Skip to main content
SpringerLink
Log in

Cell and Molecular Mechanisms of Increased Intrahepatic Resistance and Hemodynamic Correlates

  • Chapter
Portal Hypertension

Part of the book series: Clinical Gastroenterology ((CG))

Abstract

The intrahepatic circulatory system consists of three major microvascular components, including: (1) the terminal portal venule (TPV) and hepatic arteriole; (2) the sinusoids (corresponding to the capillary bed); and (3) the terminal hepatic venule (THV). Each of the functional units in theory represents a putative resistance site. The major pre- and postsinusoidal components have been presumed to reflect contraction of vascular smooth muscle cells (TPV and THV). At the sinusoidal level, the major cellular components include endothelial cells and stellate cells, either of which could have a regulatory role. Dynamic changes in endothelial fenestrae have been demonstrated, and raise the possibility that sinusoidal endothelial cells could be involved in blood flow regulation (1). From an ultrastructural standpoint, stellate cells possess long and extensive cytoplasmic processes that essentially encircle many if not all sinusoidal endothelial cells (2,3). This anatomic relationship in the sinusoid suggests that stellate cells function as liver-specific pericytes (pericytes are smooth muscle-like cells that are felt to control capillary blood flow in a wide variety of tissues (4).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Oda M, Han JY, Yokomori H. Local regulators of hepatic sinusoidal microcirculation: recent advances. Clin Hemorheol Microcirc 2000;23:85–94.

    PubMed  CAS  Google Scholar 

  2. Ekataksin W, Kaneda K. Liver microvascular architecture: an insight into the pathophysiology of portal hypertension. Semin Liver Dis 1999;19:359–382.

    PubMed  CAS  Google Scholar 

  3. Wake K. Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int Rev Cytol 1980;66:303–353.

    PubMed  CAS  Google Scholar 

  4. Shepro D, Morel NM. Pericyte physiology. FASEB J 1993;7:1031–1038.

    PubMed  CAS  Google Scholar 

  5. Lautt WW, Greenway CV. Conceptual review of the hepatic vascular bed. Hepatology 1987;7:952–963.

    Article  PubMed  CAS  Google Scholar 

  6. Sherman IA, Pappas SC, Fisher MM. Hepatic microvascular changes associated with development of liver fibrosis and cirrhosis. Am J Physiol 1990;258:H460–H465.

    PubMed  CAS  Google Scholar 

  7. Blendis LM. Hepatocyte swelling and portal hypertension [comment]. J Hepatol 1992;15:4–5.

    Article  PubMed  CAS  Google Scholar 

  8. Lautt WW. The 1995 Ciba-Geigy Award Lecture. Intrinsic regulation of hepatic blood flow. Can J Physiol Pharmacol 1996;74:223–233.

    Article  PubMed  CAS  Google Scholar 

  9. 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;24:233–240.

    Article  PubMed  CAS  Google Scholar 

  10. Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995;21:1238–1247.

    PubMed  CAS  Google Scholar 

  11. Kawada N, Klein H, Decker K. Eicosanoid-mediated contractility of hepatic stellate cells. Biochem J 1992;285:367–371.

    PubMed  CAS  Google Scholar 

  12. Rockey DC, Housset CN, Friedman SL. Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo. J Clin Invest 1993;92:1795–1804.

    PubMed  CAS  Google Scholar 

  13. Pinzani M, Failli P, Ruocco C, et al. Fat-storing cells as liver-specific pericytes. Spatial dynamics of agonist-stimulated intracellular calcium transients. J Clin Invest 1992;90:642–646.

    PubMed  CAS  Google Scholar 

  14. Zhang JX, Pegoli WJ, Clemens MG. Endothelin-1 induces direct constriction of hepatic sinusoids. Am J Physiol 1994;266:G624–G632.

    PubMed  CAS  Google Scholar 

  15. Bauer M, Paquette NC, Zhang JX, et al. Chronic ethanol consumption increases hepatic sinusoidal contractile response to endothelin-1 in the rat. Hepatology 1995;22:1565–1576.

    PubMed  CAS  Google Scholar 

  16. Clemens MG, Zhang JX. Regulation of sinusoidal perfusion: in vivo methodology and control by endothelins. Semin Liver Dis 1999;19:383–396.

    Article  PubMed  CAS  Google Scholar 

  17. Rockey DC. Characterization of endothelin receptors mediating rat hepatic stellate cell contraction. Biochem Biophys Res Commun 1995;207:725–731.

    Article  PubMed  CAS  Google Scholar 

  18. Rockey DC. Vascular mediators in the injured liver. Hepatology 2003;37:4–12.

    Article  PubMed  CAS  Google Scholar 

  19. Housset C, Rockey DC, Bissell DM. Endothelin receptors in rat liver: lipocytes as a contractile target for endothelin 1. Proc Natl Acad Sci USA 1993;90:9266–9270.

    Article  PubMed  CAS  Google Scholar 

  20. Eakes AT, Howard KM, Miller JE, Olson MS. Endothelin-1 production by hepatic endothelial cells: characterization and augmentation by endotoxin exposure. Am J Physiol 1997;272:G605–G611.

    PubMed  CAS  Google Scholar 

  21. Stephenson K, Harvey SA, Mustafa SB, Eakes AT, Olson MS. Endothelin association with the cultured rat Kupffer cell: characterization and regulation. Hepatology 1995;22:896–905.

    PubMed  CAS  Google Scholar 

  22. Okumura S, Takei Y, Kawano S, et al. Vasoactive effect of endothelin-1 on rat liver in vivo. Hepatology 1994;19:155–161.

    PubMed  CAS  Google Scholar 

  23. Rockey DC, Chung JJ. Inducible nitric oxide synthase in rat hepatic lipocytes and the effect of nitric oxide on lipocyte contractility. J Clin Invest 1995;95:1199–1206.

    PubMed  CAS  Google Scholar 

  24. Wakabayashi Y, Takamiya R, Mizuki A, et al. Carbon monoxide overproduced by home oxygcn-ase-1 causes a reduction of vascular resistance in perfused rat liver. Am J Physiol 1999;277:G1088–G1096.

    PubMed  CAS  Google Scholar 

  25. Suematsu M, Goda N, Sano T, et al. Carbon monoxide: an endogenous modulator of sinusoidal tone in the perfused rat liver [see comments]. J Clin Invest 1995;96:2431–247.

    PubMed  CAS  Google Scholar 

  26. Birney Y, Redmond EM, Sitzmann JV, Cahill PA. Eicosanoids in cirrhosis and portal hypertension. Prostaglandins Other Lipid Mediat 2003;72:3–18.

    Article  PubMed  CAS  Google Scholar 

  27. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells [see comments]. Nature 1988;332:411–415.

    Article  PubMed  CAS  Google Scholar 

  28. Inoue A, Yanagisawa M, Kimura S, et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA 1989;86:2863–2867.

    Article  PubMed  CAS  Google Scholar 

  29. Hocher B, Thone-Reineke C, Bauer C, Raschack M, Neumayer HH. The paracrine endothelin system: pathophysiology and implications in clinical medicine [see comments]. Eur J Clin Chem Clin Biochem 1997;35:175–189.

    PubMed  CAS  Google Scholar 

  30. Elshourbagy NA, Korman DR, Wu HL, et al. Molecular characterization and regulation of the human endothelin receptors. J Biol Chan 1993;268:3873–3879.

    CAS  Google Scholar 

  31. Rubanyi GM, Polokoff MA. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 1994;46:325–415.

    PubMed  CAS  Google Scholar 

  32. Lee ME, Dhadly MS, Temizer DH, Clifford JA, Yoshizumi M, Quertermous T. Regulation of eiido-thelin-1 gene expression by Fos and Jun. J Biol Chem 1991;266:19,034–19,039.

    PubMed  CAS  Google Scholar 

  33. Lee ME, Bloch KD, Clifford JA, Quertermous T. Functional analysis of the endothelin-1 gene promoter. Evidence for an endothelial cell-specific cis-acting sequence. J Biol Chem 1990;265:10,446–10,450.

    PubMed  CAS  Google Scholar 

  34. Marsen TA, Weber F, Egink G, Suckau G, Baldamus CA. Cyclosporin A induces prepro endothelin-1 gene transcription in human endothelial cells. Eur J Pharmacol 1999;379:97–106.

    Article  PubMed  CAS  Google Scholar 

  35. Quehenberger P, Bierhaus A, Fasching P, et al. Endothelin 1 transcription is controlled by nuclear factor-kappaB in AGE-stimulated cultured endothelial cells. Diabetes 2000;49:1561–1570.

    Article  PubMed  CAS  Google Scholar 

  36. Yanagisawa M. The endothelin system. A new target for therapeutic intervention [editorial; comment]. Circulation 1994;89:1320–1322.

    PubMed  CAS  Google Scholar 

  37. Ohnaka K, Takayanagi R, Nishikawa M, Haji M, Nawata H. Purification and characterization of a phosphoramidon-sensitive endothelin-converting enzyme in porcine aortic endothelium. J Biol Chem 1993;268:26,759–26,766.

    PubMed  CAS  Google Scholar 

  38. Turner AJ, Murphy LJ. Molecular pharmacology of endothelin converting enzymes. Biochem Pharmacol 1996;51:91–102.

    Article  PubMed  CAS  Google Scholar 

  39. Xu D, Emoto N, Giaid A, et al. ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1. Cell 1994;78:473–485.

    Article  PubMed  CAS  Google Scholar 

  40. Emoto N, Yanagisawa M. Endotlielin-converting enzyme-2 is a membrane-bound, phosphoramidon-sensitive metalloprotease with acidic pH optimum. J Biol Chem 1995;270:15,262–15,268.

    Article  PubMed  CAS  Google Scholar 

  41. Emoto N, Nurhantari Y, Alimsardjono H, et al. Constitutive lysosomal targeting and degredation of bovine endothelin-converting enzyme 1 a mediated by novel signals in its alternatively spliced cytoplasmic tail. J Biol Chem 1999;274:1509–1518.

    Article  PubMed  CAS  Google Scholar 

  42. Turner AJ, Barnes K, Schweizer A, Valdenaire O. Isoforms of endothelin-converting enzyme: why and where? Trends Pharmacol Sci 1998;19:483–486.

    Article  PubMed  CAS  Google Scholar 

  43. Sakurai T, Yanagisawa M, Masaki T. Molecular characterization of endothelin receptors. Trends Pharmacol Sci 1992;13:103–108.

    Article  PubMed  CAS  Google Scholar 

  44. Takasuka T, Adachi M, Miyamoto C, Furuichi Y, Watanabe T. Characterization of endothelin receptors ETA and ETB expressed in COS cells. J Biochem (Tokyo) 1992;112:396–400.

    CAS  Google Scholar 

  45. Masaki T. Historical review: Endothelin. Trends Pharmacol Sci 2004;25:219–224.

    Article  PubMed  CAS  Google Scholar 

  46. Clozel M, Gray GA, Breu V, Loffler BM, Osterwalder R. The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo. Biochem Biophys Res Commun 1992;186:867–873.

    Article  PubMed  CAS  Google Scholar 

  47. Karne S, Jayawickreme CK, Lerner MR. Cloning and characterization of an endothelin-3 specific receptor (ETC receptor) from Xenopus laevis dermal melanophores. J Biol Chem 1993;268:19,126–19,133.

    PubMed  CAS  Google Scholar 

  48. Kumar C, Mwangi V, Nuthulaganti P, et al. Cloning and characterization of a novel endothelin receptor from Xenopus heart. J Biol Chem 1994;269:13,414–13,420.

    PubMed  CAS  Google Scholar 

  49. Sokolovsky M, Ambar I, Galron R. A novel subtype of endothelin receptors. J Biol Chem 1992;267:20,551–20,554.

    PubMed  CAS  Google Scholar 

  50. Friedman SL, Maher JJ, Bissell DM. Mechanisms and therapy of hepatic fibrosis: report of the AASLD Single Topic Basic Research Conference. Hepatology 2000;32:1403–1408.

    Article  PubMed  CAS  Google Scholar 

  51. Czaja MJ, Weiner FR, Flanders KC, et al. In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis. J Cell Biol 1989;108:2477–2482.

    Article  PubMed  CAS  Google Scholar 

  52. Appleton I, Tomlinson A, Chander CL, Willoughby DA. Effect of endothelin-1 on croton oil-induced granulation tissue in the rat. A pharmacologic and immunohistochemical study [see comments]. Lab Invest 1992;67:703–710.

    PubMed  CAS  Google Scholar 

  53. Nakamura T, Ebihara I, Fukui M, Tomino Y, Koide H. Effect of a specific endothelin receptor A antagonist on mRNA levels for extracellular matrix components and growth factors in diabetic glomeruli. Diabetes 1995;44:895–899.

    Article  PubMed  CAS  Google Scholar 

  54. Tsai YT, Lin IIC, Yang MC, et al. Plasma endothelin levels in patients with cirrhosis and their relationships to the severity of cirrhosis and renal function [see comments]. J Hepatol 1995;23:681–688.

    Article  PubMed  CAS  Google Scholar 

  55. Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med 1997;156:600–608.

    PubMed  CAS  Google Scholar 

  56. Giaid AP, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732–1739.

    Article  PubMed  CAS  Google Scholar 

  57. Saleh D, Furukawa K, Tsao MS, et al. Elevated expression of endothelin-1 and endothelin-converting enzyme-1 in idiopathic pulmonary fibrosis: possible involvement of pro inflammatory cytokines. Am J Respir Cell Mol Biol 1997;16:187–193.

    PubMed  CAS  Google Scholar 

  58. Kakugawa Y, Giaid A, Yanagisawa M, et al. Expression of endothelin-1 in pancreatic tissue of patients with chronic pancreatitis. J Pathol 1996;178:78–83.

    Article  PubMed  CAS  Google Scholar 

  59. Giaid A, Saleh D, Yanagisawa M, Forbes RD. Endothelin-1 immunoreactivity and mRNA in the transplanted human heart. Transplantation 1995;59:1308–1313.

    PubMed  CAS  Google Scholar 

  60. Vancheeswaran R, Azam A, Black C, Dashwood MR. Localization of endothelin-1 and its binding sites in scleroderma skin. J Rheumatol 1994;21:1268–1276.

    PubMed  CAS  Google Scholar 

  61. Vancheeswaran R, Magoulas T, Efrat G, et al. Circulating endothelin-1 levels in systemic sclerosis subsets—a marker of fibrosis or vascular dysfunction? J Rheumatol 1994;21:1838–1844.

    PubMed  CAS  Google Scholar 

  62. Kohan DE. Endothelins in the normal and diseased kidney. Am J Kidney Dis 1997;29:2–26.

    PubMed  CAS  Google Scholar 

  63. Forbes RD, Cernacek P, Zheng S, Gomersall M, Guttmann RD. Increased endothelin expression in a rat cardiac allograft model of chronic vascular rejection. Transplantation 1996;61:791–797.

    Article  PubMed  CAS  Google Scholar 

  64. Alam I, Bass NM, Bacchetti P, Gee L, Rockey DC. Hepatic tissue endothelin-1 levels in chronic liver disease correlate with disease severity and ascites. Am J Gastroenterol 2000;95:199–203.

    Article  PubMed  CAS  Google Scholar 

  65. Rockey DC, Fouassier L, Chung JJ, et al. 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;27:472–480.

    Article  PubMed  CAS  Google Scholar 

  66. Shao R, Yan W, Rockey DC. Regulation of endothelin-1 synthesis by endotlielin-converting enzyme-1 during wound healing. J Biol Chem 1999;274:3228–3234.

    Article  PubMed  CAS  Google Scholar 

  67. Shao R, Shi Z, Gotwals PJ, Koteliansky VE, George J, Rockey DC. Cell and molecular regulation of endothelin-1 production during hepatic wound healing. Mol Biol Cell 2003;14:2327–2341.

    Article  PubMed  CAS  Google Scholar 

  68. Gondo K, Ueno T, Sakamoto M, Sakisaka S, Sata M, Tanikawa K. The endothelin-1 binding site in rat liver tissue: light-and electron-microscopic autoradiographic studies. Gastroenterology 1993;104:1745–1749.

    PubMed  CAS  Google Scholar 

  69. Kojima H, Yamao J, Tsujimoto T, Uemura M, Takaya A, Fukui H. Mixed endothelin receptor antagonist, SB209670, decreases portal pressure in biliary cirrhotic rats in vivo by reducing portal venous system resistance. J Hepatol 2000;32:43–50.

    Article  PubMed  CAS  Google Scholar 

  70. Reichen J, Gerbes AL, Steiner MJ, Sagesser H, Clozel M. The effect of endothelin and its antagonist Bosentan on hemodynamics and microvascular exchange in cirrhotic rat liver. J Hepatol 1998;28:1020–1030.

    Article  PubMed  CAS  Google Scholar 

  71. Bauer M, Zhang JX, Bauer I, Clemens MG. ET-1 induced alterations of hepatic microcirculation: sinusoidal and extrasinusoidal sites of action. Am J Physiol 1994;267:G143–G149.

    PubMed  CAS  Google Scholar 

  72. Zhang JX, Bauer M, Clemens MG. Vessel-and target cell-specific actions of endothelin-1 and endo-thelin-3 in rat liver. Am J Physiol 1995;269:G269–G277.

    PubMed  CAS  Google Scholar 

  73. Bauer M, Bauer I, Sonin NV, et al. Functional significance of endothelin B receptors in mediating sinusoidal and extrasinusoidal effects of endothelins in the intact rat liver [In Process Citation]. Hepatology 2000;31:937–947.

    Article  PubMed  CAS  Google Scholar 

  74. Cody RJ. The integrated effects of angiotensin II. Am J Cardiol 1997;79:9–11.

    Article  PubMed  CAS  Google Scholar 

  75. Riordan IF. Angiotensin II: biosynthesis, molecular recognition, and signal transduction. Cell Mol Neurobiol 1995;15:637–651.

    Article  PubMed  CAS  Google Scholar 

  76. Bataller R, Gines P, Nicolas JM, et al. Angiotensin IT induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 2000;118:1149–1156.

    Article  PubMed  CAS  Google Scholar 

  77. Bataller R, Gines P, Lora J, et al. Evidence for a local renin-angiotensin system in human liver: expression in activated hepatic stellate cells. Hepatology 2001;34:399A.

    Google Scholar 

  78. Paizis G, Gilbert RE, Cooper ME, et al. Effect of angiotensin II type 1 receptor blockade on experimental hepatic fibrogenesis. J Hepatol 2001;35:376–385.

    Article  PubMed  CAS  Google Scholar 

  79. Yoshiji H, Kuriyama S, Yoshii J, et al. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 2001;34:745–750.

    PubMed  CAS  Google Scholar 

  80. Bataller R, Schwabe RF, Choi YH, et al. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest 2003;112:1383–1394.

    Article  PubMed  CAS  Google Scholar 

  81. De BK, Bandyopadhyay K, Das TK, et al. Portal pressure response to losartan compared with propranolol in patients with cirrhosis. Am J Gastroenterol 2003;98:1371–136.

    Article  PubMed  CAS  Google Scholar 

  82. Tripathi D, Therapondos G, Lui HF, Johnston N, Webb DJ, Hayes PC. Chronic administration of losartan, an angiotensin TI receptor antagonist, is not effective in reducing portal pressure in patients with preascitic cirrhosis. Am J Gastroenterol 2004;99:390–394.

    Article  PubMed  CAS  Google Scholar 

  83. Marley R, Harry D, Anand R, Fernando B, Davies S, Moore K. 8-Isoprostaglandin F2 alpha, a product of lipid peroxidation, increases portal pressure in normal and cirrhotic rats. Gastroenterology 1997;112:208–213.

    Article  PubMed  CAS  Google Scholar 

  84. Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1985;1:325–337.

    Article  PubMed  CAS  Google Scholar 

  85. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002–2012.

    Article  PubMed  CAS  Google Scholar 

  86. Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 1991;351:714–718.

    Article  PubMed  CAS  Google Scholar 

  87. Lowenstein CJ, Glatt CS, Bredt DS, Snyder SH. Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme. Proc Natl Acad Sci USA 1992;89:6711–6715.

    Article  PubMed  CAS  Google Scholar 

  88. Lamas S, Marsden PA, Li GK, Tempst P, Michel T. Endothelial nitric oxide synthase: molecular cloning and characterization of a distinct constitutive enzyme isoform. Proc Natl Acad Sci USA 1992;89:6348–6352.

    Article  PubMed  CAS  Google Scholar 

  89. Awolesi MA, Sessa WC, Sumpio BE. Cyclic strain upregulates nitric oxide synthase in cultured bovine aortic endothelial cells. J Clin Invest 1995;96:1449–1454.

    Article  PubMed  CAS  Google Scholar 

  90. Weiner CP, Lizasoain I, Baylis SA, Knowles RG, Charles IG, Moncada S. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci USA 1994;91:5212–5216.

    Article  PubMed  CAS  Google Scholar 

  91. Qi WN, Yan ZQ, Whang PG, et al. Gene and protein expressions of nitric oxide synthases in ischemia-reperfused peripheral nerve of the rat. Am J Physiol Cell Physiol 2001;281:C849–C856.

    PubMed  CAS  Google Scholar 

  92. Saur D, Seidler B, Paehge H, Schusdziarra V, Allescher HD. Complex regulation of human neuronal nitric-oxide synthase exon 1c gene transcription. Essential role of Sp and ZNF family members of transcription factors. J Biol Chem 2002;277:25,798–25,814.

    Article  PubMed  CAS  Google Scholar 

  93. Damy T, Ratajczak P, Shah AM, et al. Increased neuronal nitric oxide synthase-derived NO production in the failing human heart. Lancet 2004;363:1365–1367.

    Article  PubMed  CAS  Google Scholar 

  94. Ranjan V, Xiao Z, Diamond SI,. Constitutive NOS expression in cultured endothelial cells is elevated by fluid shear stress. Am J Physiol 1995;269:H550–H555.

    PubMed  CAS  Google Scholar 

  95. Garcia-Cardena G, Martasek P, Masters BS, et al. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem 1997;272:25,437–25,440.

    Article  PubMed  CAS  Google Scholar 

  96. Feron O, Saldana F, Michel JB, Michel T. The endothelial nitric-oxide synthase-caveolin regulatory cycle. J Biol Chem 1998;273:3125–3128.

    Article  PubMed  CAS  Google Scholar 

  97. Feron O, Dessy C, Moniotte S, Desager JP, Balligand JL. Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase. J Clin Invest 1999;103:897–905.

    PubMed  CAS  Google Scholar 

  98. 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 

  99. Garcia-Cardena G, Fan R, Shah V, et al. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 1998;392:821–824.

    Article  PubMed  CAS  Google Scholar 

  100. Kou R, Greif D, Michel T. Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A. J Biol Chem 2002;277:29,669–29,673.

    Article  PubMed  CAS  Google Scholar 

  101. Gonzalez E, Kou R, Lin AJ, Golan DE, Michel T. Subcellular targeting and agonist-induced site-specific phosphorylation of endothelial nitric-oxide synthase. J Biol Chem 2002;277:39,554–39,560.

    Article  PubMed  CAS  Google Scholar 

  102. Cao S, Yao J, McCabe TJ, et al. Direct interaction between endothelial nitric-oxide synthase and dynamin-2. Implications for nitric-oxide synthase function. J Biol Chem 2001;276:14,249–14,256.

    PubMed  CAS  Google Scholar 

  103. Huang PL, Huang Z, Mashimo IT, et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase [see comments]. Nature 1995;377:239–242.

    Article  PubMed  CAS  Google Scholar 

  104. Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology 1998;114:344–351.

    Article  PubMed  CAS  Google Scholar 

  105. Shah V, Haddad FG, Garcia-Cardena G, et al. Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids. J Clin Invest 1997;100:2923–2930.

    PubMed  CAS  Google Scholar 

  106. Mittal MK, Gupta TK, Lee F Y, Sieber CC, Groszmann RJ. Nitric oxide modulates hepatic vascular tone in normal rat liver. Am J Physiol 1994;267:G416–G422.

    PubMed  CAS  Google Scholar 

  107. 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;28:926–931.

    Article  PubMed  CAS  Google Scholar 

  108. Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 2002;35:478–491.

    Article  PubMed  CAS  Google Scholar 

  109. 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;117:1222–1228.

    Article  PubMed  CAS  Google Scholar 

  110. McMillan K, Bredt DS, Hirsch D J, Snyder SH, Clark JE, Masters BS. Cloned, expressed rat cerebellar nitric oxide synthase contains stoichiometric amounts of heme, which binds carbon monoxide. Proc Natl Acad Sci USA 1992;89:11,141–11,145.

    Article  PubMed  CAS  Google Scholar 

  111. Denninger JW, Marietta MA. Guanylate cyclase and the.NO/cGMP signaling pathway. Biochim Biophys Acta 1999;1411:334–350.

    Article  PubMed  CAS  Google Scholar 

  112. Makino N, Suematsu M, Sugiura Y, et al. Altered expression of heme oxygenase-1 in the livers of patients with portal hypertensive diseases. Hepatology 2001;33:32–42.

    Article  PubMed  CAS  Google Scholar 

  113. Garcia N Jr, Jarai Z, Mirshahi F, Kunos G, Sanyal AJ. Systemic and portal hemodynamic effects of anandamide. Am J Physiol Gastrointest Liver Physiol 2001;280:G14–G20.

    PubMed  CAS  Google Scholar 

  114. Batkai S, Jarai Z, Wagner JA, et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 2001;7:827–832.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Liver Center, Duke University Medical Center, Durham, NC

    Don C. Rockey MD

Authors
  1. Don C. Rockey MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Gastroenterology, Virginia Commonwealth Medical Center, Richmond, VA

    Arun J. Sanyal MBBS, MD

  2. GI Research Unit, Mayo Clinic, Rochester, MN

    Vijay H. Shah MD

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Rockey, D.C. (2005). Cell and Molecular Mechanisms of Increased Intrahepatic Resistance and Hemodynamic Correlates. In: Sanyal, A.J., Shah, V.H. (eds) Portal Hypertension. Clinical Gastroenterology. Humana Press. https://doi.org/10.1007/978-1-59259-885-4_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-885-4_3

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-386-2

  • Online ISBN: 978-1-59259-885-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation