Experimental methods of portal hypertension studying
Abstract
The aim of review. To present methods of studying of portal hypertension and means of its pharmacological treatment in experiment settings.
Original positions. To study complex pathophysiological disorders, innate to portal hypertension, various pilot models providing complex evaluation and development of adequate treatment methods are used. Nowadays mechanisms of hyperdynamic circulatory status development are detailed on laboratory animals. Ex vivo studies gave physiological characteristic to the mediators causing splanchnic vasodilation and increasing of vascular tension in cirrhotic liver, and methods of molecular biology identified defects in signalling routes responsible for disorders of metabolism of these substances.
Conclusion. In the last years application of various pilot models of portal hypertension promoted progress not only in understanding of pathophysiological mechanisms laying in its basis, but also development of new perspective methods of treatment. The further randomized controlled clinical studies will help to determine their safety and efficacy comparing to traditional treatment methods.
About the Author
D. V. Garbuzenko
Челябинская государственная медицинская академия
Russian Federation
Russian Federation
References
1. Abraldes J.G., Pasarin M., Garcia-Pagan J.C. Animal model of portal hypertension // World J. Gastroenterol. – 2006. – Vol. 12, N 41. – P. 6577–6584.
2. Abraldes J.G., Rodriguez-Vilarrupla A., Graupera M. et al. Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats // J. Hepatol. – 2007. – Vol. 46, N 6. – P. 1040–1046.
3. Aller M.A., Duran M., Ortega I. et al. Comparative study of macro- and microsurgical extrahepatic cholestasis in the rat // Microsurgery. – 2004. – Vol. 24. – P. 442–447.
4. Atucha N.M., Ortнz M.C., Fortepiani L.A. et al. Mesenteric hyporesponsiveness in cirrhotic rats with ascites: role of cGMP and K+ channels // Clin. Sci. (Lond.). – 2000. – Vol. 99, N 5. – P. 455–460.
5. Aydede H., Seda Vatansever H., Erhan Y., Ilkgьl O. Effects of ocreotide on intestinal mucosa in rats with portal hypertensive enteropathy // Acta Histochem. – 2009. – Vol. 111, N 1. – P. 74–82.
6. Bhathal P.S., Grossmann H.J. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators // J. Hepatol. – 1985. – Vol. 1, N 4. – P. 325–337.
7. Blanchet L., Lebrec D.R. Changes in splanchnic blood flow in portal hypertensive rats // Eur. J. Clin. Invest. – 1982. – Vol. 12, N 4. – P. 327–330.
8. Cahill P.A., Wu Y., Sitzmann J.V. Altered adenylyl cyclase activities and G-protein abnormalities in portal hypertensive rabbits // J. Clin. Invest. – 1994. – Vol. 93, N 6. – P. 2691–2700.
9. Castaneda B., Debernardi-Venon W., Bandi J.C. et al. The role of portal pressure in the severity of bleeding in portal hypertensive rats // Hepatology. – 2000. – Vol. 31, N 3. – P. 581–586.
10. Castaneda R., Morales J., Lionetti R. et al. Effects of blood volume restitution following a portal hypertensive-related bleeding in anesthetized cirrhotic rats // Hepatology. – 2001. – Vol. 33, N 4. – P. 821–825.
11. Chen Y., Zhang Q., Liao Y. et al. A modified canine model of portal hypertension with hypersplenism // Scand. J. Gastroenterol. – 2009. – Vol. 44, N 4. – P. 478–485.
12. Cho J.J., Hocher B., Herbst H. et al. An oral endothelin-A receptor antagonist bloks collagen synthesis and deposition in advanced rat liver fibrosis // Gastroenterology. – 2000. – Vol. 118, N 6. – P. 1169–1178.
13. DeLeve L.D., Ito Y., Bethea N.W. et al. Embolization by sinusoidal lining cells obstructs the microcirculation in rat sinusoidal obstruction syndrome // Am. J. Physiol. Gastrointest. Liver Physiol. – 2003. – Vol. 284, N 6. – P. 1045–1052.
14. DeLeve L.D., Shulman H.M., McDonald G.B. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease) // Semin. Liver Dis. – 2002. – Vol. 22, N 1. – P. 27–41.
15. Diйguez B., Aller M.A., Nava M.P. et al. Chronic portal hypertension in the rat by triple-portal stenosing ligation // J. Invest. Surg. – 2002 – Vol. 15, N 6. – P. 329–336.
16. Domenicali M., Ros J., Fernбndez-Varo G. et al. Increased anandamide induced relaxation in mesenteric arteries of cirrhotic rats: role of cannabinoid and vanilloid receptors // Gut. – 2005. – Vol. 54, N 4. – P. 522–527.
17. Fernandez M., Mejias M., Garcia-Pras E. et al. Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats // Hepatology. – 2007 – Vol. 46, N 4. – P. 1208–1217.
18. Fernandez M., Semela D., Bruix J. et al. Angiogenesis in liver disease // J. Hepatol. – 2009 – Vol. 50, N 3. – P. 604–620.
19. Fiorucci S., Antonelli E., Brancaleone V. 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. – Vol. 39, N 6. – P. 932–939.
20. Geerts A.M., de Vriese A.S., Vanheule E. et al. Increased angiogenesis and permeability in the mesenteric microvasculature of rats with cirrhosis and portal hypertension: an in vivo study // Liver Int. – 2006. – Vol. 26, N 7. – P. 889–898.
21. Groszmann R.J., Abraldes J.G. Portal hypertension: from bedside to bench // J. Clin. Gastroenterol. – 2005. – Vol. 39 (suppl. 2). – P. 125–130.
22. Heller J., Shiozawa T., Trebicka J. et al. Acute haemodynamic effects of losartan in anaesthetized cirrhotic rats // Eur. J. Clin. Invest. – 2003. – Vol. 33, N 11. – P. 1006–1012.
23. Hennenberg M., Biecker E., Trebicka J. et al. Defective RhoA/Rho-kinase signaling contributes to vascular hypocontractility and vasodilation in cirrhotic rats // Gastroenterology. – 2006. – Vol. 130, N 3. – P. 838–854.
24. Hennenberg M., Trebicka J., Biecker E. et al. Vascular dysfunction in human and rat cirrhosis: role of receptor-desensitizing and calcium-sensitizing proteins // Hepatology. – 2007. – Vol. 45, N 2. – P. 495–506.
25. Hennenberg M., Trebicka J., Sauerbruch T., Heller J. Mechanisms of extrahepatic vasodilation in portal hypertension // Gut. – 2008. – Vol. 57, N 9. – P. 1300–1314.
26. Hennenberg M., Trebicka J., Stark C. et al. Sorafenib targets dysregulated Rho kinase expression and portal hypertension in rats with secondary biliary cirrhosis // Brit. J. Pharmacol. – 2009. – Vol. 157, N 2. – P. 258–270.
27. Inserte J., Perello A., Agullo L. et al. Left ventricular hypertrophy in rats with biliary cirrhosis // Hepatology. – 2003. – Vol. 38, N 3. – P. 589–598.
28. Ito Y., Bethea N.W., Baker G.L. et al. Hepatic microcirculatory dysfunction during cholestatic liver injury in rats // Microcirculation. – 2003. – Vol. 10, N 5. – P. 421–432.
29. Jensen L.S., Krarup N., Larsen A. et al. Chronic portal venous hypertension. The effect on liver blood flow and liver function and the development of esophageal varices // Scand. J. Gastroenterol. – 1987. – Vol. 22, N 4. – P. 463–470.
30. Jeong H.G. Inhibition of cytochrome P450 2E1 expression by oleanolic acid: hepatoprotective effects against carbon tetrachloride-induced hepatic injury // Toxicol. Lett. – 1999. – Vol. 105, N 3. – P. 215–222.
31. Jiang Y., Liu J., Waalkes M., Kang Y.J. Changes in the gene expression associated with carbon tetrachloride- induced liver fibrosis persist after cessation of dosing in mice // Toxicol. Sci. – 2004. – Vol. 79, N 2. – P. 404–410.
32. Jonassen T.E.N., Brond L., Torp M. Effects of renal denervation on tubular sodium handling in rats with CBL-induced liver cirrhosis // Am. J. Renal. Physiol. – 2002. – Vol. 284. – P. 555–563.
33. Jurzik L., Froh M., Straub R.H. et al. Up-regulation of nNOS and associated increase in nitrergic vasodilation in superior mesenteric arteries in pre-hepatic portal hypertension // J. Hepatol. – 2005. – Vol. 43, N 2. – P. 258–265.
34. Kai S., Bandoh T., Ohta M. et al. Expression of endothelin receptors in the gastric mucosa of portal hypertensive rats // J. Gastroenterol. Hepatol. – 2006. – Vol. 21, N 1, Pt. 2. – P. 242–250.
35. Kreft B., Dombrowski F., Block W. et al. Evaluation of different models of experimentally induced liver cirrhosis for MRI research with correlation to histopathologic findings // Invest. Radiol. – 1999. – Vol. 34, N 5. – P. 360–366.
36. Laleman W., van der Elst I., Zeegers M. et al. A stable model of cirrhotic portal hypertension in the rat: thioacetamide revisited // Eur. J. Clin. Invest. – 2006. – Vol. 36, N 4. – P. 242–249.
37. Laleman W., van Landeghem L., van der Elst I. et al. Nitroflurbiprofen, a nitric oxide-releasing cyclooxygenase inhibitor, improves cirrhotic portal hypertension in rats // Gastroenterology. – 2007. – Vol. 132, N 2. – P. 709–719.
38. Laviсa B., Gracia-Sancho J., Rodrнguez-Vilarrupla A. et al. Superoxide dismutase gene transfer reduces portal pressure in CCl4 cirrhotic rats with portal hypertension // Gut. – 2009. – Vol. 58, N 1. – P. 118–125.
39. Li X.N., Benjamin I.S., Alexander B. A new rat model of portal hypertension induced by intraportal injection of microspheres // World J. Gastroenterol. – 1998. – Vol. 4, N 1. – P. 66–69.
40. Li X.N., Benjamin I.S., Alexander B. Reproducible production of thioacetamide-induced macronodular cirrhosis in the rat with no mortality // J. Hepatol. – 2002. – Vol. 36, N 4. – P. 488–493.
41. Lopez-Talavera J.C., Cadelina G., Olchowski J. et al. Thalidomide inhibits tumor necrosis factor alpha, decreases nitric oxide synthesis, and ameliorates the hyperdynamic circulatory syndrome in portal-hypertensive rats // Hepatology. – 1996. – Vol. 23, N 6. – P. 1616–1621.
42. Luo B., Liu L., Tang L. et al. ET-1 and TNF-alpha in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats // Am. J. Physiol. Gastrointest. Liver Physiol. – 2004. – Vol. 286, N 2. – P. 294–303.
43. Matei V., Rodrнguez-Vilarrupla A., Deulofeu R. et al. Three-day tetrahydrobiopterin therapy increases in vivo hepatic NOS activity and reduces portal pressure in CCl4 cirrhotic rats // J. Hepatol. – 2008. – Vol. 49, N 2. – P. 192–197.
44. Mejias M., Garcia-Pras E., Tiani C. et al. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circula-tions in portal hypertensive and cirrhotic rats // Hepatology. – 2009. – Vol. 49, N 4. – P. 1245–1256.
45. Murad S.D., Dom V.A., Ritman E.L. et al. Early changes of the portal tract on microcomputed tomography images in a newly-developed rat model for Budd-Chiari syndrome // J. Gastroenterol. Hepatol. – 2008. – Vol. 23, N 10. – P. 1561–1566.
46. Natsume M., Tsuji H., Harada A. et al. Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloride-treated IL-6-deficient mice // J. Leukoc. Biol. – 1999. – Vol. 66, N 4. – P. 601–608.
47. Nishida R., Inoue R., Takimoto Y., Kita T. Esophageal varices in rat models of liver cirrhosis // Dig. Dis. Sci. – 1998. – Vol. 43, N 6. – P. 1296–1301.
48. Oberti F., Sogni P., Cailmail S. et al. Role of prostacyclin in hemodynamic alterations in conscious rats with extrahepatic or intrahepatic portal hypertension // Hepatology. – 1993. – Vol. 18, N 3. – P. 621–627.
49. Ohta M., Tanoue K., Tarnawski A.S. et al. Overexpressed nitric oxide synthase in portal-hypertensive stomach of rat: A key to increased susceptibility to damage? // Gastroenterology. – 1997. – Vol. 112, N 6. – P. 1920–1930.
50. Orfila C., Lepert J.C., Alric L. et al. Expression of TNF-alpha and immunohistochemical distribution of hepatic macrophage surface markers in carbon tetrachloride-induced chronic liver injury in rats // Histochem. J. – 1999. – Vol. 31, N 10. – P. 677–685.
51. Pereira R.M., dos Santos R.A.S., Oliveira E.A. et al. Development of hepatorenal syndrome in bile duct ligated rats // World J. Gastroenterol. – 2008. – Vol. 14, N 28. – P. 4505–4511.
52. Reynaert H., Urbain D., Geerts A. Regulation of sinusoidal perfusion in portal hypertension // Anat. Rec. – 2008. – Vol. 291. – P. 693–698.
53. Sarin S.K., Mosca P., Sabba C., Groszmann R.J. Hyperdynamic circulation in chronic murine schistosomiasis model of portal hypertension // Hepatology. – 1991. – Vol. 13, N 3. – P. 581–584.
54. Sikuler E., Kravetz D., Groszmann R.J. Evolution of portal hypertension and mechanisms involved in its maintenance in a rat model // Am. J. Physiol. – 1985. – Vol. 248, N 6, Pt. 1. – P. 618–625.
55. Tazi K., Moreau R., Herve P. et al. Norfloxacin reduces aortic NO synthases and proinflammatory cytokine up-regulation in cirrhotic rats: role of Akt signaling // Gastroenterology. – 2005. – Vol. 129, N 1. – P. 303–314.
56. Trebicka J., Hennenberg M., Laleman W. et al. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase // Hepatology. – 2007. – Vol. 46, N 1. – P. 242–253.
57. Tu C.T., Guo J.S., Wang M., Wang J.Y. Antifibrotic activity of rofecoxib in vivo is associated with reduced portal hypertension in rats with carbon tetrachloride-induced liver injury // J. Gastroenterol. Hepatol. – 2007. – Vol. 22, N 6. – P. 877–884.
58. Vallance P., Moncada S. Hypothesis: induction of nitric oxide synthase in the vasculature underlies the hyperdynamic circulation of cirrhosis // Lancet. – 1991. – Vol. 337. – P. 776–778.
59. Van de Casteele M., van Pelt J.F., Nevens F. et al. 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. – Vol. 2, N 1. – P. 1–8.
60. Veal N., Oberti F., Moal F. et al. Spleno-renal shunt blood flow is an accurate index of collateral circulation in different models of portal hypertension and after pharmacological changes in rats // J. Hepatol. – 2000. – Vol. 32, N 3. – P. 434–440.
61. Vorobioff J., Bredfeldt J.E., Groszmann R.J. Hyperdynamic circulation in portal-hypertensive rat model: A primary factor for maintenence of chronic portal hypertension // Am. J. Physiol. – 1983. – Vol. 244, N 1. – P. 52–57.
62. Vorobioff J., Bredfeldt J.E., Groszmann R.J. Increased blood flow through the portal system in cirrhotic rats // Gastroenterology. – 1984. – Vol. 87, N 4. – P. 1120–1126.
63. Xu B., Zhu G.H., Weng J.F. et al. The roles of caveolin-1 and endothelial nitric oxide synthase in the development of portal hypertension in rats with liver cirrhosis // Zhonghua Gan Zang Bing Za Zhi. – 2008. – Vol. 16, N 3. – P. 184–187.
64. Zipprich A. Hemodynamics in the isolated cirrhotic liver // J. Clin. Gastroenterol. – 2007. – Vol. 41 (suppl. 3). – P. 254–258.
Review
For citations:
Garbuzenko D.V. Experimental methods of portal hypertension studying. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2010;20(2):4-12. (In Russ.)
Views:
62
Email this article 
