Plasma endothelin levels in patients with cirrhosis and their relationships to the severity of cirrhosis and renal function

Tsai, Yang‐Te; Lin, Han‐Chieh; Yang, Meng; Lee, Fa-Yuah; Hou, Ming‐Chih; Chen, Ling-Sheng; Lee, Shou‐Dong

doi:10.1016/0168-8278(95)80034-4

Cited by 55 publications

(28 citation statements)

References 43 publications

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“…The possible role of ET in the pathophysiology of PHT has recently been addressed in humans 34,35 and in animal models of PHT with or without parenchymal dysfunction. [20][21][22] While an overwhelming number of studies have demonstrated increased ET levels in cirrhotic animals, 20,21 several studies have also reported decreased circulating levels of ET-1 in PHT.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of endothelin receptors in the vasculature of portal hypertensive rats: Role in splanchnic hemodynamics

et al. 1998

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Portal hypertension (PHT) is characterized by a hyperdynamic circulatory state that is commonly observed in patients with chronic liver disease and in experimental models of PHT with extensive collateral circulation. 1,2 Experimental models have improved our understanding of the pathophysiology of PHT. 1,2 It is now clear that an increased vascular resistance to portal flow is the initial factor responsible for the increase in portal pressure due to changes in hepatic circulation. 1,2 In the latter stages of the development of PHT, an increased portal venous blood inflow, promoted by splanchnic vasodilation, contributes to the maintenance and aggravation of PHT. 1,2 The splanchnic circulation is therefore the vascular bed with the most pronounced vasodilation, although there is also hyperkinetic syndrome systemically with reduced arterial pressure and peripheral vascular resistance. 1,2 An expanded plasma volume is also apparent in PHT and represents another mechanism that further contributes to the increased portal pressure. 3,4 Endothelin (ET) is a 21-amino acid peptide with potent vasoconstrictive and mitogenic properties. 5,6 ET is produced by several cell types including vascular endothelial cells. The cellular action of ET on vascular tissue is initiated by peptide binding to specific cell surface receptors. Two different receptors for ET have been identified: cloned and characterized. 7,8 The ET-A receptor on vascular tissue, which preferentially binds ET-1, is linked to phospholipase C enzyme activity, subsequent phosphoinositide metabolism, and the mobilization of intracellular calcium via a Gq protein. [5][6][7][8][9][10] The ET-B receptor, which equally binds ET-1 and ET-3, respectively, is functionally coupled to nitric oxide (NO) synthase activity via an inhibitory G-protein (Gi) on endothelial cells and coordinates the generation of NO via a tyrosine kinasedependent and a calcium/calmodulin-dependent pathway. 5,6,9,11 ET-B receptors are also present on vascular smooth muscle cells and have been shown to mediate vasoconstriction in veins 12,13 and some arteries. [14][15][16] The possible role of ET in the pathophysiology of PHT has recently been addressed in humans and animal models of PHT with or without parenchymal dysfunction. [17][18][19][20][21][22][23][24] While an overwhelming number of clinical studies have demonstrated increased ET levels in cirrhotic patients, 20,21 several studies have also reported decreased circulating levels of ET-1 in PHT. 22,23 Therefore, the pathophysiological importance of ET in PHT remains unclear. A reduced pressor responsiveness to high doses of ET in cirrhotic rats with PHT has been reported. 24 This hyporesponsiveness to ET-1 appears to be dependent on NO production and may contribute to the maintenance of splanchnic blood flow in these animals. However, the role of endogenous ET in controlling splanchnic hemodynamics in PHT has not been evaluated. Of note, studies in cirrhotic rats and PHT animals have demonstrated that ET receptors are up-regulated in the ki...

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Section: Discussionmentioning

confidence: 99%

Increased expression of endothelin receptors in the vasculature of portal hypertensive rats: Role in splanchnic hemodynamics

et al. 1998

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“…A predominant observation is reversible renal vasoconstriction that can lead to hepatorenal syndrome and renal failure. The mechanism of the renal vasoconstriction is unclear, but it may be related to elevated levels of endothelin-1 (ET-1) during cirrhosis (13)(14)(15) that are a consequence of the hyperdynamic systemic circulation. Despite the state of renal vasoconstriction, increased endothelium-dependent renal vasodilation has been reported during cirrhosis (16).…”

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Increased Epoxyeicosatrienoic Acid Formation in the Rat Kidney during Liver Cirrhosis

Miyazono

Zhu

Nemenoff³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Vascular complications during liver cirrhosis are often severe, particularly in the kidney. These complications are the result of complex and poorly understood interactions between the injured liver and other organs such as the lungs, heart, and kidney. The purpose of this study was to investigate the alterations to renal hemodynamics during cirrhosis, focusing on the actions of epoxyeicosatrienoic acids (EET), known to be potent regulators of renal hemodynamics. Cirrhosis was induced in rats by common bile duct ligation (CBDL), and they were compared with sham rats. Experiments were conducted 4 wk after either the sham or CBDL surgery. Vasoreactivity was assessed in isolated perfused kidneys. cPLA 2 expression and cytochrome P450 (CYP450) expression were measured using Western blot. cPLA 2 enzymatic activity was measured by radioenzymatic assay. EET production was measured using rpHPLC analysis. The major findings were that kidneys from CBDL rats had significantly greater acetylcholine-induced vasodilation that was partially blocked by nitric oxide (NO) and prostaglandin inhibition and fully blocked by the combined inhibition of NO, prostaglandins, and CYP450 metabolites. Expression and activity of cPLA 2 in CBDL kidneys was increased, providing arachidonic acid substrate to the CYP450 enzymes. Finally, expression and activity of CYP450 enzymes was elevated in CBDL kidneys, resulting in significantly greater production of the vasodilating 11,12-EET and 14,15-EET. While it is well documented that renal vasoconstriction leading to impaired renal function occurs during cirrhosis, our data clearly demonstrate that endogenous production of EET is increased in cirrhotic kidneys. This may be a homeostatic response to preserve renal perfusion.Endothelium-dependent vasodilation is an important regulatory mechanism in the kidney. Many studies indicate that peripheral vasodilation of splanchnic organs may be the leading factor causing the renal dysfunction of cirrhosis (for review, see reference 1). Endothelial cells produce a wide array of biologic active agents that regulate vascular tone. These agents include NO, prostaglandin, and an unidentified substance that hyperpolarizes vascular smooth muscle called endothelium-derived hyperpolarizing factor (EDHF). The biologic actions of epoxyeicosatrienoic acids (EET) make them a strong candidate for being EDHF, because EET dilate blood vessels by activating vascular smooth muscle calcium-activated K ϩ (K Ca ) channels resulting in membrane hyperpolarization. EET are produced from arachidonic acid cleaved from membrane-associated phospholipid pools by phospholipase-A2 (cPLA 2 ) (2-4) and are further metabolized by specific cytochrome P450 (CYP450) enzymes (5-9). It is known that CYP450 2C isoforms are responsible for the majority of EET biosynthesis in the rat kidney, and CYP 2C11, 2C23, and 2C24 are the predominant 2C isoforms expressed in the male rat kidney (10 -12). However, the vascular sites of action responsible for the CYP component in cirrhotic rat kidney a...

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“…[1][2][3][4][5][6][7][8] Despite this, these patients have low arterial pressure and systemic vascular resistance. This discrepant finding may be caused, at least in part, by a vascular hyporesponsiveness to endothelins that has been identified in cirrhotic rats.…”

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Beneficial hemodynamic effects of bosentan, a mixed ETA and ETB receptor antagonist, in portal hypertensive rats

et al. 1998

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In patients with cirrhosis, the plasma level of endothelin, a potent vasoconstrictor peptide, is elevated, and endothelin plays a role in increased intrahepatic vascular resistance. Thus, the aim of this study was to evaluate the hemodynamic effects of bosentan, a mixed ET A and ET B endothelin receptor antagonist in three models of portal hypertension. In all groups of rats, endothelin (2 g/kg intravenously) administration significantly increased intrahepatic vascular resistance. In rats with secondary biliary cirrhosis, bosentan (30 mg/kg) significantly reduced portal pressure from 14.6 ؎ 1.2 to 12.1 ؎ 0.6 mm Hg, while portal blood flow and cardiac output increased by 45% and 57%, respectively. Thus, hepatocollateral vascular resistance decreased significantly from 177 ؎ 19 to 101 ؎ 9 dyn · s · cm ؊5 ؋ 10 ؊3 . Similar results were observed in rats with CCl 4 -induced cirrhosis. In isolated perfused cirrhotic rat livers, bosentan (1 to 100 mol/L) had no significant effect on hepatic vascular resistance. In portal vein-stenosed rats, bosentan administration significantly decreased portal pressure from 13.1 ؎ 0.6 to 11.4 ؎ 0.5 mm Hg by reducing portosystemic vascular resistance, because bosentan had no effect on vascular resistance of normal rat liver. In conclusion, bosentan administration decreased portal pressure in vivo by reducing hepatocollateral vascular resistance in rats with cirrhosis. Thus, mixed endothelin receptor antagonists might be a new approach in the pharmacological treatment of portal hypertension. (HEPATOLOGY 1998;28:655-659.)Numerous studies have found that plasma concentrations of endothelin-1 (ET-1) and endothelin-3 (ET-3) are increased in patients with cirrhosis and are related to the severity of the liver disease. 1-8 Despite this, these patients have low arterial pressure and systemic vascular resistance. This discrepant finding may be caused, at least in part, by a vascular hyporesponsiveness to endothelins that has been identified in cirrhotic rats. 9,10 Moreover, it has been shown that endothelins induce sinusoidal vasoconstriction through both ET A and ET B receptors and increase intrahepatic vascular resistance in the normal and perfused cirrhotic liver. [11][12][13][14][15] These results suggest that endothelins play a role in the mechanism of intrahepatic portal hypertension. Thus, administration of the mixed ET A and ET B receptor antagonist, 16,17 bosentan, may decrease intrahepatic vascular resistance and decrease portal hypertension. The aim of this study was to evaluate the acute hemodynamic effect of both bosentan and endothelin in two animal models of cirrhosis and in one model with extrahepatic portal hypertension. MATERIALS AND METHODSAnimals. Sixty-four male Sprague-Dawley rats (Charles River Laboratories, Saint-Aubin-lès-Elbeuf, France) were divided into four groups. The first group contained 16 normal rats. The second group contained 16 rats with portal hypertension induced by the partial ligation of the portal vein, as previously described. 18 The hemodynamic study w...

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Plasma endothelin levels in patients with cirrhosis and their relationships to the severity of cirrhosis and renal function

Cited by 55 publications

References 43 publications

Increased expression of endothelin receptors in the vasculature of portal hypertensive rats: Role in splanchnic hemodynamics

Increased expression of endothelin receptors in the vasculature of portal hypertensive rats: Role in splanchnic hemodynamics

Increased Epoxyeicosatrienoic Acid Formation in the Rat Kidney during Liver Cirrhosis

Beneficial hemodynamic effects of bosentan, a mixed ETA and ETB receptor antagonist, in portal hypertensive rats

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