens F. Oesophageal varices: assessment of the risk of bleeding and mortality. J Gastroenterol Hepatol 2000;15:842-8.
12. The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med 1988;319:983-9.
13. Ben-Ari Z, Cardin F, McCormick AP, Wannamethee G, Burroughs AK. A predictive model for failure to control bleeding during acute variceal haemorrhage. J Hepatol 1999;31;443-50.
14. Goulis J, Armonis A, Patch D, Sabin C, Greenslade L, Burroughs AK. Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal haemorrhage. Hepatology 1998;27:1207-12.
15. Moitinho E, Escorsell A, Bandi JC, Salmeron JM, Garcia-Pagan JC, Rodes J et al. Prognostic value of early measurements of portal pressure in acute variceal bleeding. Gastroenterology 1999;117:626-31.
16. D'Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liv Dis 1999;19:475-505.
17. Groszmann RJ, Bosch J, Grace ND, Conn HO, Garcia-Tsao G, Navasa M et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990;90:1401-7.
18. Feu F, Garcia-Pagan JC, Bosch J, Luca A, Teres J, Escorsell A et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet 1995;346:1056-9.
19. Escorsell A, Bordas JM, Castaneda B, Llach J, Garcia-Pagan JC, Rodes J et al. Predictive value of the variceal pressure response to continued pharmacological therapy in patients with cirrhosis and portal hypertension. Hepatology 2000;31:1061-7.
20. Merkel C, Bolognesi M, Sacerdoti D, Bombonato G, Bellini B, Bighin R et al. The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal rebleeding. Hepatology 2000;32: 930-4.
21. Villanueva C, Balanzo J, Novella MT, Soriano G, Sainz S, Torras X et al. Nadolol plus isosorbide mononitrate compared with sclerotherapy for the therapy for prevention of variceal rebleeding. N Engl J Med 1996;334:1624-9.
22. Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodes J, Bosch J. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology 2003;37:902-8.
23. Lebrec D, Poynard T, Hillon P, Benhamou JP. Propanolol for the prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study. N Engl J Med 1981;305:1371-4.
24. Pascal JP, Cales P. Propanolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med 1987;317:856-61.
25. Ideo G, Bellati G, Fesce E, Grimoldi D. Nadolol can prevent the first gastrointestinal bleeding in cirrhotics: a prospective, randomized study. Hepatology 1998;8: 6-9.
26. Strauss E, De Sa MFG, Albano A. A randomized controlled trial for the prevention of the first upper gastrointestinal bleeding due to portal hypertension in cirrhosis. Sclerotherapy or propanolol versus control groups. Hepatology 1988;8:1395.
27. Lebrec D, Poynard T, Capron JP, Hillon P, Geoffroy P, Roulot D et al. Nadolol for prophylaxis of gastrointestinal bleeding in patients with cirrhosis. A randomized trial. J Hepatol 1988;7:118-25.
28. The Italian Multicenter Project for Propranolol in Prevention of Bleeding. Propranolol prevents first gastrointestinal bleeding in non-ascitic cirrhotic patients. Final report of a multicenter randomized trial. J Hepatol 1989;9:75-83.
29. Colman J, Jones P, Finch C, Dudley F. Propanolol in the prevention of variceal hemorrhage in alcoholic cirrhotic patients. Hepatology 1990;12:851.
30. Andreani T, Poupon RE, Balkau BJ, Trinchet JC, Grange JD, Peigney N et al. Preventive therapy of first gastrointestinal bleeding in patients with cirrhosis: results of a controlled trial comparing propanolol, endoscopic sclerotherapy and placebo. Hepatology 1990;12:1413-9.
31. Conn HO, Grace ND, Bosch J, Groszmann RJ, Rodes J, Wright SC et al. Propanolol in the prevention of the first hemorraghe from esophagogastric varices: a multicenter, randomized clinical trial. The Boston-New Haven-Barcelona Portal hypertension study group. Hepatology 1991;13:902-12.
32. The PROVA Study Group. Prophylaxis of first hemorrhage from esophagal varices by sclerotherapy, propanolol or both in cirrhotic patients: a randomized multicenter trial. Hepatology 1991;14:1016-24.
33. Van Buuren HR. The results of two long-term randomized controlled trials evaluating endoscopic sclerotherapy and propanolol as prophylaxis for variceal bleeding. J Hepatol 1995;23:114.
34. Abraczinskas DR, Ookubo R, Grace ND, Groszmann RJ, Bosch J, Garcia-Tsao G et al. Propanolol for the prevention of first esophageal variceal hemorrhage: a lifetime commitment? Hepatology 2001;34:1096-102.
35. De Franchis R. Updating consensus in portal hypertension: report of the Baveno III consensus workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol 2000;33:846-52.
36. D'Amico G, Garcia-Tsao G, Gales P. Diagnosis of portal hypertension: how and when. In: De Franchis R., editor. Proceedings of the third Baveno international consensus workshop on definitions, methodology, and therapeutic strategies. Oxford: Blackwell-Science; 1996.
37. Merli M, Nicolini G, Angeloni S, Rinaldi V, De Santis A, Merkel C et al. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 2003;38:266-72.
38. Schepis F, Gamma C, Niceforo D, Magnano A, Pallio S, Cinquegrani M et al. Which patients should undergo endoscopic screening for esophageal varices detection. Hepatology 2001;33:333-8.
39. Burroughs AK, Jenkins WJ, Sherlock S, Dunk A, Walt RP, Osuafor TO et al. Controlled trial of propanolol for the prevention of recurrent variceal hemorrhage in patients with cirrhosis. N Engl J Med 1983;309:1539-42.
40. Villeneuve JP, Pomier-Layrargues G, Infante-Rivard C, Willems B, Huet PM, Marleau D et al. Propanolol for the prevention of recurrent variceal rebleeding in cirrhosis: a controlled trial. Hepatology 1986;6:1239-43.
41. Cerebelaud P, La Vignolle A, Perrin D. Propanolol et prevention des récidives de rupture de varice oesophagienne du cirrhotique. Gastroenterol Clin Biol 1986;18:A10.
42. Queuniet AM, Czernichow P, Lerebours E, Ducrotte P, Tranvouez JL, Colin R. [Controlled study of propranolol in the prevention of recurrent hemorrhage in cirrhotic patients]. Gastroenterol Clin Biol 1987;11:41-7.
43. Gatta A, Merkel C, Sacerdoti D, Bolognesi M, Caregaro L, Zuin R et al. Nadolol for the prevention of variceal rebleeding in cirrhosis: a controlled clinical trial. Digestion 1987;37:22-8.
44. Kobe E, Schentke KU. Unsichere Rezidivprophylaxe von Ö sophagusvarizenblutungen durch Propanolol bei Leberzirrhotikern: eine prospektive kontrollierte Studie. Z Klin Med 1987;42:507-10.
45. Colombo M, de Franchis R, Tommasini M, Sangiovanni A, Dioguardi N. Beta-blockade prevents recurrent gastrointestinal bleeding in well compensated patients with alcoholic cirrhosis: a multicenter randomized controlled trial. Hepatology 1989;9:433-8.
46. Sheen IS, Chen TY, Liaw YF. Randomized controlled study of propanolol for prevention of recurrent esophageal varices bleeding in patients with cirrhosis. Liver 1989;9:1-5.
47. Garden OJ, Mills PR, Birnie GG, Murray GD, Carter DC. Propanolol in the prevention of recurrent variceal hemorrhage in cirrhotic patients. A controlled trial. Gastroenterology 1990;98:185-90.
48. Rossi V, Cales P, Burtin P, Chameau J, Person B, Pujol P et al. Prevention of recurrent variceal bleeding in alcoholic cirrhotic patients: prospective controlled trial of propanolol and sclerotherapy. J Hepatol 1991;12: 283-9.
49. Bernard B, Lebrec D, Mathurin P, Opolon P, Poynard T. Beta-adrenergic antagonists in the prevention of gastrointestinal rebleeding in patients with cirrhosis: a meta-analysis. Hepatology 1997;25:63-70.
50. Garcia-Pagan JC, Navasa M, Rivera F, Bosch J, Rodes J. Beta-2-adrenoreceptors and plasma catecholamines in patients with cirrhosis. Relationship with the hemodynamic response to propanolol. Gastroenterology 1992;102:2015-23.
51. Pizcueta MP, de Lacy AM, Kravetz D, Bosch J, Rodes J. Propanolol decreases portal pressure without changing portocollateral resistance in cirrhotic rats. Hepatology 1989;10:953-7.
52. Bhatal PS, Grossmann HJ. Reduction of increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1985;1:325-9.
53. Navasa M, Chesta J, Bosch J, Rodes J. Reduction of portal pressure by isosorbide-5-mononitrate in patients with cirrhosis. Effect on splanchnic and systemic hemodynamics and liver function in patients with cirrhosis and portal hypertension. Gastroenterology 1989;96:1110-8.
54. Salmeron JM, Ruiz del Arbol L, Gines A, Garcia-Pagan JC, Gines P, Feu F et al. Renal effects of acute isosorbide-5-mononitrate administration in cirrhosis. Hepatology 1993;17:800-6.
55. Angelico M, Carli L, Piat C, Gentile S, Rinaldi V, Bologna E et al. Isosorbide-5-mononitrate compared with propanolol in the prevention of first variceal bleeding in cirrhosis. Gastroenterology 1993;104:1460-5.
56. Angelico M, Carli L, Piat C, Gentile S, Capocaccia L. Effects of isosorbide-5-mononitrate compared with propanolol on first bleeding and long term survival in cirrhosis. Gastroenterology 1997;113:1632-9.
57. Salerno F, Borroni G, Cazzaniga M. Nadolol and isosorbide-5-mononitrate for preventing bleeding in cirrhotics with ascites. J Hepatol 1996;25 Suppl 1:92.
58. Garcia-Pagan JC for the Spanish Variceal Bleeding Study Group. Isosorbide-5-mononitrate vs placebo in the prevention of the first variceal bleeding in patients with contraindications or intolerance to beta-blockers. J Hepatol 2000;32 Suppl 2:28A.
59. Merkel C, Marin R, Enzo E, Donada C, Cavallarin G, Torboli P et al. Randomized trial of nadolol alone or with isosorbide-5-mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Lancet 1996;348:1677-81.
60. Merkel C, Marin R, Sacerdoti D, Donada C, Cavallarin G, Torboli P et al. Long-term results of a clinical trial of nadolol with and without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2000;31:324-9.
61. Garcia-Pagan JC, Morillas R, Banares R, Albillos A, Villanueva C, Vila C et al. Propanolol plus placebo vs propanolol plus isosorbide-5-mononitrate in the prevention of the first variceal bleeding. A multicenter double-blind randomized controlled trial. Hepatology 2003;37:1260-6.
62. Pietrosi G, D'Amico G, Pasta L. Isosorbide mononitrate with nadolol compared to nadolol alone for the prevention of first variceal bleeding in cirrhosis. A double-blind placebo-controlled randomized trial. J Hepatol 1999;30:55.
63. Garcia-Pagan JC, Feu F, Bosch J, Rodes J. Propanolol compared with propanolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis. Ann Intern Med 1991;114:869-73.
64. Merkel C, Sacerdoti D, Bolognesi M, Enzo E, Marin R, Bombonato G et al. Hemodynamic evaluation of the addition of isosorbide-5-mononitrate to nadolol in cirrhotic patients with insufficient response to beta-blocker alone. Hepatology 1997;26:34-9.
65. Kroeger RJ, Groszmann RJ. Increaded portal venous resistance hinders portal pressure reduction during the administration of beta-adrenergic blocking agents in a portal hypertensive model. Hepatology 1985;5:97-101.
66. Escorsell A, Ferayorni L, Bosch J, Garcia-Pagan JC, Garcia-Tsao G, Grace ND et al. The portal pressure response to beta-blockade is greater in cirrhotic patients without varices than in those with varices. Gastroenterology 1997;112:2012-6.
67. Pasta L, D'Amico G, Patti R. Isosorbide mononitrate with nadolol compared with nadolol alone for the prevention of recurrent bleeding in cirrhosis. A double-blind placebo-controlled randomized trial. J Hepatol 1999;30:81A.
68. Gournay J, Masliah C, Martin T, Perrin D, Galmiche JP. Isosorbide mononitrate and propanolol compared with propanolol alone for the prevention of variceal rebleeding. Hepatology 2000;31:1239-45.
69. Bureau C, Peron JM, Alric L, Morales J, Sanchez J, Barange K et al. A la carte treatment for portal hypertension: adapting medical therapy to hemodynamic response for the prevention of bleeding. Hepatology 2002;36:1361-6.
70. Grace ND, Groszmann RJ, Garcia-Tsao G, Burroughs AK, Pagliaro L, Makuch RW et al. Portal hypertension and variceal bleeding: an AASLD single topic symposium. Hepatology 1998;28:868-80.
71. Boyer TD. Changing clinical practice with measurements of portal pressure. Hepatology 2004;39:283-5.
72. Nevens F, Rutgeerts P. Variceal band ligation in the management of bleeding oesophageal varices: an overview. Dig Liver Dis 2001;33:284-7.
73. Nevens F. Gastrointestinal hemorrhage. Which indications for endoscopic treatments? Gastroenterol Clin Biol 2004;28:190-3.
74. Imperiale TF, Chalasani N. A meta-analysis of endoscopic variceal ligation for primary prophylaxis of esophageal variceal bleeding. Hepatology 2001;33:802-7.
75. Lo GH, Chen WC, Chen MH, Hsu PI, Lin CK, Tsai WL et al. Banding ligation versus nadolol and isosorbide mononitrate for the prevention of esophageal variceal rebleeding. Gastroenterology 2002;123:728-34.
76. Patch D, Sabin CA, Goulis J, Gerunda G, Greenslade L, Merkel C et al. A randomized, controlled trial of medical therapy versus endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis. Gastroenterology 2002;123:1013-9.
77. Villanueva C, Minana J, Ortiz J, Gallego A, Soriano G, Torras X et al. Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding. N Engl J Med 2001;345:647-55.
78. Lo GH, Lai KH, Cheng JS, Chen MH, Huang HC, Hsu PI et al. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial. Hepatology 2000;32:461-5.
79. De Franchis R. Portal hypertension. II. Proceedings of the Second Baveno International Consensus Workshop on Definitions, Methodology and Therapeutic strategies. Oxford: Blackwell; 1996.
80. Maleux G, Nevens F, Wilmer A, Heye S, Verslype C, Thijs M et al. Early and long-term clinical and radiological follow-up results of expanded-polytetrafluoroethylene-covered stem-grafts for transjugular intrahepatic portosystemic shunt procedures. Eur Radiol 2004;14:1842-50.
81. Zhang JX, Pegoli WJ, Clemens MG. Endothelin-1 induces direct constriction of the hepatic sinusoids. Am J Physiol 1994;266:G624-32.
82. Kawada N, Tran-Thi TA, Klein H, Decker C. The contraction of hepatic stellate (Ito) cells stimulated with vasoactive substances. Possible involvement of endothelin-1 and nitric oxide in the regulation of the sinusoidal tonus. Eur J Biochem 1993;213:815-23.
83. Rockey DC, Housset CN, Friedman SL. Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo. J Clin Invest 1993;92:1795-804.
84. Cassiman D, Roskams T. Beauty is in the eye of the beholder: emerging concepts and pitfalls in hepatic stellate cell research. J Hepatol 2002;37:527-35.
85. Friedman SL. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med 1993;328:1828-35.
86. Pinzani M, Failli P, Ruocco C, Casini A, Milani S, Baldi E et al. Fat-storing cells as liver-specific pericytes. Spatial dynamics of agonist-stimulated intracellular calcium transients. J Clin Invest 1992;90:642-6.
87. Rockey DC. Vascular mediators in the injured liver. Hepatology 2003;37:4-12.
88. Van de Casteele M, Omasta A, Janssens S, Roskams T, Desmet V, Nevens F 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.
89. Shah V, Toruner M, Haddad F, Cadelina G, Papapetropoulos A, Choo K et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology 1999;117:1222-8.
90. Morales-Ruiz M, Cejudo-Martin P, Fernandez-Varo G, Tugues S, Ros J, Angeli P et al. Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats. Gastroenterology 2003;125:522-31.
91. 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.
92. Laleman W, Omasta A, Van de Casteele M, Zeegers M, Vander Elst I, Van Landeghem L et al. A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis. Hepatology 2005;42:1382-90.
93. Langer DA, Shah VH. A gas, an amino acid, and an imposter: the story of nitric oxide, L-arginine, and ADMA in portal hypertension. Hepatology 2005;42:1255-7.
94. Van De Casteele M, Van Pelt JF, Nevens F, Fevery J, Reichen J. Low NO bioavailability in CC14 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.
95. Graupera M, Garcia-Pagan JC, Pares M, Abraldes JG, Rosello J, Bosch J et al. Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers. J Hepatol 2003;39:515-21.
96. Vorobioff J, Bredfeldt J, Groszmann RJ. Hyperdynamic circulation in a portal hypertensive rat model: a primary factor for the maintenance of chronic portal hypertension. Am J Physiol 1983;244:G52-6.
97. Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 2002;35:478-91.
98. Sikuler E, Groszmann RJ. Interaction of flow and resistance in maintenace of portal hypertension in a rat model. Am J Physiol 1986;250:G205-12.
99. Möller S, Bendtsen F, Henriksen JH. Vasoactive substances in the circulatory dysfunction of cirrhosis. Scand J Clin Lab Invest 2001;61:421-30.
100. Benoit JN, Barrowman JA, Harper SL, Kvietys PR, Granger DN. Role of humoral factors in the intestinal hyperemia associated with chronic portal hypertension. Am J Physiol 1984;247:E486-93.
101. Genecin P, Polio J, Colombato LA, Ferraioli G, Reuben A, Groszmann RJ. Role of bile acids do not mediate the hyperdynamic circulation in portal hypertensive rats. Am J Physiol 1990;259:G21-5.
102. Thomas SH, Joh T, Benoit JN. Role of bile acids in splanchnic hemodynamic response to chronic portal hypertensive rats. Dig Dis Sci 1991;36:1243-8.
103. Fernandez M, Casadevall M, Schuligoi R, Pizcueta P, Panes J, Barrachina MD et al. Neonatal capsaicin treatment does not prevent splanchnic vasodilation in portal hypertensive rats. Hepatology 1994;20:1609-14.
104. Lee SS, Sharkey KA. Capsaicin treatment blocks development of hyperkinetic circulation in portal hypertensive rats. Am J Physiol 1993;264:G868-73.
105. Gomis R, Fernandez-Alvarez J, Pizcueta P, Fernandez M, Casamitjana R, Bosch J et al. Impaired function of pancreatic islets from rats with portal hypertension resulting from cirrhosis and partial vein ligation. Hepatology 1994;19:1257-61.
106. Silva G, Navasa M, Bosch J, Chesta J, Pilar Pizcueta M, Casamitjana R et al. Hemodynamic effects of glucagon in portal hypertension. Hepatology 1990;11:668-73.
107. Kravetz D, Bosch J, Arderiu MT, Pizcueta MP, Casamitjana R, Rivera F et al. Effects of somatostatin on splanchnic hemodynamics and plasma glucagons in portal hypertensive rats. Am J Physiol 1988;254:G322-5.
108. Benoit JN, Zimmerman B, Premen AJ, Go VL, Granger DN. Role of glucagons in splanchnic hyperemia of chronic portal hypertension. Am J Physiol 1986;251:G674-8.
109. Fernandez M, Garcia-Pagan JC, Casadevall M, Mourelle MI, Pique JM, Bosch J et al. Acute and chronic cyclooxygenase blockade in portal hypertensive rats: influence on nitric oxide biosynthesis. Gastroenterology 1996;110:1529-35.
110. Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet 1991;1:776.
111. Martin PY, Xu DL, Niederberger M, Weigert A, Tsai P, St John J et al. Upregulation of endothelial constitutive NOS: a major role in the increased NO production in cirrhotic rats. Am J Physiol 1996;270:F494-9.
112. Fernandez M, Garcia-Pagan JC, Casadevall M, Bernadich C, Piera C, Whittle BJ et al. Evidence against a role for inducible nitric oxide synthase in the hyperdynamic circulation of portal hypertensive rats. Gastroenterology 1995;108:1487-95.
113. Blendis L, Wong F. The hyperdynamic circulation in cirrhosis: an overview. Pharm Therap 2001;89:221-31.
114. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988;8:1151-7.
115. Arroyo V, Jimenez W. Complications of cirrhosis. II. Renal and circulatory dysfunction. Light and shadows in an important clinical problem. J Hepatol 2000;32 Suppl 1:157-70.
116. Pizcueta P, Pique JM, Fernandez M, Bosch J, Rodes J, Whittle BJ et al. Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition. Gastroenterology 1992;103:1909-15.
117. Niederberger M, Martin PY, Gines P, Morris K, Tsai P, Xu DL et al. Normalization of nitric oxide production corrects arterial vasodilation and hyperdynamic circulation in cirrhotic rats. Gastroenterology 1995;109:1624-30.
118. Sieber CC, Sumanovski LT, Moll-Kaufmann C, Stalder GA. Hyposensitivity to nerve stimulation in portal hypertensive rats: role of nitric oxide. Eur J Clin Invest 1997;27:902-7.
119. Sieber CC, Lopez-Talavera JC, Groszmann RJ. Role of nitric oxide in the in vitro splanchnic vascular hyporeactivity in ascitic cirrhotic rats. Gastroenterology 1993;104:1750-4.
120. Wiest R, Hori N, Cadelina G, Garcia-Tsao G, Milstien S, Groszmann RJ. Increased nitric oxide release in response to vasoconstrictors in the superior mesenteric arterial bed of cirrhotic rats. Hepatology 1997;26:A390.
121. Yu Q, Shao R, Qian HS, George SE, Rockey DC. Gene transfer of the neuronal NO synthase isoform to cirrhotic rat liver ameliorates portal hypertension. J Clin Invest 2000;105:741-8.
122. Rockey DC. Cellular pathophysiology of portal hypertension and prospects for management with gene therapy. Clin Liv Dis 2001;5:851-65.
123. Zafra C, Abraldes JG, Turnes J, Berzigotti A, Fernandez M, Garca-Pagan JC et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology 2004;126:749-55.
124. Yanase M, Ikeda H, Matsui A, Noiri E, Tomiya T, Arai M et al. HMG-COA reductase inhibitor modulates collagen gel-contraction by hepatic myofibroblast-like stellate cell line: involvement of geranylgeranylated proteins. Comp Hepatol 2004;3:S21.
125. Zhou Q, Hennenberg M, Trebicka J, Jochem K, Leifeld L, Biecker E et al. Intrahepatic upregulation of RhoA and Rho-kinase signalling contributes to increased hepatic vascular resistance in rats with secondary biliary cirrhosis. Gut 2006 [Epub ahead of print].
126. Fiorucci S, Antonelli E, Brancaleone V, Sanpaolo L, Orlandi S, Distrutti E et al. NCX-1000, a nitric oxide releasing derivative of ursodeoxycholic acid, ameliorates portal hypertension and lowers norepinephrine-induced intrahepatic resistance in the isolated and perfused rat liver. J Hepatol 2003;39:932-9.
127. Loureira-Silva MR, Cadelina GW, Iwakiri Y, Groszmann RJ. A liver-specific nitric oxide donor improves the intrahepatic vascular response to both portal blood flow increase and methoxamine in cirrhotic rats. J Hepatol 2003;39:940-6.
128. Rockey DC, Chung JJ. Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing. J Clin Invest 1996;98:1381-8.
129. Kojima H, Sakurai S, Kuriyama S, Yoshiji H, Imazu H, Uemura M et al. Endothelin-1 plays a major role in portal hypertension of biliary cirrhotic rats through endothelin receptor subtype B togheter with subtype A in vivo. J Hepatol 2001;34:805-11.
130. Reichen J, Gerbes AL, Steiner MJ, Sagesser H, Clozel M. The effect of endothelin and its agonist bosentan on hemodynamics and microvascular exchange in cirrhotic rat liver. J Hepatol 1998;28:1020-30.
131. Sogni P, Moreau R, Gomola A, Gadano A, Cailmail S, Calmus Y et al. Beneficial effects of bosentan, a mixed ET(A) and ET(B) receptor antagonist, in portal hypertensive rats. Hepatology 1998;28:655-9.
132. Poo JL, Jimenez W, Maria Munoz R, Bosch-Marce M, Bordas N, Morales-Ruiz M et al. Chronic blockade of endothelin receptors in cirrhotic rats: hepatic and hemodynamic effects. Gastroenterology 1999;116:161-7.
133. Cho JJ, Hocher B, Herbst H, Jia JD, Ruehl M, Hahn EG et al. An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis. Gastroenterology 2000;118:1169-78.
134. Channinck RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:S62-7.
135. Arroyo V, Bosch J, Mauri M, Viver J, Mas A, Rivera F et al. Effect of angiotensin-II blockade on systemic and hepatic hemodynamics and on the renin-angiotensin-aldosterone system in cirrhosis with ascites. Eur J Clin Invest 1981;11:221-9.
136. Schepke M, Werner E, Biecker E, Schiedermaier P, Heller J, Neef M et al. Hemodynamic effects of the angiotensin II receptor antagonist irbesartan in patients with cirrhosis and portal hypertension. Gastroenterology 2001;121:389-95.
137. Gonzalez-Abraldes J, Albillos A, Banares R, Del Arbol LR, Moitinho E, Rodriguez C et al. Randomized comparison of long-term losartan versus propanolol in lowering portal pressure in cirrhosis. Gastroenterology 2001;121:382-8.
138. Debernardi-Venon W, Barletti C, Alessandria C, Marzano A, Baronio M, Todros L et al. Efficacy of irbesartan, a receptor selective antagonist of angiotensin II, in reducing portal hypertension. Dig Dis Sci 2002;47:401-4.
139. Friedman SL. The answer: angiotensin II. The question: what do inflammation, oxidant stress and fibrogenesis have in common. J Hepatol 2004;40:1050-2.
140. Albillos A, Lledo JL, Rossi I, Perez-Paramo M, Tabuenca MJ, Banares R et al. Continuous prazosin administration in cirrhotic patients: effects on portal hemodynamics and on liver and renal function. Gastroenterology 1995;109:1257-65.
141. Albillos A, Garcia-Pagan JC, Iborra J, Bandi JC, Cacho G, Perez-Paramo M et al. Propanolol plus prazosin compared with propanolol plus isosorbide-5-mononitrate in the treatment of portal hypertension. Gastroenterology 1998;115:116-23.
142. Frishman WH. Carvedilol. N Engl J Med 1998;339:1759-65.
143. Lopez-Parra M, Claria J, Planaguma A, Titos E, Masferrer JL, Woerner BM et al. Cyclooxygenase-1 derived prostaglandins are involved in the maintenance of renal function in rats with cirrhosis and ascites. Br J Pharmacol 2002;135:891-900.
144. Hemstreet BA. Evaluation of carvedilol for the treatment of portal hypertension. Pharmacotherapy 2004;24:94-104.
145. Nevens F, Sprengers D, Fevery J. The effect of different doses of a bolus injection of somatostatin combined with a slow infusion on transmural oesophageal variceal pressure in patients with cirrhosis. J Hepatol 1994;20:27-31.
146. Avgerinos A, Nevens F, Raptis S, Fevery J. Early administration of somatostatin and efficacy of sclerotherapy in acute oesophageal variceal bleeds: the European Acute Bleeding Oesophageal Variceal Episodes (ABOVE) randomised trial. Lancet 1997;350:1495-9.
147. Nevens F. Review article: a critical comparison of drug therapies in currently used therapeutic strategies for variceal hemorrhage. Aliment Pharmacol Ther 2004;20 Suppl 3:18-22.
148. Reynaert H, Geerts A. Review article: pharmacological rationale for the use of somatostatin and analogues in portal hypertension. Aliment Pharmacol Ther 2003;18:375-86.
149. Abraldes JG, Bosch J. Somatostatin and analogues in portal hypertension. Hepatology 2002;35:1305-12.
150. Nakabayashi H, Nijima A, Kurata Y. Somatostatin-sensitive neural system in the liver. Neurosci Lett 1986;67:78-81.
151. Claria J, Kent JD, Lopez-Parra M, Escolar G, Ruiz-Del-Arbol L, Gines P et al. Effects of celecoxib and naproxen on renal function in nonazotemic patients with cirrhosis and ascites. Hepatology 2005;41:579-87.
152. Pilette C, Kirstetter P, Sogni P, Cailmail S, Moreau R, Lebrec D. Dose-dependent effects of a nitric oxide biosynthesis inhibitor on hyperdynamic circulation in two models of portal hypertension in conscious rats. J Gastroenterol Hepatol 1996;11:1-6.
153. Pizcueta P, Pique JM, Fernandez M, Bosch J, Rodes J, Whittle BJ et al. Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition. Gastroenterology 1992;103:1909-15.
154. Forrest EH, Jones AL, Dillon JF, Walker J, Hayes PC. The effect of nitric oxide synthase inhibition on portal pressure and azygos blood flow in patients with cirrhosis. J Hepatol 1995;23:254-8.