Vasoconstrictors have long been used in an attempt to mitigate the effects of portal hypertension. In this review, we discuss the current understanding of portal hypertension and the use of vasoconstrictors in the management of its sequlae, including variceal hemorrhage, hepatorenal syndrome, and paracentesis-induced circulatory dysfunction. Experimental and clinical evidence for the use of vasoconstrictors is considered, and several exciting recent developments are reviewed.
Albillos, A., Garcia-Pagan, J.C., Iborra, J., Bandi, J.C., Cacho, G., Perez-Paramo, M. et al. (1998) Propranolol plus prazosin compared with propranolol plus isosorbide-5-mononitrate in the treatment of portal hypertension , Gastroenterology115: 116-123.
2.
Albillos, A., Lledo, J.L., Rossi, I., Perez-Paramo, M., Tabuenca, M.J., Banares, R. et al. (1995) Continuous prazosin administration in cirrhotic patients: effects on portal hemodynamics and on liver and renal function, Gastroenterology109: 1257-1265.
3.
Alessandria, C., Venon, W.D., Marzano, A., Barletti, C., Fadda, M. and Rizzetto, M. (2002) Renal failure in cirrhotic patients: role of terlipressin in clinical approach to hepatorenal syndrome type 2, Eur J Gastroenterol Hepatol14: 1363-1368.
4.
Angeli, P., Volpin, R., Gerunda, G., Craighero, R., Roner, P., Merenda, R. et al. (1999) Reversal of type-1 hepatorenal syndrome with the administration of midodrine and octreotide, Hepatology29: 1690-1697.
5.
Appenrodt, B., Wolf, A., Grunhage, F., Trebicka, J., Schepke, M., Rabe, C. et al. (2008) Prevention of paracentesis-induced circulatory dysfunction: midodrine vs albumin. A randomized pilot study, Liver Int28: 1019-1025.
6.
Arroyo, V., Gines, P., Gerbes, A.L., Dudley, F.J., Gentilini, P., Laffi, G. et al. (1996) Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club , Hepatology23: 164-176.
7.
Ballet, F., Chretien, Y., Rey, C. and Poupon, R. (1988) Differential response of normal and cirrhotic liver to vasoactive agents - a study in the isolated perfused rat-liver, J Pharmacol Exp Ther244: 283-289.
8.
Banares, R., Albillos, A., Rincon, D., Alonso, S., Gonzalez, M., Ruiz-del-Arbol, L. et al. (2002) Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: A meta-analysis, Hepatology35: 609-615.
9.
Banares, R., Moitinho, E., Piqueras, B., Casado, M., Garcia-Pagan, J.C., de Diego, A. et al. (1999) Carvedilol, a new nonselective beta-blocker with intrinsic anti-alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrosis, Hepatology30: 79-83.
10.
Batkai, S., Jarai, Z., Wagner, J.A., Goparaju, S.K., Varga, K., Liu, J. et al. (2001) Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis, Nat Med7: 827-832.
11.
Bhathal, P.S. and Grossman, H.J. (1985) Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators, J Hepatol1: 325-337.
12.
Bosch, J., Bordas, J.M., Mastai, R., Kravetz, D., Navasa, M., Chesta, J. et al. (1988) Effects of vasopressin on the intravariceal pressure in patients with cirrhosis: comparison with the effects on portal pressure, Hepatology8: 861-865.
13.
Bosch, J. and Garcia-Pagan, J.C. (2000) Complications of cirrhosis. 1. Portal hypertension, J Hepatol32: 141-156.
14.
Bosch, J., Groszmann, R.J., Garcia-Pagan, J.C., Teres, J., Garcia-Tsao, G., Navasa, M. et al. (1989) Association of transdermal nitroglycerin to vasopressin infusion in the treatment of variceal hemorrhage: a placebo-controlled clinical trial, Hepatology10: 962-968.
15.
Bosch, J., Kravetz, D. and Rodes, J. (1981) Effects of somatostatin on hepatic and systemic hemodynamics in patients with cirrhosis of the liver: comparison with vasopressin , Gastroenterology80: 518-525.
16.
Burroughs, A.K., McCormick, P.A., Hughes, M.D., Sprengers, D., D'Heygere, F. and McIntyre, N. (1990) Randomized, double-blind, placebo-controlled trial of somatostatin for variceal bleeding. Emergency control and prevention of early variceal rebleeding, Gastroenterology99: 1388-1395.
17.
Cahill, P.A., Redmond, E.M., Hodges, R., Zhang, S. and Sitzmann, J.V. (1996) Increased endothelial nitric oxide synthase activity in the hyperemic vessels of portal hypertensive rats, J Hepatol25: 370-378.
18.
Cardenas, A. and Arroyo, V. (2003) Mechanisms of water and sodium retention in cirrhosis and the pathogenesis of ascites, Best Pract Res Clin Endocrinol Metab17: 607-622.
19.
Chalasani, N., Kahi, C., Francois, F., Pinto, A., Marathe, A., Bini, E.J. et al. (2003) Improved patient survival after acute variceal bleeding: a multicenter, cohort study, Am J Gastroenterol98: 653-659.
20.
Cheng, Y.Q., Ndisang, J.F., Tang, G.H., Cao, K. and Wang, R. (2004) Hydrogen sulfide-induced relaxation of resistance mesenteric artery beds of rats, Am J Physiol Heart Circ Physiol287: H2316-H2323.
21.
Colle, I., Durand, F., Pessione, F., Rassiat, E., Bernuau, J., Barriere, J. et al. (2002) Clinical course, predictive factors and prognosis in patients with cirrhosis and type 1 hepatorenal syndrome treated with terlipressin: A retrospective analysis, J Gastroenterol Hepatol17: 882-888.
22.
D'Amico, G. and Luca, A. (1997) Natural history. Clinical-haemodynamic correlations . Prediction of the risk of bleeding, Baillieres Clin Gastroenterol11: 243-256.
23.
D'Amico, G., Pagliaro, L. and Bosch, J. (1995) The treatment of portal hypertension: a meta-analytic review, Hepatology22: 332-354.
24.
D'Amico, G., Traina, M., Vizzini, G., Tine, F., Politi, F., Montalbano, L. et al. (1994) Terlipressin or vasopressin plus transdermal nitroglycerin in a treatment strategy for digestive bleeding in cirrhosis. A randomized clinical trial. Liver Study Group of V. Cervello Hospital, J Hepatol20: 206-212.
25.
Duvoux, C., Zanditenas, D., Hezode, C., Chauvat, A., Monin, J.L., Roudot-Thoraval, F. et al. (2002) Effects of noradrenalin and albumin in patients with type-1 hepatorenal syndrome: a pilot study, Hepatology36: 374-380.
26.
Escorsell, A., Bandi, J.C., Andreu, V., Moitinho, E., Garcia-Pagan, J.C. and Bosch, J. (2001) Desensitization to the effects of intravenous octreotide in cirrhotic patients with portal hypertension, Gastroenterology120: 161-169.
27.
Esrailian, E., Pantangco, E.R., Kyulo, N.L., Hu, K. and Runyon, B. (2007) Octreotide/midodrine therapy significantly improves renal function and 30-day survival in patients with type-1 hepatorenal syndrome , Dig Dis Sci52: 742-748.
28.
Fernandez, J., Navasa, M., Garcia-Pagan, J.C., G-Abraldes, J., Jimenez, W., Bosch, J. et al. (2004) Effect of intravenous albumin on systemic and hepatic hemodynamics and vasoactive neurohormonal systems in patients with cirrhosis and spontaneous bacterial peritonitis, J Hepatol33: 423-429.
29.
Fernandez, M., Garcia-Pagan, J.C., Casadevall, M., Mourelle, M.I., Pique, J.M., Bosch, J. et al. (1996) Acute and chronic cyclooxygenase blockage in portal-hypertensive rats: influence in nitric oxide biosynthesis, Gastroenterology110: 1529-1535.
30.
Fernandez, M., Lambrecht, R.W. and Bonkovsky, H.L. (2001) Increased heme oxygenase activity in splanchnic organs from portal hypertensive rats: role in modulating mesenteric vascular reactivity, J Hepatol34: 812-817.
31.
Fernandez-Seara, J., Prieto, J., Quiroga, J., Zozaya, J.M., Cobos, M.A., Rodriguez-Eire, J.L. et al. (1989) Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure , Gastroenterology97: 1304-1312.
32.
Garcia-Pagan, J.C., Escorsell, A., Moitinho, E. and Bosch, J. (1999) Influence of pharmacological agents on portal hemodynamics: basis for its use in the treatment of portal hypertension, Semin Liver Dis19: 427-438.
33.
Garcia-Pagan, J.C., Villanueva, C., Albillos, A., Banares, R., Planas, R., Casado, M. et al. (2006) Nadolol + isosorbide-5-mononitrate (NAD+ISMN) vs. NAD+ISMN + endoscopic band ligation in the prevention of rebleeding in patients with cirrhosis. Preliminary results of a multicenter RCT [Abstract] , J Hepatol44: S11.
34.
Garcia-Tsao, G., Sanyal, A.J., Grace, N.D., Carey, W., Practice Guidelines Committee of the American Association for the Study of Liver Disease and Practice Parameters Committee of the American College of Gastroenterology (2007) Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis , Hepatology46: 922-938.
35.
Gimson, A.E., Westaby, D., Hegarty, J., Watson, A. and Williams, R. (1986) A randomized trial of vasopressin and vasopressin plus nitroglycerin in the control of acute variceal hemorrhage, Hepatology6: 410-413.
36.
Gines, A., Escorsell, A., Gines, P., Salo, J., Jimenez, W., Inglada, L. et al. (1993) Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites, Gastroenterology105: 229-236.
37.
Gines, A., Salmeron, J.M., Gines, P., Jimenez, W., Salo, J., Piera, C. et al. (1992) Effects of somatostatin on renal function in cirrhosis, Gastroenterology103: 1868-1874.
38.
Gines, P., Tito, L., Arroyo, V., Planas, R., Panes, J., Viver, J. et al. (1988) Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis, Gastroenterology94: 1493-502.
39.
Gonzalez, R., Zamora, J., Gomez-Camarero, J., Molinero, L., Banares, R. and Albillos, A. (2008) Meta-analysis: Combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis, Ann Int Med149: 109-122.
40.
Gotzsche, P.C. and Hrobjartsson, A. (2008) Somatostatin analogues for acute bleeding oesophageal varices, Cochrane Syst Rev 3: CD000193.
41.
Grace, N.D. (1992) Prevention of initial variceal hemorrhage, Gastroenterol Clin North Am21: 149-161.
42.
Graupera, M., Garcia-Pagan, J.C., Abraldes, J.G., Peralta, C., Bragulat, M., Corominola, H. et al. (2003) Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers, Hepatology37: 172-181.
43.
Gupta, T., Chen, L. and Groszmann, R. (1997) Pathophysiology of portal hypertension, Baillieres Clin Gastoenterol11: 203-219.
44.
Gupta, T.K., Toruner, M., Chung, M.K. and Groszmann, R.J. (1998) Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats, Hepatology28: 926-931.
45.
Hidaka, H., Kokubu, S., Nakazawa, T., Okuwaki, Y., Ono, K., Watanabe, M. et al. (2007) New angiotensin II type 1 receptor blocker olmesartan improves portal hypertension in patients with cirrhosis, Hepatol Res37: 1011-1017.
46.
Imperiale, T.F., Teran, J.C. and McCullough, A.J. (1995) A meta-analysis of somatostatin versus vasopressin in the management of acute esophageal variceal hemorrhage , Gastroenterology109: 1289-1294.
47.
Ink, O., Martin, T., Poynard, T., Reville, T., Anciaux, M.L. and Lenoir, C. (1992) Does elective sclerotherapy improve the efficacy of long-term propranolol for prevention of recurrent bleeding in patients with severe cirrhosis? A prospective multicenter, randomized trial, Hepatology16: 912-919.
48.
Ioannou, G., Doust, J. and Rockey, D.C. (2003) Systematic review: Terlipressin in acute oesophageal variceal haemorrhage, Aliment Pharmacol Ther17: 53-64.
49.
Krag, A., Bendtsen, F., Pedersen, E.B., Holstein-Rathlou, N.H. and Moller, S. (2008) Effects of terlipressin on the aquaretic system - evidence of antidiuretic effects, Am J Physiol Renal Physiol295: F1295-F1300.
50.
Levacher, S., Letoumelin, P., Pateron, D., Blaise, M., Lapandry, C. and Pourriat, J.L. (1995) Early administration of terlipressin plus glyceryl trinitrate to control active upper gastrointestinal bleeding in cirrhotic patients, Lancet346: 865-868.
51.
Lo, G.H., Chen, M.H. and Lai, K.H. (2005) A randomized, controlled trial of banding ligation plus drug therapy vs. drug therapy alone in the prevention of esophageal variceal rebleeding [Abstract], Gut54: A78.
52.
Martin-Llahi, M., Pepin, M., Guevara, M., Diaz, F., Torre, A., Monescillo, A. et al. (2008) Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study, Gastroenterology134: 1352-1359.
53.
McCormick, P.A., Biagini, M.R., Dick, R., Greenslade, L., Chin, J., Cardin, F. et al. (1992) Octreotide inhibits the meal-induced increases in the portal venous pressure of cirrhotic patients with portal hypertension: a double-blind, placebo-controlled study, Hepatology16: 1180-1186.
54.
Moitinho, E., Planas, R., Banares, R., Albillos, A., Ruiz del Arbol, L., Galvez, C. et al. (2001) Multicenter randomized controlled trial comparing different schedules of somatostatin in the treatment of acute variceal bleeding, J Hepatol35: 712-718.
55.
Moreau, R., Asselah, T., de Kerguenec, C., Pessione, F., Bernard, B., Poynard, T. et al. (2002) Comparison of the effect of terlipressin and albumin on arterial blood volume in patients with cirrhosis and tense ascites treated by paracentesis: a randomized pilot study, Gut50: 90-94.
56.
Moreau, R. and Lebrec, D. (2006) The use of vasoconstrictors in patients with cirrhosis: Type 1 HRS and beyond, Hepatology43: 385-394.
57.
O'Connor, K.W., Lehman, G., Yune, H., Brunelle, R., Christiansen, P. and Hast, J. (1989) Comparison of three nonsurgical treatments for bleeding esophageal varices, Gastroenterology96: 899-906.
58.
Ortega, R., Gines, P., Uriz, J., Cardenas, A., Calahorra, B., De Las Heras, D. et al. (2002) Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: Results of a prospective, nonrandomized study Hepatol36: 941-948.
59.
Pagliaro, L., D'Amico, G., Pasta, L., Politi, F., Vizzini, G., Traina, M. et al. (1994) Portal hypertension in cirrhosis: Natural history. In Bosch, J. and Groszmann, R.J. (eds) Portal Hypertension: Pathophysiology and Treatment. Oxford: Blackwell Scientific.
60.
Pinzani, M., Milani, S., De Franco, R., Grappone, C., Caligiuri, A., Gentilini, A. et al. (1996) Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells, Gastroenterology110: 534-548.
61.
Pinzani, M. and Vizzutti, F. (2005) Pathophysiology of portal hypertension. In Sanyal, A.J. and Shah, V.H. (eds) Clinical Gastroenterology: Portal Hypertension . Totowa: Humana Press.
62.
Pomier-Layrargues, G., Paquin, S.C., Hassoun, Z., Lafortune, M. and Tran, A. (2003) Octreotide in hepatorenal syndrome: A randomized, double-blind, placebo-controlled, crossover study, Hepatology38: 238-243.
63.
Rasaratnam, B., Kaye, D., Jennings, G., Dudley, F. and Chin-Dusting, J. (2003) The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis. A randomized trial, Ann Intern Med139: 186-193.
64.
Restuccia, T., Ortega, R., Guevara, M., Gines, P., Alessandria, C., Ozdogan, O. et al. (2004) Effects of treatment of hepatorenal syndrome before transplantation on posttransplantation outcome. A case-control study , J Hepatol40: 140-146.
65.
Rodriguez-Roisin, R., Krowka, M.J., Herve, P. and Fallon, M.B. (2004) Pulmonary-hepatic vascular disorders (PHD), Eur Respir J24: 861-880.
66.
Rodriguez-Vilarrupla, A., Fernandez, M., Bosch, J. and Garcia-Pagan, J.C. (2007) Current concepts in the pathophysiology of portal hypertension, Ann Hepatol6: 28-36.
67.
Ros, J., Jimenez, W., Lamas, S., Claria, J., Arroyo, V., Rivera, F. et al. (1995) Nitric oxide production in arterial vessels of cirrhotic rats, Hepatology21: 554-560.
68.
Runyon, B.A. (2004) Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of adult patients with ascites due to cirrhosis, Hepatology39: 841-856.
69.
Sanyal, A.J., Boyer, T., Garcia-Tsao, G., Regenstein, F., Rossaro, L., Appenrodt, B. et al. (2008) A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome, Gastroenterology134: 1360-1368.
70.
Schepke, M., Wiest, R., Flacke, S., Heller, J., Stoffel-Wagner, B. and Herold, T. (2008) Irbesartan plus low-dose propranolol versus low-dose propranolol alone in cirrhosis: a placebo-controlled, double blind study, Am J Gastroenterol103: 1152-1158.
71.
Shah, V., Cao, S., Hendrickson, H., Yao, J. and Katusic, Z.S. (2001) Regulation of hepatic eNOS by caveolin and calmodulin after bile duct ligation in rats, Am J Physiol Gastrointest Liver Physiol280: G1209-G1216.
72.
Shah, V., Haddad, F.G., Garcia-Cardena, G., Frangos, J.A., Mennone, A., Groszmann, R.J. et al. (1997) Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids, J Clin Invest100: 2923-2930.
73.
Sharma, P., Kumar, A., Shrama, B.C. and Sarin, S.K. (2008) An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response, Am J Gastroenterol103: 1689-1697.
74.
Signorelli, S., Paris, B., Bonelli, M. and Girola, M. (1996) Prevention of re-bleeding from varices: Trial of nadolol compared to nadolol plus sclerotherapy, [Abstract]J Hepatol25: 92.
75.
Sieber, C. and Groszmann, R.J. (1992) Nitric oxide mediates hyporeactivity to vasopressors in mesenteric vessels of portal hypertensive rats, Gastroenterology103: 235-239.
76.
Sikuler, E. and Groszmann, R.J. (1986) Hemodynamic studies in long- and short-term portal hypertensive rats: The relation to systemic glucagon levels, Hepatology6: 414-418.
77.
Singh, V., Dheerendra, P.C., Singh, B., Nain, C.K., Chawla, D., Sharma, N. et al. (2008) Midodrine versus albumin in the prevention of paracentesis-induced circulatory dysfunction in cirrhotics: a randomized pilot study, Am J Gastroenterol103: 1399-1405.
78.
Singh, V., Kumar, B., Nain, C.K., Singh, B., Sharma, N., Bhalla, A. et al. (2006A) Noradrenaline and albumin in paracentesis-induced circulatory dysfunction in cirrhosis: a randomized pilot study, J Int Med260: 62-68.
79.
Singh, V., Kumar, R., Nain, C.K., Singh, B. and Sharma, A.K. (2006B) Terlipressin versus albumin in paracentesis-induced circulatory dysfunction in cirrhosis: A randomized study, J Gastroenterol Hepatol21: 303-307.
80.
Smith, W.L. (1989) The eicosanoids and their biochemical mechanisms of action, Biochem J259: 315-324.
81.
Solanki, P., Chawla, A., Garg, R., Gupta, R., Jain, M. and Sarin, S. (2003) Beneficial effects of terlipressin in hepatorenal syndrome: A prospective, randomized placebo-controlled clinical trial, J Gastroenterol and Hepatol18: 152-156.
82.
Spahr, L., Giostra, E., Frossard, J.L., Morard, I., Mentha, G. and Hadengue, A. (2007) A 3-month course of long-acting repeatable octreotide (Sandostatin LAR) improves portal hypertension in patients with cirrhosis: a randomized controlled study, Am J Gastroenterol102: 1397-1405.
83.
Spahr, L., Martin, P.Y., Giostra, E., Niederberger, M., Lang, U., Capponi, A. et al. (2002) Acute effects of nitric oxide synthase inhibition on systemic, hepatic, and renal hemodynamics in patients with cirrhosis and ascites, J Investig Med50: 116-224.
84.
Topper, J.N., Cai, J., Falb, D. and Gimbrone, M.A. (1996) Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: Cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress, Proc Natl Acad Sci USA93: 10417-10422.
85.
Tsai, Y.T., Lee, F.Y., Lin, H.C., Lee, S.D., Hsia, H.C., Lin, W.J. et al. (1991) Hyposensitivity to vasopressin in patients with hepatitis B-related cirrhosis during acute variceal hemorrhage, Hepatology13: 407-412.
86.
Walker, S., Kreichgauer, H.P. and Bode, J.C. (1992) Terlipressin vs somatostatin in bleeding esophageal varices: a controlled double blind study, Hepatology15: 1023-1030.
87.
Wiest, R., Das, S., Cadelina, G., Garcia-Tsao, G., Milstien, S. and Groszmann, R.J. (1999) Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility, J Clin Invest104: 1223-1233.
88.
Wong, F., Pantea, L. and Sniderman, K. (2004) Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome, Hepatology40: 55-64.
89.
Wu, Y., Burns, R.C. and Sitzmann, J.V. (1993) Effects of nitric oxide and cyclooxygenase inhibition on splanchnic hemodynamics in portal hypertension, Hepatology18: 1416-1421.
90.
Zipprich, A. (2007) Hemodynamics in the cirrhotic liver, J Clin Gastroenterol41: S254-S258.
