Frontiers of Medicine

, Volume 13, Issue 3, pp 398–408 | Cite as

Urotensin II receptor antagonist reduces hepatic resistance and portal pressure through enhanced eNOS-dependent HSC vasodilatation in CCl4-induced cirrhotic rats

  • Ruoxi Zhang
  • Jing Chen
  • Diangang LiuEmail author
  • Yu Wang
Research Article


Increased serum urotensin II (UII) levels in human cirrhotic populations have been recently shown, but the long-term effects of UII receptor antagonist on the cirrhosis have not been investigated. To investigate the therapeutic effects of urotensin II receptor (UT) antagonist palosuran on rats with carbon tetrachloride (CCl4)-induced cirrhosis, the hepatic and systemic hemodynamics, liver fibrosis, the metalloproteinase-13 (MMP-13)/tissue inhibitor of metalloproteinase-1 (TIMP-1) ratio, hepatic Rho-kinase activity, and the endothelial nitric oxide synthase (eNOS) activity are measured in CCl4-cirrhotic rats treated with palosuran or vehicle for 4 weeks. Primary hepatic stellate cells (HSCs) are used to investigate the changes in UII/UT expression and the in vitro effect of palosuran. Compared with the vehicle-treated cirrhotic rats, treatment with palosuran can reduce the portal pressure (PP), decrease the risk of liver fibrosis and the level of α smooth muscle actin, collagen-I (COL-I), and transforming growth factor β expression. However, treatment with palosuran can increase MMP-13/TIMP-1, pvasodilator-stimulated phosphoprotein (p-VASP), and p-eNOS expression. Moreover, in vitro UII/UT mRNA expression increases during HSC activation. MMP-13/TIMP-1, COL-I, and p-VASP are inhibited after palosuran treatment. Our data indicate that long-term administration of palosuran can decrease PP in cirrhosis, which results from decreased hepatic fibrosis and enhanced eNOS-dependent HSC vasodilatation.


portal hypertension cirrhosis urotensin II palosuran hepatic stellate cell 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



This study was supported by the National Natural Science Foundation of China (No. 81170408 to Diangang Liu), the Wang Baoen Liver Fibrosis Research Foundation of the China Hepatitis Prevention Foundation (No. 20120124 to Diangang Liu), and the China Postdoctoral Science Foundation (No. 2012M510094 to Diangang Liu).


  1. 1.
    Groszmann RJ, Abraldes JG. Portal hypertension: from bedside to bench. J Clin Gastroenterol 2005; 6(4 Suppl 2): S125–S130CrossRefGoogle Scholar
  2. 2.
    McConnell M, Iwakiri Y. Biology of portal hypertension. Hepatol Int 2018; 12(Suppl 1):11–23CrossRefGoogle Scholar
  3. 3.
    Vilaseca M, García-Calderó H, Lafoz E, García-Irigoyen O, Avila MA, Reverter JC, Bosch J, Hernández-Gea V, Gracia-Sancho J, García-Pagán JC. The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells. Hepatology 2017; 65(6): 2031–2044CrossRefGoogle Scholar
  4. 4.
    Vilaseca M, García-Calderó H, Lafoz E, Ruart M, López-Sanjurjo CI, Murphy MP, Deulofeu R, Bosch J, Hernández-Gea V, Gracia-Sancho J, García-Pagán JC. Mitochondria-targeted antioxidant mitoquinone deactivates human and rat hepatic stellate cells and reduces portal hypertension in cirrhotic rats. Liver Int 2017; 37(7): 1002–1012CrossRefGoogle Scholar
  5. 5.
    Rockey DC, Fouassier L, Chung JJ, Carayon A, Vallee P, Rey C, Housset C. Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells. Hepatology 1998; 27(2): 472–480CrossRefGoogle Scholar
  6. 6.
    Iwakiri Y. Pathophysiology of portal hypertension. Clin Liver Dis 2014; 18(2): 281–291CrossRefGoogle Scholar
  7. 7.
    Nishimura Y, Ito T, Hoe K, Saavedra JM. Chronic peripheral administration of the angiotensin II AT(1) receptor antagonist candesartan blocks brain AT(1) receptors. Brain Res 2000; 871(1): 29–38CrossRefGoogle Scholar
  8. 8.
    Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, Louden CS, Foley JJ, Sauermelch CF, Coatney RW, Ao Z, Disa J, Holmes SD, Stadel JM, Martin JD, Liu WS, Glover GI, Wilson S, McNulty DE, Ellis CE, Elshourbagy NA, Shabon U, Trill JJ, Hay DW, Ohlstein EH, Bergsma DJ, Douglas SA. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 1999; 401(6750): 282–286CrossRefGoogle Scholar
  9. 9.
    Ross B, McKendy K, Giaid A. Role of urotensin II in health and disease. Am J Physiol Regul Integr Comp Physiol 2010; 298(5): R1156–R1172CrossRefGoogle Scholar
  10. 10.
    Thanassoulis G, Huyhn T, Giaid A. Urotensin II and cardiovascular diseases. Peptides 2004; 25(10): 1789–1794CrossRefGoogle Scholar
  11. 11.
    Kemp W, Roberts S, Krum H. Increased circulating urotensin II in cirrhosis: potential implications in liver disease. Peptides 2008; 29 (5): 868–872CrossRefGoogle Scholar
  12. 12.
    Liu D, Chen J, Wang J, Zhang Z, Ma X, Jia J, Wang Y. Increased expression of urotensin II and GPR14 in patients with cirrhosis and portal hypertension. Int J Mol Med 2010; 25(6): 845–851Google Scholar
  13. 13.
    Liu DG, Wang J, Zhang ZT, Wang Y. The urotension II antagonist SB-710411 arrests fibrosis in CCl4 cirrhotic rats. Mol Med Rep 2009; 2(6): 953–961Google Scholar
  14. 14.
    Clozel M, Binkert C, Birker-Robaczewska M, Boukhadra C, Ding SS, Fischli W, Hess P, Mathys B, Morrison K, Müller C, Müller C, Nayler O, Qiu C, Rey M, Scherz MW, Velker J, Weller T, Xi JF, Ziltener P. Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)- ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin system. J Pharmacol Exp Ther 2004; 311(1): 204–212CrossRefGoogle Scholar
  15. 15.
    Mejias M, Coch L, Berzigotti A, Garcia-Pras E, Gallego J, Bosch J, Fernandez M. Antiangiogenic and antifibrogenic activity of pigment epithelium-derived factor (PEDF) in bile duct-ligated portal hypertensive rats. Gut. 2015; 64(4): 657–666CrossRefGoogle Scholar
  16. 16.
    Clozel M, Hess P, Qiu C, Ding SS, Rey M. The urotensin-II receptor antagonist palosuran improves pancreatic and renal function in diabetic rats. J Pharmacol Exp Ther 2006; 316(3): 1115–1121CrossRefGoogle Scholar
  17. 17.
    Hsu SJ, Lee FY, Wang SS, Hsin IF, Lin TY, Huang HC, Chang CC, Chuang CL, Ho HL, Lin HC, Lee SD. Caffeine ameliorates hemodynamic derangements and portosystemic collaterals in cirrhotic rats. Hepatology 2015; 61(5): 1672–1684CrossRefGoogle Scholar
  18. 18.
    Delgado MG, Gracia-Sancho J, Marrone G, Rodríguez-Vilarrupla A, Deulofeu R, Abraldes JG, Bosch J, García-Pagán JC. Leptin receptor blockade reduces intrahepatic vascular resistance and portal pressure in an experimental model of rat liver cirrhosis. Am J Physiol Gastrointest Liver Physiol 2013; 305(7): G496–G502CrossRefGoogle Scholar
  19. 19.
    Darlington AS, Dippel DW, Ribbers GM, van Balen R, Passchier J, Busschbach JJ. A prospective study on coping strategies and quality of life in patients after stroke, assessing prognostic relationships and estimates of cost-effectiveness. J Rehabil Med 2009; 41(4): 237–241CrossRefGoogle Scholar
  20. 20.
    Mülsch A, Oelze M, Klöss S, Mollnau H, Töpfer A, Smolenski A, Walter U, Stasch JP, Warnholtz A, Hink U, Meinertz T, Münzel T. Effects of in vivo nitroglycerin treatment on activity and expression of the guanylyl cyclase and cGMP-dependent protein kinase and their downstream target vasodilator-stimulated phosphoprotein in aorta. Circulation 2001; 103(17): 2188–2194CrossRefGoogle Scholar
  21. 21.
    Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008; 3(6): 1101–1108CrossRefGoogle Scholar
  22. 22.
    Ramm GA. Isolation and culture of rat hepatic stellate cells. J Gastroenterol Hepatol 1998; 13(8): 846–851CrossRefGoogle Scholar
  23. 23.
    Rockey DC, Weisiger RA. Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance. Hepatology 1996; 24 (1): 233–240CrossRefGoogle Scholar
  24. 24.
    Liu J, Gong H, Zhang ZT, Wang Y. Effect of angiotensin II and angiotensin II type 1 receptor antagonist on the proliferation, contraction and collagen synthesis in rat hepatic stellate cells. Chin Med J (Engl) 2008; 121(2): 161–165CrossRefGoogle Scholar
  25. 25.
    Kemp W, Krum H, Colman J, Bailey M, Yandle T, Richards M, Roberts S. Urotensin II: a novel vasoactive mediator linked to chronic liver disease and portal hypertension. Liver Int 2007; 27(9): 1232–1239Google Scholar
  26. 26.
    Kemp W, Kompa A, Phrommintikul A, Herath C, Zhiyuan J, Angus P, McLean C, Roberts S, Krum H. Urotensin II modulates hepatic fibrosis and portal hemodynamic alterations in rats. Am J Physiol Gastrointest Liver Physiol 2009; 297(4): G762–G767CrossRefGoogle Scholar
  27. 27.
    Sidharta PN, Rave K, Heinemann L, Chiossi E, Krähenbühl S, Dingemanse J. Effect of the urotensin-II receptor antagonist palosuran on secretion of and sensitivity to insulin in patients with type 2 diabetes mellitus. Br J Clin Pharmacol 2009; 68(4): 502–510CrossRefGoogle Scholar
  28. 28.
    Trebicka J, Leifeld L, Hennenberg M, Biecker E, Eckhardt A, Fischer N, Pröbsting AS, Clemens C, Lammert F, Sauerbruch T, Heller J. Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats. Hepatology 2008; 47 (4): 1264–1276CrossRefGoogle Scholar
  29. 29.
    Heller J, Schepke M, Neef M, Woitas R, Rabe C, Sauerbruch T. Increased urotensin II plasma levels in patients with cirrhosis and portal hypertension. J Hepatol 2002; 37(6): 767–772CrossRefGoogle Scholar
  30. 30.
    Leifeld L, Clemens C, Heller J, Trebicka J, Sauerbruch T, Spengler U. Expression of urotensin II and its receptor in human liver cirrhosis and fulminant hepatic failure. Dig Dis Sci 2010; 55(5): 1458–1464CrossRefGoogle Scholar
  31. 31.
    Yadav L, Puri N, Rastogi V, Satpute P, Ahmad R, Kaur G. Matrix metalloproteinases and cancer-roles in threat and therapy. Asian Pac J Cancer Prev 2014; 15(3): 1085–1091CrossRefGoogle Scholar
  32. 32.
    Liu LM, Liang DY, Ye CG, Tu WJ, Zhu T. The UII/UT system mediates upregulation of proinflammatory cytokines through p38 MAPK and NF-kB pathways in LPS-stimulated Kupffer cells. PLoS One 2015; 10(3): e0121383CrossRefGoogle Scholar
  33. 33.
    Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 2002; 35(2): 478–491CrossRefGoogle Scholar
  34. 34.
    Verbeke L, Farre R, Trebicka J, Komuta M, Roskams T, Klein S, Elst IV, Windmolders P, Vanuytsel T, Nevens F, Laleman W. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014; 59(6): 2286–2298CrossRefGoogle Scholar
  35. 35.
    Mallat A, Lotersztajn S. Targeting cannabinoid receptors in hepatocellular carcinoma. Gut 2016; 65(10):1582–1583CrossRefGoogle Scholar
  36. 36.
    Cheng K, Yang N, Mahato RI. TGF-ß1 gene silencing for treating liver fibrosis. Mol Pharm 2009; 6(3): 772–779CrossRefGoogle Scholar
  37. 37.
    Chen RJ, Wu HH, Wang YJ. Strategies to prevent and reverse liver fibrosis in humans and laboratory animals. Arch Toxicol 2015; 89 (10): 1727–1750CrossRefGoogle Scholar
  38. 38.
    Trebicka J, Hennenberg M, Laleman W, Shelest N, Biecker E, Schepke M, Nevens F, Sauerbruch T, Heller J. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology 2007; 46(1): 242–253CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of General Surgery, Xuanwu HospitalCapital Medical UniversityBeijingChina
  2. 2.Department of Gastroenterologythe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
  3. 3.Department of General Surgery, Beijing Friendship HospitalCapital Medical UniversityBeijingChina

Personalised recommendations