The endothelin-1 binding site in rat liver tissue: Light- and electron-microscopic autoradiographic studies

Gondo, Kazuhisa; Ueno, Takato; Sakamoto, Masaharu; Sakisaka, Shotaro; Sata, Michio; Tanikawa, Kyuichi

doi:10.1016/0016-5085(93)90654-u

Cited by 80 publications

(38 citation statements)

References 18 publications

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“…In normal and diseased livers, the hemodynamic regulation in the hepatic lobules is mainly conducted by perisinusoidal cells and endothelial cells by releasing ET and NO as effector molecules (Gondo et al, 1993;Leivas et al, 1998, Rockey et al, 1998. Regarding the hemodynamics around the intrahepatic biliary tree, the endothelium of PVP may take part in the regulation of vascular tone through the release of relaxing and contracting factors under basal conditions, and when activated by different stimuli, as has been speculated for other organs (Laffi and Marra, 1999;Luscher et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Evidence of the Participation of Peribiliary Mast Cells in Regulation of the Peribiliary Vascular Plexus Along the Intrahepatic Biliary Tree

Koda

Harada

Tsuneyama

et al. 2000

Laboratory Investigation

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SUMMARY:Our pilot study disclosed that tryptase-positive mast cells (MC) were densely distributed around the intrahepatic bile ducts (peribiliary MC). In this study, the pathophysiologic roles of these MC were examined with respect to the microcirculation around the bile duct in 71 cases of histologically normal liver, 24 cases of chronic hepatitis, and 45 cases of liver cirrhosis. The tryptase-positive MC were very close to the microvessels of the peribiliary vascular plexus (PVP), which supply the intrahepatic biliary tree. The tryptase-positive MC were frequently found adjacent to vascular smooth muscle cells, including pericytes. The location of the tryptase-positive MC was confirmed by ultrastructural analysis. In cirrhosis, the numbers of both microvessels of PVP and peribiliary MC increased in parallel. Peribiliary MC were immunoreactive for endothelin 1 (ET-1), and were variably immunoreactive for histamine, chymase, inducible nitric oxide synthase (iNOS), and endothelin A and B (ET A and ET B ) receptors, particularly in cirrhotic livers. On vascular endothelial cells of PVP, endothelial nitric oxide synthase (eNOS) and ET-1 were consistently detectable, and ET A receptors, ET B receptors, and iNOS were variably detectable. Pericytes of PVP expressed ET A and ET B receptors in addition to ET-1 and iNOS. Biliary epithelial cells also focally expressed iNOS, ET-1, and ET A and ET B receptors. These vasoactive substances were strongly expressed on the cellular components in cirrhotic liver. By in situ hybridization, iNOS mRNA signals were observed on iNOS-immunoreactive cell components, including peribiliary MC. These morphologic and immunohistochemical findings suggest that the cellular components displaying vasoactive substances in the milieu of the intrahepatic biliary tree are very dynamic in the vasoregulation of PVP in normal livers, even more so in cirrhosis, and that peribiliary MC exert local effects on the microcirculation of PVP, directly and indirectly. A list of abbreviations: AMeX, acetone, methyl benzoate, and xylene; ASMA, ␣-smooth muscle actin; ET, endothelin; ET-1, endothelin 1; ET A receptor, endothelin A receptor; ET B receptor, endothelin B receptor; eNOS, endothelial nitric oxide synthase; MC, mast cell; MC T , tryptase positive, chymase negative mast cells; MC TC , tryptase positive, chymase positive mast cells; NO, nitric oxide; iNOS, inducible nitric oxide synthase; PBS, phosphate buffer saline; PVP, peribiliary vascular plexus; TNF-, tumor necrosis factor ␣ (Lab Invest 2000, 80:1007-1017.

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Section: Discussionmentioning

confidence: 99%

Evidence of the Participation of Peribiliary Mast Cells in Regulation of the Peribiliary Vascular Plexus Along the Intrahepatic Biliary Tree

Koda

Harada

Tsuneyama

et al. 2000

Laboratory Investigation

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“…44 Indeed, localization of infused, labeled ET-1 in the liver is consistent with binding to stellate cells. 15,45 Further, endothelin receptors are up-regulated in the injured liver 40,46 and specifically in stellate cells 19 (Fig. 1).…”

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confidence: 89%

Vascular mediators in the injured liver

2003

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“…Endothelins are 1 of several vasoactive substances that contribute to the increase in portal pressure. ET-1 regulates blood flow within the liver by stimulating contraction of HSCs through the ET-1 type A receptor, 14 presinusoidal portal venules, 15 and hepatic sinusoids. 16 ET-1-induced constriction of preterminal portal venules causes significant increases in portal pressure in rats, 17 whereas bosentan, a non-receptor-selective antagonist, and BQ123, an ET-1 type A-receptor antagonist, can decrease portal pressure.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Localization of Endothelin-1 in Patients With Idiopathic Portal Hypertension and Cirrhosis of the Liver

Kamath

Carpenter

Lloyd

et al. 2000

Liver Transplantation

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Endothelin-1 (ET-1) may mediate increased resistance to hepatic sinusoidal blood flow. We evaluated the hepatic distribution of ET-1 in patients with idiopathic portal hypertension (IPH), in which liver architecture may be normal, and in patients with cirrhosis, in which distortion of hepatic sinusoidal architecture is prominent. Immunohistochemistry and in situ hybridization were used to localize ET-1 in hepatic tissue of patients with IPH and cirrhosis. ET-1 was measured in plasma from a peripheral vein, the hepatic vein, and the portal vein of patients with cirrhosis of the liver and controls. On immunohistochemistry and in situ hybridization, ET-1 was localized to periportal hepatocytes and sinusoidal cells in patients with IPH and cirrhosis. Minimal positive staining for ET-1 was observed in control livers. Plasma ET-1 levels were significantly greater in patients with cirrhosis than in controls. In patients with cirrhosis, ET-1 was greater in the hepatic vein compared with the portal vein. However, the level of plasma ET-1 in patients with cirrhosis did not correlate with either the presence of ascites or portacaval pressure gradient. We conclude that in IPH, ET-1 is localized to sites in which it can modulate intrahepatic resistance. In late stages of cirrhosis, ET-1 may not modulate resistance. We speculate that vascular resistance in late stages of cirrhosis probably results from distortion of hepatic architecture. (Liver Transpl 2000;6:596-602.) P ortal hypertension results mainly from increased resistance to hepatic sinusoidal blood flow. 1 Factors increasing hepatic sinusoidal resistance include a fixed component related to fibrosis and nodule formation that distorts hepatic sinusoidal architecture and a reversible component that may be humoral in origin. 2,3 The fixed and reversible components of hepatic sinusoidal resistance may not be operative at the same time.The reversible component may precede the fixed component and result either from impaired production of vasodilators that decrease sinusoidal resistance in normal livers 4 or from increased production of vasoconstrictors that stimulate contraction of hepatic stellate cells (HSCs) distributed around the hepatic sinusoids. 5 One humoral factor modulating increased resistance may be endothelin-1 (ET-1). 5 Endothelins are a family of vasoactive peptides designated ET-1, ET-2, and ET-3. 6 ET-1 levels are elevated in patients with cirrhosis of the liver, especially in the presence of ascites and hepatorenal syndrome. 7 ET-1 not only modulates sinusoidal flow, but may also facilitate collagen production and hepatic remodeling. 8 Whether ET-1 levels increase in early portal hypertension is not known. In rats with portal hypertension, hepatic sinusoidal resistance increases even before the onset of fibrosis, an action mediated by ET-1. 9 Because endothelin levels are increased in idiopathic pulmonary hypertension (IPH), 10 we postulate that ET-1 level similarly may increase in humans early in the onset of portal hypertension before diffuse fibrosis a...

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The endothelin-1 binding site in rat liver tissue: Light- and electron-microscopic autoradiographic studies

Cited by 80 publications

References 18 publications

Evidence of the Participation of Peribiliary Mast Cells in Regulation of the Peribiliary Vascular Plexus Along the Intrahepatic Biliary Tree

Evidence of the Participation of Peribiliary Mast Cells in Regulation of the Peribiliary Vascular Plexus Along the Intrahepatic Biliary Tree

Vascular mediators in the injured liver

Hepatic Localization of Endothelin-1 in Patients With Idiopathic Portal Hypertension and Cirrhosis of the Liver

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