Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to investigate the relationship between ET plasma concentrations and other hormonal systems in acute volume regulation of patients with cirrhosis. Ten healthy controls and 10 cirrhotic patients, five without and five with ascites were studied after 1 h in a sitting posture and subsequently subjected to 1 h head-out water immersion. Blood was collected for determinations of ET-1, ET-3, ANF, aldosterone, renin activity and noradrenaline. In addition, in 10 patients with compensated cirrhosis the effect of loop diuretics on ET-3, aldosterone and renin was studied. ETs in cirrhosis were significantly (P < 0.01) higher than in controls both before (ET-1, 19.6 +/- 1.3 pgmL-1 vs. 11.8 +/- 0.4 pgmL-1; ET-3, 18.5 +/- 1.4 pgmL-1 vs. 9.5 +/- 0.5 pgmL-1) and after water immersion (ET-1, 18.6 +/- 1.2 pgmL-1 vs. 12.4 +/- 0.3 pgmL-1; ET-3, 18.7 +/- 1.7 pgmL-1 vs. 10.0 +/- 0.5 pgmL-1). In cirrhotic patients, basal and immersion concentrations of ET-1 were significantly correlated to noradrenaline plasma concentrations (r = 0.79, P < 0.05). ET-3 plasma concentrations in cirrhosis were correlated to renin activity (r = 0.65, P < 0.05). Furthermore, ET-3 in cirrhosis was inversely correlated to systolic and mean arterial blood pressure (r = -0.55, P < 0.01 and r = -0.50, P < 0.05; respectively). To investigate the effect of hypovolaemia in compensated cirrhosis, 10 patients without ascites were studied before and after treatment with loop diuretics. In compensated cirrhosis ET-3 was significantly increased 6h after oral diuretic treatment (17.9 +/- 1.0 pgmL-1 vs. 15.5 +/- 0.4 pgmL-1, P < 0.001). The presented data demonstrate relations of endothelins, particularly of ET-3 to neurohumoral systems in patients with cirrhosis of the liver.
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PMID:Relation of endothelins to volume regulating neurohumoral systems in patients with cirrhosis of the liver. 871 27

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

Short-term (end-of-treatment) responses (ETR) to interferon (IFN) therapy for chronic hepatitis C are encouraging; however, the relapse rate is high, and long-term response is obtained in only 12-25% of patients. The Australian Hepatitis C Study Group conducted a trial of 230 patients that compared the standard 3 MU three times a week six-month course of IFN-alpha2b with 5 MU three times a week for six months (5 MU group) or 3 MU three times a week for two years (two-year group). ETR (normalization of serum aminotransferase level until the end of treatment) rates based on an intent-to-treat analysis were 64% for the 5 MU group and 58% for the combined 3 MU groups. After six months of treatment, the overall relapse rate was 71%, and the long-term response (LTR; continued normal aminotransferase until six month follow up) rate did not differ significantly between the 3 MU (17% of all treated, 27% ETR) and 5 MU groups (20% of all treated, 31% ETR). In contrast, among the 46 patients who exhibited an ETR in the two-year group, 27 (59%) had a LTR to IFN, resulting in an overall LTR rate of 33% for all patients treated for up to two years (P < 0.001 compared with 3 MU group). Among these 46 subjects, 11 did not complete the full two-year course, including eight who withdrew due to adverse effects. Nine of these 11 patients had received at least 12 months of therapy. All 18 LTR subjects tested (irrespective of treatment group) were serum HCV-RNA negative at the 12-month follow-up evaluation. Improvement in hepatic inflammation was significantly greater among those treated for two years compared with six months, but there was no reduction in fibrosis score in any group. Among the entire study group, treatment duration, liver histology, and liver function (assessed by antipyrine clearance test) were the only independent predictors of ETR, although HCV genotype was closely related to histological severity (eg, cirrhosis was present in 60% of type 1 and 18% of type 3). Viral load and duration of infection were additional predictors of LTR; however, there were insufficient data to determine whether prolonging treatment beyond six months overcomes the negative impact of these predictors. Continuing IFN therapy for at least 12 months decreases the relapse rate by 50% and thereby improves the LTR rate compared with a six-month treatment course. However, our experience of 24 months of treatment indicates that initial IFN treatment courses of this duration are not well tolerated by approximately 20% (8/46) of patients and are unlikely to improve the results obtained with 12-18 months of treatment.
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PMID:Two years versus six months of interferon therapy for chronic hepatitis C. 901 83

Apart from the initially described vasoconstriction, endothelins have been shown to cause a variety of biological activities in non-vascular tissues. A rapidly growing body of data supports the concept of endothelin as a paracrine acting hormone. In this review, we will discuss the impact of this local endothelin system for various cardiovascular pathophysiological states, especially atherosclerotic vascular disease, restenosis, myocardial infarction, congestive heart failure, and arterial hypertension. In addition, the endothelin system is a modulator of renal function via its binding to abundant receptors in renal tissue and by the ability of renal endothelial and epithelial cells to synthesize and release endothelin. In the kidney, endothelin may function as a paracrine/autocrine factor in the regulation of renal blood flow, glomerular haemodynamics, and sodium and water homeostasis. The renal endothelin system is involved in kidney diseases such as impaired renal function in liver cirrhosis, cyclosporin toxicity, acute renal failure and renal glomerular and interstitial fibrosis. Therapeutic approaches with new orally active endothelin receptor antagonists are also discussed.
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PMID:The paracrine endothelin system: pathophysiology and implications in clinical medicine. 929 57

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

Previous experimental studies have suggested that the paracrine endothelin system may participate in the regulation of hepatic hemodynamics in cirrhosis. The present study assesses the relationship between increased portal pressure and preproET-1, ET(A) receptor and ET(B) receptor gene expression in human cirrhosis. PreproET-1, ET(A) receptor and ET(B) receptor mRNA abundance was estimated by quantitative PCR in human hepatic tissue from subjects with normal liver and in cirrhotic patients in whom a hepatic hemodynamic study was performed. The expression of the three transcripts was significantly higher in liver samples of cirrhotic patients than in those obtained from subjects without any histological alteration. Moreover, while no significant correlation was found between preproET-1 mRNA abundance and portal pressure, there was a highly significant direct relationship between ET(A) and ET(B) receptor gene expression and portal pressure in cirrhotic patients. These results indicate that the liver paracrine endothelin system is overactivated in human cirrhosis and that a direct relationship exists between endothelin receptor mRNA abundance and the degree of portal hypertension in these patients.
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PMID:Gene expression of endothelin-1 and ET(A) and ET(B) receptors in human cirrhosis: relationship with hepatic hemodynamics. 964 33

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 microg/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 x s x cm(-5) x 10(-3). Similar results were observed in rats with CCl4-induced cirrhosis. In isolated perfused cirrhotic rat livers, bosentan (1 to 100 micromol/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.
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PMID:Beneficial hemodynamic effects of bosentan, a mixed ET(A) and ET(B) receptor antagonist, in portal hypertensive rats. 973 54

In order to clarify the characteristics of cellular localization of ET-1/big ET-1 in liver tissues, we carried out immunohistochemical study on 30 normal, 87 cirrhosis (LC) and 55 hepatocellular carcinoma (HCC) liver specimens using anti-ET-1 antibody and anti-big ET-1 antibody and further performed in situ hybridization on 5 LC liver specimens. Positive immunostaining of hepatocytes of normal and LC livers, and tumor cells of HCC was obtained. The frequency of positive cells for ET-1 and big ET-1 of normal liver was very low. In contrast, LC hepatocytes were stained much more frequently for both ET-1 and big ET-1 than those of normal liver (P < 0.01). In the HCC livers hepatoma cells showed intermediate frequency of positive cells between normal and LC livers. Big ET-1, not ET-1, expression in HCC was significantly high compared with that of normal liver (P < 0.01). Specific signals for ET-mRNA were not detected in hepatocytes of LCs by in situ hybridization. ETs detected in hepatocytes by immunohistochemistry, therefore, seem not to have been synthesized locally. The origin of ETs is not clear but they might have been taken up from the circulation through ET receptors on hepatocytes. Although the clearance mechanism of ETs by ET-converting enzyme or other peptidases in liver has not been elucidated, the mechanisms seem to be absent or impaired in LC and/or HCC liver since the frequency and intensity of ET-positivity in the diseased hepatocytes are significantly high than those of normal liver. In addition, a disturbance of ET excretion into the bile may be also responsible for the ET storage. Elevation of serum ET levels in LC may be caused by disturbance of ET degradation and/or leakage of bile into the blood, as the ET is excreted through the biliary system.
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PMID:Immunohistochemical localization of endothelin-1/big endothelin-1 in normal liver, liver cirrhosis and hepatocellular carcinoma. 1009 81

Endothelin (ET) is one of the most potent vasoconstrictors known so far. It has been proposed that the ET-induced contraction of hepatic stellate cells (Ito, endothelial cells) is an important mechanism for the development of portal hypertension. The purpose of this study was to investigate in an in vitro model whether ET causes a contraction of the portal vein which can contribute to portal hypertension in cirrhosis. Portal veins from normal and cirrhotic rats were used for experiments. Measurements were performed in vitro for cumulative concentrations of ET-1 and ET-3 (1, 5, 10, 50 and 100 nM). Both ETs caused a dose-dependent increase in portal venous tension; the maximal tension (Tmax) was measured at 50 nM. The measured Tmax was higher for cirrhotic (ET-1: Tmax = 189%; ET-3: Tmax = 175%) than for normal rats (ET-1: Tmax = 130%; ET-3: Tmax = 151%). ET-3 produced a higher tension of portal veins in normal rats than ET-1. In conclusion, this study shows that portal veins from cirrhotic rats react more sensitively to ET than those from normal rats. Besides the ET-induced contraction of hepatic stellate cells, contraction of the portal vein and its intrahepatic branches, especially in cirrhotic individuals, has to be considered as a further mechanism of ET contributing to portal hypertension.
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PMID:Endothelin-induced contraction of the portal vein in cirrhosis. 1035 58

Pulmonary hypertension (PH) may develop because of a spectrum of insults to the lungs; in some patients, there seems to be no cause. Noninvasive tests, such as standard chest radiography, electrocardiography, and transthoracic Doppler echocardiography, provide effective screening if PH is suspected. This synopsis focuses on these screening studies and the more common clinical problems, including primary cardiac abnormalities, obstructive sleep apnea, chronic pulmonary embolism, pulmonary parenchymal problems, connective tissue disorders, cirrhosis with portal hypertension, and use of appetite suppressants, that should be considered when PH exists. Treatment options for PH, including intravenous prostacyclin (epoprostenol), and investigational agents such as subcutaneous or oral prostacyclin analogues and oral endothelin receptor antagonists are described.
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PMID:Pulmonary hypertension: diagnostics and therapeutics. 1085 24


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