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)

It is well known that nitric oxide, a vasodilator, is overproduced in liver cirrhosis. This study was designed to elucidate the role of nitric oxide (NO) in portal hemodynamics and to determine the mechanism underlying the increased serum NO levels in rats with liver cirrhosis induced by the oral intake of CCl4. Using rats, liver cirrhosis was induced by oral administration of CCl4. The serum levels of NO2-/NO3-(NOx) were measured, and portal hemodynamic parameters were evaluated with and without the administration of the NO synthase inhibitor N omega-nitro-L-arginine (NNA). Furthermore, Northern blot analysis was used to detect iNOS and cNOS mRNA, and immunohistochemical methods were used to detect iNOS-like immunoreactivity. In cirrhotic rats, the portal flow had increased significantly and the portal resistance had decreased significantly when compared with normal control rats. Hepatic capillary flow in the cirrhotic rats was similar to the control rats. NNA decreased portal flow and increased portal resistance in both groups, but the change was greater in the cirrhotic rats than in controls. The serum levels of NOx were significantly higher in cirrhotic rats than in normal control rats and were positively correlated with portal flow and negatively correlated with portal resistance. The expression of iNOS mRNA, which was barely detectable in control rats, had increased in all organs of the cirrhotic rats, whereas no significant increase in cNOS mRNA was found in any of the organs from cirrhotic rats. The immunohistochemical analysis was generally consistent with the results of the Northern blot analysis. In the control rats, only the bronchial epithelial cells were stained with the anti-iNOS antibody, but in cirrhotic rats, the bronchial cells in the lungs as well as the histiocytic mesenchymal cells in all organs, and the alveolar epithelial cells of the lungs, were stained. This study demonstrated that NO plays a significant role in portal hypertensive hemodynamics in CCl4-induced liver cirrhosis, and that NO is a useful indicator for the evaluation of portal hypertension. Furthermore, the increased serum levels of NO were found to be derived at least in part from the increased expression of iNOS mRNA in the liver, spleen, and lung.
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PMID:NO as an indicator of portal hemodynamics and the role of iNOS in increased NO production in CCl4-induced liver cirrhosis. 924 60

Recent work indicates that nitric oxide (NO) plays an important role in the systemic and renal alterations of cirrhosis. In the present study, we have evaluated whether the inducible NO synthase (iNOS) isoform participates in the enhanced renal and systemic NO production of a rat model of cirrhosis. In vitro and in vivo experiments were performed in rats subjected to chronic bile duct ligation (BDL) and in sham-operated (SO) animals. Plasma nitrite (3.1 +/- 0.1 micromol/L in SO and 6.6 +/- 0.2 micromol/L in BDL), glomerular nitrite production (6.4 +/- 0.1 vs. 9.8 +/- 0.1 nmol/24h/7,000 glomeruli, respectively), and mononuclear lymphocyte cells nitrite production (0.3 +/- 0.04 vs. 0.6 +/- 0.12 nmol/10(6) cells, respectively) were all significantly higher in BDL than in SO. Moreover, mononuclear lymphocytes and glomeruli from BDL rats showed an increased expression of macrophage-type iNOS, detected by Western blot. Kidneys from BDL animals also showed an increased calcium-independent NO synthase activity, compared with those from SO rats. Constitutive endothelial-type NO synthase expression in glomeruli or the activity of calcium-dependent NO synthase in whole kidney did not show differences between BDL and SO rats. In cultured mesangial cells from normal rats, the addition of plasma from BDL but not of plasma from SO significantly stimulated (35%) nitrite production and increased the expression of macrophage-type iNOS. In addition, administration of aminoguanidine (AG), a preferential iNOS inhibitor, elevated dose-dependently mean arterial pressure in both groups, but this increase was greater in BDL (26.5 +/- 4.4 mm hg) than in SO (13.6 +/- 2.6). In BDL, AG also increased sodium and water excretion and glomerular filtration rate. In contrast, there were only small nonsignificant changes in SO animals. Therefore, these results indicate that the expression, activity and production of NO in kidneys, glomeruli, and mononuclear lymphocyte cells is elevated in BDL rats, and this is partly because of a plasma-derived substance(s), which stimulates iNOS formation. The amelioration of the arterial hypotension and the associated reduced excretory levels of these cirrhotic animals by aminoguanidine further support the involvement of the inducible NO synthase isoform in the renal alterations observed in BDL animals.
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PMID:Elevated glomerular and blood mononuclear lymphocyte nitric oxide production in rats with chronic bile duct ligation: role of inducible nitric oxide synthase activation. 925 33

Nitric oxide (NO) production via inducible NO synthase (iNOS) is prominent in the liver after stimulation with cytokines and/or lipopolysaccharide. The aim of this study was to investigate the production of NO via iNOS in specific liver cell populations during toxin-mediated and obstructive hepatic injury and fibrogenesis. After a single dose of carbon tetrachloride, iNOS mRNA and nitrite (a metabolic product of NO) were detected only in Kupffer cells. They were not detectable in any cell type after recurrent administration of carbon tetrachloride, including in animals with far advanced cirrhosis (i.e., portal hypertension and/or ascites). After bile duct ligation, a mechanistically different form of liver injury and fibrogenesis, iNOS mRNA and nitrite were identified in all nonparenchymal cells but not in hepatocytes. Twenty-four hours after bile duct ligation, iNOS mRNA and NO production were greatest in Kupffer cells, but after prolonged bile duct ligation, iNOS was found predominantly in sinusoidal endothelial cells. These data indicate that iNOS expression varies temporally and spatially in the liver after injury and also varies with the type of insult.
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PMID:Regulation of inducible nitric oxide synthase and nitric oxide during hepatic injury and fibrogenesis. 925 18

Normalization of the increased vascular nitric oxide (NO) generation with low doses of NG-nitro-L-arginine methyl ester (L-NAME) corrects the hemodynamic abnormalities of cirrhotic rats with ascites. We have undertaken this study to investigate the effect of the normalization of vascular NO production, as estimated by aortic cyclic guanosine monophosphate (cGMP) concentration and endothelial nitric oxide synthase (eNOS) protein expression in the aorta and mesenteric artery, on sodium and water excretion. Rats with carbon tetrachloride-induced cirrhosis and ascites were investigated using balance studies. The cirrhotic rats were separated into two groups, one receiving 0.5 mg/kg per day of L-NAME (CIR-NAME) during 7 d, whereas the other group (CIR) was administrated the same volume of vehicle. Two other groups of rats were used as controls, one group treated with L-NAME and another group receiving the same volume of vehicle. Sodium and water excretion was measured on days 0 and 7. On day 8, blood samples were collected for electrolyte and hormone measurements, and aorta and mesenteric arteries were harvested for cGMP determination and nitric oxide synthase (NOS) immunoblotting. Aortic cGMP and eNOS protein expression in the aorta and mesenteric artery were increased in CIR as compared with CIR-NAME. Both cirrhotic groups had a similar decrease in sodium excretion on day 0 (0.7 versus 0.6 mmol per day, NS) and a positive sodium balance (+0.9 versus +1.2 mmol per day, NS). On day 7, CIR-NAME rats had an increase in sodium excretion as compared with the CIR rats (sodium excretion: 2.4 versus 0.7 mmol per day, P < 0.001) and a negative sodium balance (-0.5 versus +0.8 mmol per day, P < 0.001). The excretion of a water load was also increased after L-NAME administration (from 28+/-5% to 65+/-7, P < 0.05). Plasma renin activity, aldosterone and arginine vasopressin were also significantly decreased in the CIR-NAME, as compared with the CIR rats. The results thus indicate that normalization of aortic cGMP and eNOS protein expression in vascular tissue is associated with increased sodium and water excretion in cirrhotic rats with ascites.
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PMID:Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites. 942 86

Patients with liver cirrhosis exhibit a hyperdynamic circulatory state as evidenced by tachycardia and an increase in cardiac output accompanied by an elevation of sympathetic tone. This condition is due to the excessive release of nitric oxide (NO), an endogenous vasodilator, which is in turn related to the abnormal induction of NO synthase. The present study investigated whether the intravenous infusion of L-arginine, the precursor of NO, may cause a similar hyperdynamic circulatory state. A new method, the analysis of power spectrum heart rate variability, was used to evaluate autonomic nervous activity. Twenty patients with liver cirrhosis underwent continuous Holter monitoring of the ECG during the intravenous administration of L-arginine (10 g) (Fisher's solution) infused over 60 min. Power spectral analysis was computed from 512 beats of the Holter ECG data. Low frequency (LF; 0.04-0.15 Hz) and high frequency (HF; 0.15-0.40 Hz) spectral powers and the ratio of LF to HF (LF/HF) were calculated every 10 min before and after the infusion of L-arginine. The LF power, which reflects sympathetic tone modified by vagal tone, and the LF/HF, an indicator of sympathetic tone, were both significantly increased during the infusion (p<0.05). HF power, an indicator of parasympathetic tone, showed no significant change in the early stage of the infusion but was significantly increased in the late stage (p<0.05). The administration of L-arginine thus led to an elevation of sympathetic tone. Fisher's solution, which is administered to patients with hepatic insufficiency, contains L-arginine, and may also produce a hyperdynamic circulatory state as an adverse effect related to an elevation of the plasma level of NO by L-arginine. The monitoring of such patients is thus indicated.
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PMID:Autonomic nervous system activity during infusion of L-arginine in patients with liver cirrhosis. 954 64

1. Nitric oxide is a potent vasodilator which plays a major role in the control of blood pressure. The hyperdynamic circulation of cirrhosis has been linked to nitric oxide.2. We measured neutrophil nitric oxide synthase activity in relation to the level of hepatic dysfunction in patients with liver disease of varying aetiology and severity.3. Neutrophils were isolated from 21 patients (7 Child-Pugh score A, 6 grade B and 8 grade C) aged 28-76 (median 49) years. Nitric oxide synthase activity was measured using the conversion of oxyhaemoglobin to methaemoglobin by nitric oxide and expressed in terms of cell protein. Blood pressure and biochemical indices were recorded. Data were assessed using Kruskal-Wallis one-way analysis of variance, Mann-Whitney U-test or Pearson correlation as appropriate.4.Systolic, mean arterial and diastolic blood pressures decreased with increasing hepatic damage (P=0.031, P=0.01 and P=0. 038 respectively). Nitric oxide synthase activity increased with the degree of liver dysfunction (P=0.033) and was highest in patients with Child-Pugh score C. Systolic blood pressure correlated with nitric oxide synthase activity in patients with Child-Pugh score C (P=0.029).5. Our results show that nitric oxide synthase activity increases with increasing Child-Pugh score and is associated with the development of systemic hypotension. These data may support the involvement of nitric oxide in the haemodynamic disturbances seen in liver disease.
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PMID:Nitric oxide synthase activity is increased in relation to the severity of liver dysfunction. 973 Aug 56

1. The synthesis and release of nitric oxide may play a role in the pathogenesis of peripheral vasodilatation and hyperdynamic circulation observed in liver cirrhosis. In this work, we analysed the synthesis of nitric oxide by the lympho-mononuclear cells of peripheral blood from patients with chronic alcoholic and non-alcoholic liver disease and we identified the isoform of nitric oxide synthase involved in the increased nitric oxide synthesis. 2. Patients were classified following clinical and histological criteria in non-alcoholic cirrhotic, alcoholic cirrhotic and non-cirrhotic chronic liver disease. We studied clinical and analytical characteristics, haemodynamic parameters and endotoxin levels in these patients. 3. Cirrhotic patients showed an increase of cardiac output and a decrease of peripheral vascular resistance. These patients had higher levels of plasma endotoxin than those observed in the control group. N omega-Nitro-L-arginine methyl ester (L-NAME)-inhibitable nitrite production from mononuclear lymphocyte cells was higher in patients than in the control group, the highest levels being in non-alcoholic cirrhotic patients, and the lowest levels in patients with non-cirrhotic alcoholic liver disease. 4. Immunocytochemistry studies revealed a positive immunoreactivity for the inducible isoform of nitric oxide synthase in lympho-mononuclear cells that was more evident in non-alcoholic than in alcoholic cirrhotic patients. By Northern blot, inducible nitric oxide synthase mRNA expression was observed only in lymphomononuclear cells from non-alcoholic cirrhotic patients. 5. Our patients show a correlation between nitric oxide synthesis, endotoxin levels and haemodynamic parameters. 6. These findings indicate that lympho-mononuclear cell stimulation may play a role in elevated nitric oxide production in hepatic cirrhosis. Thus, this increased nitric oxide synthesis could be implicated in the pathogenesis of the haemodynamic disturbances frequently found in cirrhotic patients. This increase seems to be induced, at least in part, by activation of an inducible isoform of nitric oxide synthase.
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PMID:Increased nitric oxide synthesis and inducible nitric oxide synthase expression in patients with alcoholic and non-alcoholic liver cirrhosis. 985 62

Chronic bile duct ligation is associated with the development of oxidant injury, biliary cirrhosis, portal hypertension, and a hyperdynamic circulation. We have previously demonstrated that the hyperdynamic circulation in the partial portal vein-ligated rat can be prevented by the administration of N-acetylcysteine. To extend these findings, we have examined the effect of lipoic acid, a thiol-containing antioxidant, on hemodynamics, oxidative stress, and nitric oxide (NO) production in bile duct-ligated (BDL) cirrhotic rats. Lipoic acid was given continuously in drinking water to normal and BDL rats; control rats received ordinary drinking water, and animals were studied at 24 days following surgery. Lipoic acid prevented the development of the hyperdynamic circulation (cardiac index [CI]: 15.7 +/- 2.0 vs. 29.5 +/- 2.1 mL x min-1 x 100 g-1; P <. 05) and significantly attenuated the rise in portal pressure (PP) (12.7 +/- 0.8 vs. 15.2 +/- 0.5 mm Hg; P <.05). Hepatic nitric oxide synthase (NOS) activity and plasma nitrite/nitrate concentration increased significantly following bile duct ligation, and both of these were prevented by lipoic acid. Lipoic acid had no effect on the biochemical or histological parameters of liver function in the cirrhotic group. We conclude that lipoic acid prevents the development of the hyperdynamic circulation in the rat model of biliary cirrhosis, and that this is associated with decreased synthesis of NO.
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PMID:Lipoic acid prevents development of the hyperdynamic circulation in anesthetized rats with biliary cirrhosis. 1021 16

Ethanol is one of the few nutrients that is profoundly toxic. Alcohol causes both whole-body and tissue-specific changes in protein metabolism. Chronic ethanol missuse increases nitrogen excretion with concomitant loss of lean tissue mass. Even acute doses of alcohol elicit increased nitrogen excretion. The loss of skeletal muscle protein (i.e., chronic alcoholic myopathy) is one of several adverse reactions to alcohol and occurs in up to two-thirds of all ethanol misusers. There are a variety of other diseases and tissue abnormalities that are entirely due to ethanol-induced changes in the amounts of individual proteins or groups of tissue proteins; for example, increased hepatic collagen in cirrhosis, reduction in myosin in cardiomyopathy, and loss of skeletal collagen in osteoporosis. Ethanol induces changes in protein metabolism in probably all organ or tissue systems. Clinical studies in alcoholic patients without overt liver disease show reduced rates of skeletal muscle protein synthesis though whole-body protein turnover does not appear to be significantly affected. Protein turnover studies in alcohol misusers are, however, subject to artifactual misinterpretations due to non-abstinence, dual substance misuse (e.g., cocaine or tobacco), specific nutritional deficiencies, or the presence of overt organ dysfunction. As a consequence, the most reliable data examining the effects of alcohol on protein metabolism is derived from animal studies, where nutritional elements of the dosing regimen can be strictly controlled. These studies indicate that, both chronically and acutely, alcohol causes reductions in skeletal muscle protein synthesis, as well as of skin, bone, and the small intestine. Chronically, animal studies also show increased urinary nitrogen excretion and loss of skeletal muscle protein. With respect to skeletal muscle, the reductions in protein synthesis do not appear to be due to the generation of reactive oxygen species, are not prevented with nitric oxide synthase inhibitors, and may be indirectly mediated by the reactive metabolite acetaldehyde. Changes in skeletal muscle protein metabolism have profound implications for whole body physiology, while protein turnover changes in organs such as the heart (exemplified by complex alterations in protein profiles) have important implications for cardiovascular function and morbidity.
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PMID:Protein metabolism in alcoholism: effects on specific tissues and the whole body. 1042 97

The present study assessed whether peritoneal macrophages isolated from cirrhotic patients produce nitric oxide (NO) and express NO synthase type II (NOS II) mRNA and protein. Patients with cirrhosis and ascites without peritonitis or with unresolved or resolved spontaneous bacterial peritonitis (SBP) were studied. Following paracentesis, ascites NO(2)(-) + NO(3)(-) content (NOx) was measured. Peritoneal macrophages from ascites were seeded on well plates, and NO(2)(-) in the medium was determined. NOx was higher in patients with unresolved or resolved SBP than in cirrhotic patients without peritonitis. Macrophages of patients with SBP or resolved SBP produced NO(2)(-) after 30 hours in culture, but those obtained from patients without peritonitis did not. Reverse-transcription polymerase chain reaction (RT-PCR) and immunocytochemical analysis revealed the presence of a clear signal for NOS II mRNA and protein in macrophages of SBP patients, regardless of whether or not the infection subsided. Therefore, peritoneal macrophages isolated from cirrhotic patients with unresolved or resolved SBP produce NO and express the NOS II mRNA and protein, suggesting that NOS II may contribute to the control of SBP, or to its associated pathology, in human cirrhosis.
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PMID:Nitric oxide production and inducible nitric oxide synthase expression in peritoneal macrophages of cirrhotic patients. 1046 73


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