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)

Nitric oxide (NO) and prostaglandins have been proposed as vasodilator substances involved in peripheral vasodilatation characteristic of the liver cirrhosis. A link between NO and prostanoids has been suggested. The present study investigated the effect of simultaneous blockade of both, NO synthase (NOS) and cyclooxigenase (COX) in sham-operated (SO), or rats with bile-duct ligation (BDL) in the development of liver fibrosis. Animals were distributed in two groups SO (n=15) or BDL (n=15). Treatments (5 days) started three weeks after surgical procedure. Both, SO and BDL animals were treated with indomethacin (INDO) (5 mg/kg/day) alone, with NG-nitro-L-arginine-methyl-ester (NAME) (4 mg/kg/day) alone or with INDO and NAME combination at the same doses. At the end of follow-up body weight, packed cell volume, mean arterial blood pressure (MAP) and heart rate were measured. Liver tissue was processed for histological studies. In this study, BDL animals showed a decreased MAP. Treatment with L-NAME in BDL rats increased MAP. The chronic COX inhibition alone did not play an important role in the haemodynamic changes. The BDL produced a loss of hepatic structure, with ductular metaplasia that occupied the greater part of the hepatic parenchyma. Also, an important degree of fibrosis was observed. Both NO and PG synthesis inhibitors, alone or in combination, induced enhancing collagen fiber deposition in the hepatic parenchyma. These findings support the notion that the interaction between the NOS and COX pathways should be relevant in hepatic cirrhosis in which both NOS and COX are induced.
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PMID:Role of prostanoids and nitric oxide inhibition in rats with experimental hepatic fibrosis. 1119 54

We examined the functional role of nitric oxide (NO) and nitric oxide synthase (NOS) isoforms in the pulmonary dysfunction seen in cirrhosis. Lungs were isolated from control and carbon tetrachloride (CCl(4))-induced cirrhotic rats and perfused at constant flow with a whole blood mixture. Ventilation with hypoxic gas resulted in attenuated hypoxic pulmonary vasoconstriction (HPV) in lungs from cirrhotic animals. Administration of the non-selective NOS inhibitor N-omega-Nitro-L-Arginine (L-NNA) resulted in HPV responses that were not different between groups. However, inhibition of inducible nitric oxide synthase (iNOS) did not restore cirrhotic HPV responses. Lungs from cirrhotic rats demonstrated enhanced endothelial-dependent vasodilation to vasopressin when preconstricted with hypoxia but not when preconstricted with thromboxane mimetic. Western blot analysis failed to demonstrate differences in pulmonary endothelial NOS (eNOS) or iNOS levels between groups. Our data suggest that, while NO may play a role in mediating the reduced pulmonary vasoreactivity observed in cirrhosis, other vasoactive factors are likely also important modulators of the pulmonary dysfunction seen in this disease.
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PMID:Role of nitric oxide (NO) in pulmonary dysfunction associated with experimental cirrhosis. 1131 11

High concentrations of nitric oxide (NO) are generated by the inducible form of the enzyme nitric oxide synthase (iNOS), which is expressed in activated macrophages and in hepatocytes. Increased expression of iNOS in hepatocytes or macrophages might be expected in chronic HCV liver disease and HIV infections. This might in turn be reflected in increased serum NO levels in these two conditions. In view of the discrepant findings in published reports, we measured serum NO levels in a large number of chronic HCV-infected patients and patients with chronic HIV infections with or without AIDS-related opportunistic infection. We also localized HCV and iNOS antigens by immunohistochemistry, in liver biopsy tissue from patients with chronic HCV-related hepatitis, HCV-related cirrhosis, and HCV-related hepatocellular carcinoma. A group of 121 subjects with serological evidence of HCV with or without HIV infection were studied. These were compared with 14 controls without HIV or HCV disease (group A). Among the subjects with HCV, 35 were negative for HIV (group B), 66 were HIV positive (group C), and 20 had AIDS-related opportunistic infection (group D). The serum NO concentration was determined by the Brucine method. A well-characterized commercially available antibody (HCV88) directed against a synthetic NS3 peptide fragment of HCV, which localizes to the hepatocyte nuclei, and an antibody to human macrophage iNOS, were both used to detect these proteins in liver biopsy tissue by immunohistochemistry. Mean serum NO values in HIV negative/HCV negative control patients (group A) (54.6+/-12 microM) were similar to those in HIV negative/HCV positive patients (group B) (55.0+/-13 microM) and HIV positive without AIDS-related disease/HCV positive patients (group C) (47.2+/-25 microM). By contrast, the mean serum NO (70.1+/-24 microM) was significantly increased in HCV-positive patients with AIDS-related infection (group D) compared to controls (P = 0.02). HCV NS3 and iNOS antibody staining hepatocytes were not detected in any of the control non-HCV-infected biopsy samples. In early chronic HCV hepatitis (fibrosis scores F0-F2), HCV NS3 antigen localized focally to only a small number of hepatocytes. In cirrhosis (fibrosis score F4) with or without hepatocellular carcinoma, the majority of hepatocyte nuclei stained positively with HCV NS3 antibody. The majority of hepatocytes in chronic HCV hepatitis expressed iNOS, irrespective of histological disease severity. The staining was present uniformly in the cytoplasm. In chronic HCV and HIV coinfection, the pattern and number of iNOS staining cells were similar to that in patients with chronic HCV infection alone. In conclusion, there is widespread expression of iNOS in hepatocytes in chronic HCV liver disease, irrespective of liver disease stage. However, elevated NO levels in serum were related only to active AIDS-related bacterial, protozoan, and fungal infections, rather than to chronic viral infection with HCV or HIV alone. NO may play a role in the local control of chronic viral infections at tissue level, but this is not reflected in serum levels.
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PMID:Nitric oxide and chronic HCV and HIV infections. 1134 51

To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 +/- 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N(G)-monomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg. min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-controlled, crossover study. Administration of L-NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. L-NMMA also significantly reduced cardiac index (-13%) and increased systemic vascular resistance (+26%), arterial pressure (+9%), renal blood flow (+12%), glomerular filtration rate (+12%), and sodium excretion (+25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to L-NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves renal function and sodium excretion.
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PMID:Hemodynamic, renal, and endocrine effects of acute inhibition of nitric oxide synthase in compensated cirrhosis. 1143 29

Portal hypertension resulting from increased intrahepatic resistance is a common complication of chronic liver diseases and a leading cause of death in patients with liver cirrhosis, a scarring process of the liver that includes components of both increased fibrogenesis and wound contraction. A reduced production of nitric oxide (NO) resulting from an impaired enzymatic function of endothelial NO synthase and an increased contraction of hepatic stellate cells (HSCs) have been demonstrated to contribute to high intrahepatic resistance in the cirrhotic liver. 2-(Acetyloxy) benzoic acid 3-(nitrooxymethyl) phenyl ester (NCX-1000) is a chemical entity obtained by adding an NO-releasing moiety to ursodeoxycholic acid (UDCA), a compound that is selectively metabolized by hepatocytes. In this study we have examined the effect of NCX-1000 and UDCA on liver fibrosis and portal hypertension induced by i.p. injection of carbon tetrachloride in rats. Our results demonstrated that although both treatments reduced liver collagen deposition, NCX-1000, but not UDCA, prevented ascite formation and reduced intrahepatic resistance in carbon tetrachloride-treated rats as measured by assessing portal perfusion pressure. In contrast to UDCA, NCX-1000 inhibited HSC contraction and exerted a relaxing effect similar to the NO donor S-nitroso-N-acetylpenicillamine. HSCs were able to metabolize NCX-1000 and release nitrite/nitrate in cell supernatants. In aggregate these data indicate that NCX-1000, releasing NO into the liver microcirculation, may provide a novel therapy for the treatment of patients with portal hypertension.
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PMID:NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension. 1858 15

Plasma concentrations of endothelin-1 (ET-1) and nitrite/nitrate of patients with portal hypertension were measured. Sixteen patients with liver cirrhosis (the LC group) and 14 patients with idiopathic portal hypertension (the IPH group) and 12 healthy subjects (normal controls) were included in this study. The peripheral venous plasma concentration of ET-1 was significantly higher in the LC group (6.69+/-2.44 pg/ml) than in the IPH group (3.07+/-0.84 pg/ml) and normal controls (1.79+/-0.36 pg/ml), while the value in the IPH group was also significantly higher than that in normal controls. The peripheral venous plasma concentration of nitrite/nitrate was significantly higher in the LC group (67.7+/-38.9 &mgr;Mol/l) than in the IPH group (32.3+/-24.4 &mgr;Mol/l) and normal controls (26.1+/-9.8 &mgr;Mol/l). Hepatic venous plasma concentrations of ET-1 and nitrite/nitrate were measured in 8 patients from the LC group and 10 patients from the IPH group. The plasma concentration of ET-1 in the hepatic vein was significantly higher than that in the peripheral vein in both the LC and the IPH groups. The plasma concentration of nitrite/nitrate in the hepatic vein was significantly higher than that in the peripheral vein in the LC group. We also investigated the localization of ET-1, endothelin receptor (ET receptor) and nitric oxide synthase (NOS) in the liver tissue of LC patients (n=10), IPH patients (n=10) and normal controls (n=10). The expressions of ET-1, ET A receptors, ET B receptors, and inducive NOS (iNOS) were detected in patients with LC, and the labeling index (LI) was significantly higher than that in patients with IPH and normal controls. The expressions of ET-1, ET A receptors, and ET B receptors were found in patients with IPH, and the LI was significantly higher than that in normal controls. The expression of endothelial NOS (eNOS) was scarce in both LC and IPH patients. From these results, overproduction of ET-1 in the liver was regarded as one of the causes of the high plasma concentration of ET-1 in patients with LC and IPH. One of the causes of the high plasma concentration of nitrite/nitrate in LC was considered to be overproduction of nitric oxide (NO) in the liver. And we suggested that ET-1 is at a relatively higher density than NO in the hepatic sinusoid in LC and IPH.
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PMID:Clinical investigation of endothelin-1 and nitric oxide in patients with portal hypertension focusing on plasma levels and immunohistological staining of liver tissues. 1147 Jun 27

AIM:To observe the nitric oxide synthase (NOS) distribution in the esophageal mucosa and hemodynamic changes in cirrhotic rats.METHODS:NOS distribution in the lower esophagus of rats with carbon tetrachloride-induced cirrhosis was assessed by using NADPH-diaphorase (NADPH-d) histochemical method.Concentration of NO in serum were measured by fluorometric assay. Mean arterial pressure (MAP), cardiac output (CO), cardiac index (CI), splanchnic vascular resistance (SVR), and splanchnic blood flow (SBF) were also determined using (57)Co-labled microsphere technique.RESULTS:Intensity of NOS staining in the esophageal epithelium of cirrhotic rats was significantly stronger than that in controls. There was a NOS-positive staining area in the endothelia of esophageal submucosal vessels of cirrhotic rats, but the NOS staining was negative in normal rats. NO concentration of serum in cirrhotic rats were significantly higher in comparison with that of controls. Cirrhotic rats had significantly lower MAP, SVR and higher SBF than those of the controls.CONCLUSION:Splanchnic hyperdynamic circulatory state was observed in rats with cirrhosis. The endogenous NO may play an important role in development of esophageal varices and in changes of hemodynamics in cirrhosis.
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PMID:Nitric oxide synthase distribution in esophageal mucosa and hemodynamic changes in rats with cirrhosis. 1181 32

Nitric oxide (NO) has diverse physiological and pathophysiological effects. The roles of NO in the renal and cardiac dysfunction found in cirrhosis are reviewed. In the kidneys of experimental animals with cirrhosis, several lines of evidence speak in favour of an enhanced production of NO, through the activation of both endothelial constitutive and inducible isoforms of NO synthase. In contrast with the situation in normal animals, inhibition of NO synthesis in rats with cirrhosis improves sodium and water excretion via blood pressure-dependent and -independent mechanisms, which indicates that the renal sodium and water retention of cirrhosis is related to an excess of NO production. The deleterious effect of excessive NO on the kidney may be mediated by peroxynitrite, a potent oxidant that is readily formed whenever superoxide anions and the *NO radical are produced together. The peroxidation of arachidonic acid by peroxynitrite leads to the formation of F(2a)-isoprostanes, which are powerful renal vasoconstrictors. F(2a)-isoprostane levels are correlated with the severity of liver injury during cirrhosis. However, whether peroxynitrite or F(2a)-isoprostanes are the elusive mediator of the NO-induced renal alterations in cirrhosis remains to be firmly established. NO is also involved in cardiac contractility, probably in the normal heart as well as in disease conditions such as non-cirrhotic and cirrhotic cardiomyopathy. In the latter state, evidence suggests that inducible NO synthase attenuates ventricular contractility, mediated by cGMP. Another gas that transduces its signal through cGMP, carbon monoxide, is also likely to play a role in cirrhotic cardiomyopathy, but the nature of the interaction between NO and carbon monoxide in this syndrome remains unclear.
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PMID:Nitric oxide and renal and cardiac dysfunction in cirrhosis. 1183 41

Previous studies have shown that acute inhibition of nitric oxide (NO) synthesis improves sodium and water excretion and increases blood pressure in cirrhotic rats with ascites, thus suggesting that NO is an important factor contributing to the arterial hypotension and sodium retention of liver cirrhosis. In the present work we have analyzed the renal effects derived from the chronic oral treatment (10 days) with aminoguanidine (AG, 100 mg/kg/day), a preferential inhibitor of inducible NO synthase (iNOS), or Nw-Nitro-L-Arginine Methyl Ester (L-NAME, 0.5 mg/kg/day), a nonselective inhibitor of NOS, in an experimental model of liver cirrhosis with ascites (carbon tetrachloride inhalation). Untreated cirrhotic rats showed lower mean arterial pressure (MAP), diuresis, natriuresis and glomerular filtration rate (GFR) and similar renal blood flow (RBF) compared with the untreated control rats. Chronic administration of AG did not modify significantly any parameter in cirrhotic and control animals. Conversely, long-term L-NAME administration to cirrhotic rats normalized MAP and significantly increased water and sodium excretion, whereas in control animals these parameters were not significantly modified. These results show that chronic NO synthesis inhibition with L-NAME, but not with aminoguanidine, improves renal perfusion pressure and increases the lower sodium and water excretion of cirrhotic rats with ascites. Thus, an enhanced production of NO is an important factor contributing to the renal sodium and water retention characteristic of liver cirrhosis.
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PMID:[Renal effects of the chronic inhibition of nitric oxide synthesis in cirrhotic rats with ascites]. 1188 25

Nitric oxide (NO) has been implicated in playing a role in liver cirrhosis, but the regulatory mechanisms are still unclear. As arginase shares a common substrate with NO synthase (NOS), the aim of this study was to investigate the expression of arginase I and II in cirrhotic liver. Liver cirrhosis was induced in rats by chronic bile duct ligation (BDL). Controls were sham-operated. Competitive polymerase chain reaction was performed to assay the expression of messenger RNA of arginase I and II. Protein expression was detected by immunohistochemistry and western-blotting. The level of arginine in plasma was lower in BDL rats, while the ornithine level in plasma was correspondingly higher (r= -0.96, P<0.0001). Arginase I messenger RNA was reduced significantly in BDL rats (3.34+/-0.32 vs. 1.32+/-0.21 x 10(4) attomole/microg of total RNA, sham vs. BDL, P<0.001), as well as arginase I protein. In contrast, arginase II mRNA was induced in the livers of BDL rats, with negligible expression in controls (0.35+/-0.11 vs. 3.64+/-0.54 attomole/microg of total RNA, sham vs. BDL, P<0.001). Arginase II protein was localized in some hepatocytes and hyperplastic bile ductular epithelial cells of cirrhotic livers but not in control livers. In conclusion, arginase II was induced in BDL livers, while the expression of arginase I was down-regulated. These data suggest that arginase I and II are regulated differently and may have different functions in the livers of BDL rats. Reduction of arginase I in BDL livers may be responsible for the lowering of arginine levels in the plasma, while induction of arginase II could be important in regulating NO synthesis as well as other important mechanisms involved in liver cirrhosis.
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PMID:Induction of arginase II in livers of bile duct-ligated rats. 1193 36


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