UMLS:C0023890 - FACTA Search

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Query: UMLS:C0023890 (cirrhosis)
42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 belongs to a family of potent vasoconstrictors, recently isolated from endothelial cells. Endothelin-1 has a variety of hepatic effects and hepatic clearance from the circulation is important. Elevated plasma concentrations of Endothelin-1 are found after orthotopic liver transplantation and in cirrhosis with ascites. This study in piglets on hepatic bloodflow was designed to compare differences in effects between central venous and intraportal injection of endothelin-1, and to evaluate effects of repeated injections. Central venous injection of endothelin-1 caused a larger reduction in portal vein flow, while intraportal injection caused a larger increase in portal vein pressure. Repeated injections resulted in a reduction in portal vein flow and an increase in portal vein vascular resistance.
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PMID:Effects of endothelin-1 on hepatic blood flow. 872 56

1. Liver cirrhosis was induced in rats by CCl4 administration. We analysed the expression of endothelin receptor subtypes in the renal cortex and medulla using Scatchard analysis and receptor autoradiography, and measured plasma as well as renal-tissue endothelin-1 concentrations using a specific radioimmunoassay. Furthermore, we analysed the effects of the non-selective (A/B) endothelin receptor antagonist, bosentan (6 and 100 mg kg-1 day-1) on mean arterial blood pressure, water and sodium excretion and glomerular filtration rate. 2. Our study revealed an overexpression of the endothelin B receptor (ETB) in the renal medulla of rats with liver cirrhosis (Cir: 2775 +/- 299 fmol mg-1; Con: 1695 +/- 255 fmol mg-1; n = 8; means +/- s.d., P < 0.01), whereas the density of ETB in the cortex and the endothelin A receptor (ETA) in the cortex and medulla were similar in both cirrhotic and control rats. Receptor autoradiography showed that the upregulation of medullary ETB in cirrhotic rats was due to an upregulation of ETB in the inner medullary collecting duct cells. 3. The tissue endothelin-1 concentrations were increased in the renal medulla of cirrhotic rats (Cir: 271 +/- 68 pg g-1wet wt.; Con: 153 +/- 36 pg g-1 wet wt., n = 8; means +/- s.d., P < 0.01). 4. The glomerular filtration rate was slightly decreased in cirrhotic rats but not altered after bosentan treatment in either cirrhotic or control rats. Bosentan decreased sodium excretion to a similar extent in both cirrhotic and control rats, whereas water excretion was significantly reduced by both dosages of bosentan in cirrhotic rats only (Cir + vehicle: 12.5 +/- 0.62 m day-1, Cir + 6 mg kg-1 day-1 bosentan: 8.6 +/- 1.0 ml day-1; Cir + 100 mg kg-1 day-1 bosentan: 7.4 +/- 0.6 ml day-1; n = 10; means +/- s.e.mean). 5. We therefore suggest that the upregulation of the medullary ETB in cirrhotic rats is involved in the regulation of water excretion in rats with CCl4-induced liver cirrhosis.
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PMID:Paracrine renal endothelin system in rats with liver cirrhosis. 873 18

Isolated, perfused rat liver preparations (IPRL), obtained from rats with carbon tetrachloride-induced cirrhosis and normal controls, were used to investigate responses to the vasoactive peptide endothelin-1 (ET-1). The mean perfusion resistance (R) of cirrhotic IPRL was significantly greater than that of controls (2.63 +/- 0.24 vs 1.54 +/- 0.14 mmHg/mL per min per g; P < 0.01). Both control and cirrhotic IPRL demonstrated a concentration-related increase in resistance (delta R) in response to ET-1, with a minimum effective concentration of approximately 3 x 10(-11) mol/L. The EC50 (-log of the 50% effective concentration) was not significantly different between cirrhotic and control IPRL (8.48 +/- 0.19 and 8.79 +/- 0.11, respectively); however, the maximum response to ET-1 was significantly greater in cirrhotic preparations (R: 10.4 +/- 2.2 vs 4.4 +/- 0.5 mmHg/mL per min per g, P < 0.01; DR, 7.8 +/- 2.1 vs 2.8 +/- 0.4 mmHg/mL per min per g, P < 0.01). Following maximal stimulation by ET-1, the mean portal-hepatic venous pressure gradient at a physiological flow rate of 1 mL/min per g was approximately 90% greater across cirrhotic IPRL than that across normal IPRL (11.2 +/- 2.0 vs 5.9 +/- 0.9 mmHg, respectively; P < 0.05). These results support the hypothesis that endogenously released ET-1 has a significant influence on the portal vascular resistance of cirrhotic liver in vivo and has an important role in the pathogenesis of portal hypertension.
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PMID:Endothelin-induced vasoconstriction in isolated perfused liver preparations from normal and cirrhotic rats. 919 72

Patients with cirrhosis exhibit characteristic hemodynamic changes with a hyperkinetic circulation and an abnormal distribution of the blood volume and neurohumoral regulation. Their plasma and noncentral blood volumes are increased, and the central and arterial blood volume and systemic vascular resistance are decreased. A peripheral arterial vasodilatation may be of pathogenic importance to the low systemic vascular resistance as it directly correlates to the degree of central hypovolemia. It may therefore be an important element in the development of the low arterial blood pressure and hyperkinetic circulation in cirrhosis. Various vasodilators such as atrial natriurectic peptide, calcitonin gene-related peptide, adrenomedullin, and nitric oxide are among potential candidates in the arterial vasodilatation in cirrhosis. Besides enhanced sympathetic nervous activity, activation of the renin-angiotensin-aldosterone system, and elevated circulating vasopressin, endothelin-1 may also be implicated in the hemodynamic counter-regulation in cirrhosis. Recent research has focused on the assertion that the hemodynamic and neurohumoral abnormalities in cirrhosis are part of a general circulatory dysfunction influencing the course of the disease.
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PMID:Circulatory abnormalities in cirrhosis with focus on neurohumoral aspects. 935 62

Endothelin (ET) peptides have been implicated in the pathogenesis of several biological processes within the liver. ET levels are elevated in the circulation of patients with cirrhosis, and recent data suggest that ET may be overproduced in the liver itself in this condition. The aims of the current study were to elucidate the cellular source and expression of endothelin-1 (ET-1) in normal and injured liver, and to investigate its biological effects on stellate cells, the primary target of ETs in the liver. In normal hepatic cells, preproET-1 messenger RNA (mRNA) was detected in only nonparenchymal cells, predominantly in sinusoidal endothelial cells. After biliary fibrosis and early cirrhosis induced by bile duct ligation, preproET-1 mRNA and immunoreactive ET levels increased with progressive injury in whole liver extracts, as well as in isolated stellate and endothelial cell fractions. Eight days after bile duct ligation, the relative increase in preproET-1 mRNA was 1.6- and 7.6-fold above normal in sinusoidal endothelial and stellate cells, respectively. Additionally, immunoreactive ET peptide levels increased by 60% +/- 27% over basal values in sinusoidal endothelial cells and 98% +/- 40% in stellate cells. Cultured stellate cells responded dramatically to exogenous ET-1 by the spreading and up-regulation of smooth muscle alpha actin expression. Furthermore, in early culture before cellular activation, ET-1 (10 nmol/L) caused over a twofold increase in [3H]thymidine incorporation, while activated cells (i.e., those cultured for >1 week) exposed to ET-1 exhibited up to a fivefold decrease in [3H]thymidine incorporation. The data indicate that not only is ET-1 overproduced by both sinusoidal endothelial and stellate cells during liver injury, but that it also has potent effects on features of stellate cell activation. We conclude that autocrine and paracrine production of ET-1 is prominent and is likely to be important in the pathogenesis of hepatic diseases.
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PMID:Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells. 946 46

Hepatic levels of a powerful vasoconstrictor endothelin-1 (ET-1) and its receptors increase in human and carbon tetrachloride (CCl4)-induced liver cirrhosis. The aim of this study was to determine whether antagonism of hepatic ET-1 receptors ameliorates CCl4-induced hepatic injury and portal hypertension in rats. Acute liver injury was induced by a single intraperitoneal injection of CCl4 (0.3 ml/kg), whereas cirrhosis and portal hypertension were induced by CCl4 treatment (0.15 ml/kg twice a week) for 8 weeks. Hepatic morphology, ET-1 and its receptors, and portal venous pressures were determined. Increases in ET-1 and its receptors occurred within 24 h of CCl4 administration, and progressively thereafter during the development of cirrhosis. The acute CCl4-induced hepatic injury was characterized by significant increases in portal pressure (from 8.7+/-1.8 to 17.6+/-3.3 mmHg; p<0.01) and serum levels of liver enzymes, as well as massive hepatocellular necrosis (62+/-8%). Intravenous administration of an ET-1 receptor antagonist TAK-044 reduced portal pressure to 13.6+/-2.8 mmHg (p<0.05), and ameliorated hepatocellular necrosis by about 35% (p<0.001). TAK-044 treatment also produced significant reduction in serum levels of liver enzymes. In cirrhotic rats, portal venous infusion of TAK-044 reduced portal hypertension by about 40% (p<0.05). In conclusion, these results indicate involvement of ET-1 in acute liver injury as well as portal hypertension associated with hepatic cirrhosis, and a potential for ET-1 receptor antagonists in the treatment of these pathologic conditions.
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PMID:An endothelin receptor antagonist TAK-044 ameliorates carbon tetrachloride-induced acute liver injury and portal hypertension in rats. 954 66

Patients with cirrhosis and portal hypertension exhibit characteristic haemodynamic changes with a hyperkinetic systemic circulation, an abnormal distribution of the blood volume and neurohumoral dysregulation. Their plasma and noncentral blood volumes are increased, but the central and arterial blood volume and systemic vascular resistance are decreased. A systemic and splanchnic vasodilatation is of pathogenic importance to the low systemic vascular resistance and abnormal volume distribution. These are important elements in the development of the low arterial blood pressure and hyperkinetic circulation in cirrhosis. Various vasodilators such as nitric oxide, calcitonin gene-related peptide, and adrenomedullin are among potential candidates in the vasodilatation in cirrhosis. Besides reflex induced enhanced sympathetic nervous activity, activation of the renin-angiotensin-aldosterone system, and elevated circulation vasopressin, endothelin-1 may also be implicated in the haemodynamic counter-regulation in cirrhosis. Recent research has focused on the assertion that the haemodynamic and neurohumoral abnormalities in cirrhosis are part of a general circulatory dysfunction, influencing the course of the disease with reduction of kidney function and sodium-water retention as the outcome.
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PMID:Haemodynamics and fluid retention in liver disease. 975 6

Hepatic stellate cells (HSCs) participate in the regulation of hepatic microcirculation and have receptors for many vasoconstrictor factors. It is unknown whether HSCs have receptors for circulating vasodilators such as atrial natriuretic peptide (ANP). This study investigated the presence of ANP receptors in human HSCs and whether ANP antagonizes the effects of endothelin-1 in these cells. ANP receptors were assessed by binding and cross-linking studies, reverse-transcriptase polymerase chain reaction (PCR), and measuring intracellular cyclic guanosine monophosphate concentration. Intracellular calcium concentration ([Ca(2+)](i)) and cell contraction were measured in individual cells loaded with fura-2 using a morphometric method. Binding and cross-linking affinity experiments showed the existence of ANP receptors in human HSCs. PCR products with the expected length were obtained for guanylate cyclase A receptor, the physiological receptor of ANP, both in quiescent and activated human cells. ANP induced a dose-dependent increase in intracellular cyclic guanosine monophosphate concentration and blunted the increase in [Ca(2+)](i) elicited by endothelin-1. Most importantly, ANP markedly reduced cell contraction induced by endothelin-1. HSCs isolated from rats with carbon tetrachloride-induced cirrhosis showed a higher number of ANP receptors compared with HSCs isolated from normal rats, indicating that in vivo activation of HSCs is associated with an up-regulation of ANP receptors. These results indicate that human HSCs have receptors for ANP, the activation of which reduces the effects of endothelin-1 on [Ca(2+)](i) and cell contraction. ANP could participate in regulating the contractility of HSCs by antagonizing the effect of vasoconstrictors.
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PMID:Atrial natriuretic peptide antagonizes endothelin-induced calcium increase and cell contraction in cultured human hepatic stellate cells. 1042 60

Biliary cirrhosis in the rat triggers intrapulmonary vasodilatation and gas exchange abnormalities that characterize the hepatopulmonary syndrome. This vasodilatation correlates with increased levels of pulmonary microcirculatory endothelial nitric oxide synthase (eNOS) and hepatic and plasma endothelin-1 (ET-1). Prehepatic portal hypertension induced by portal vein ligation (PVL) does not cause similar changes, suggesting that ET-1 in cirrhosis may modulate pulmonary eNOS and vascular tone. We assessed whether ET-1 altered eNOS expression and nitric oxide production in bovine pulmonary artery endothelial cells (BPAECs) and if a 2-wk low-level intravenous ET-1 infusion in PVL animals modulated pulmonary eNOS levels, microcirculatory tone, and gas exchange. ET-1 caused a 2.5-fold increase in eNOS protein in BPAECs, inhibitable with an endothelin B receptor antagonist, and an increase in eNOS mRNA and nitrite production. ET-1 infusion in PVL animals caused increased pulmonary eNOS levels, intrapulmonary vasodilatation, and gas exchange abnormalities without increasing pulmonary arterial pressure. ET-1 produced during hepatic injury may contribute to the hepatopulmonary syndrome by modulating eNOS and inducing pulmonary microcicrulatory vasodilatation.
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PMID:Endothelin-1 stimulation of endothelial nitric oxide synthase in the pathogenesis of hepatopulmonary syndrome. 1056 99

By using a selective ROCK inhibitor Y-27632, the role of Rho-ROCK signaling in the function of hepatic stellate cells in culture was studied. Stellate cells maintained the "star-like" configuration of the quiescent stage in the presence of Y-27632, while the expression of smooth muscle alpha-actin and PDGF receptor beta was not affected by the agent. Serum-stimulated migration of the cells was significantly suppressed by Y-27632. The contraction of stellate cells induced by 5 nM endothelin-1 was attenuated by the agent in a dose-dependent manner. Formation of F-actin stress fibers and phosphorylation of myosin light chain was apparently reduced by Y-27632 even under the stimulation with endothelin-1. On the other hand, ex vivo liver perfusion experiment revealed that endothelin-1 (2 nM)-induced increase of portal vein constriction was almost completely inhibited by 20 microM Y-27632 with a concomitant improvement of hepatocyte degeneration. These results suggest that ROCK is one of the key regulators of stellate cell motility and that the clinical application of ROCK inhibitors such as Y-27632 should be considered in the reduction of portal hypertension in liver fibrosis and cirrhosis.
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PMID:ROCK inhibitor Y-27632 attenuates stellate cell contraction and portal pressure increase induced by endothelin-1. 1060 Apr 96

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