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

Tumor necrosis factor-alpha (TNF) causes vasodilatation and a hyperdynamic state by activating nitric oxide (NO) synthesis. Tyrphostins, specific inhibitors of protein tyrosine kinase (PTK), block the signaling events induced by TNF and NO production. A hyperdynamic circulatory syndrome (HCS) is often observed in portal hypertension (PHT). TNF and NO seem to mediate these hemodynamic changes. The aim of this work was to study the effect of PTK inhibition on the systemic and portal hemodynamics, TNF and NO production, in cirrhotic rats with portal hypertension. Rats with liver cirrhosis induced by chronic inhalation of carbon tetrachloride were used. Animals were treated daily with tyrphostin AG 126 (alpha-cyano-(3-hydroxy-4-nitro) cinnamonitrile) or placebo for 5 d. Mean arterial pressure (MAP), heart rate (HR), and portal pressure (PP) were measured by indwelling catheters. Cardiac output (CI) and stroke volume (SV) were estimated by thermodilution, systemic vascular resistance (SVR) was calculated (MAP/CI), and portal systemic shunting (PSS) was quantitated using radioactive microspheres. Serum and mesenteric lymph node (MLN) TNF levels were measured using an immunoassay kit, and serum NOx was determined photometrically by its oxidation products. The AG 126-treated group showed a statistically significant increase in MAP and SVR, and decreases in CI, SV, MLN TNF, and serum NO oxidation products nitrite and nitrate (NOx) in comparison with the placebo-treated rats. No significant differences were noticed in HR, PP, PSS, or serum TNF. Significant correlations were observed between MAP and NOx, MAP and MLN TNF, PSS and NOx, and serum TNF and serum NOx. The HCS observed in PHT seems to be mediated, at least in part, by TNF and NO by the activation of PTKs and their signaling pathways. PTK activity inhibition ameliorates the hyperdynamic abnormalities that characterize animals with cirrhosis and PHT.
 ...
PMID:Tyrosine kinase inhibition ameliorates the hyperdynamic state and decreases nitric oxide production in cirrhotic rats with portal hypertension and ascites. 923 14

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.
 ...
PMID:NO as an indicator of portal hemodynamics and the role of iNOS in increased NO production in CCl4-induced liver cirrhosis. 924 60

Impaired arterial oxygenation, ranging from increased alveolar-arterial oxygen gradient (AaDo2) to hypoxemia, is commonly present in patients with cirrhosis. Nitric oxide (NO), through pulmonary vasodilatation, may play a major role in the oxygen abnormalities of cirrhosis. Our aim was to study the relationship between NO production and O2 abnormalities in 45 nonsmoking patients with cirrhosis and without major cardiovascular and respiratory diseases. Intrapulmonary shunting was detected by contrast-enhanced (CE) echocardiography. Lung volumes and diffusion, arterial blood gas analysis, serum NO2-/NO3-, NO output in the exhaled air, and cardiac index by the echocardiographic method were determined in all patients. Twenty-seven (60%) patients had an abnormally increased (> 15 mm Hg) AaDo2. The mean values of exhaled NO output and serum NO2-/NO3- were significantly higher in cirrhotic patients than in controls (252 +/- 117 vs. 75.2 +/- 19 nL/min/m2, P < .0001; and 47.5 +/- 29.4 vs. 32.9 +/- 10.1 micromol/L, P < .02, respectively). In all patients, there was a significant correlation between exhaled NO and AaDo2 (r = .78, P < .0001). Twelve patients (26.6%) were found to have CE-echocardiographic evidence of intrapulmonary shunting (positive CE-echo). Nine patients were considered to have hepatopulmonary syndrome (HPS) on the basis of an AaDo2 > 15 mm Hg and positive CE-echo. These 9 patients had a mean value of exhaled NO significantly higher than patients without HPS (331 +/- 73.2 vs. 223 +/- 118.4 nL/min/m2, P < .05). In all patients, cardiac index was positively correlated with exhaled NO (r = .47, P < .001) and with serum NO2-/NO3- (r = .43, P < .01). The results suggest an important role of NO in the oxygenation and circulatory abnormalities of patients with cirrhosis.
 ...
PMID:Exhaled nitric oxide and oxygenation abnormalities in hepatic cirrhosis. 958 8

To investigate the role of nitric oxide (NO) with respect to kidney function and liver cirrhosis, we evaluated renal function, as well as cyclic guanosine monophosphate (cGMP) and NOx (nitrite/nitrate [NO3-/NO2-]) as indirect markers of NO formation in plasma and urine at rest and during amino acid (aa)-induced glomerular hyperfiltration in patients with Child A liver cirrhosis and portal hypertension (n = 12), and in healthy controls (n = 10). Baseline filtration rate (GFR) and effective renal plasma flow (ERPF) were significantly lower in patients with cirrhosis than in controls (GFR: mean 88 +/- SD 16 mL/min vs. 106 +/- 15 mL/min, P = .01, ERPF: 477 +/- 93 vs. 561 +/- 72 mL/min, P = .002). In both groups amino acid (aa) infusion increased GFR, ERPF, as well as cGMP and urinary NOx. Changes in GFR were similar in cirrhotic patients and controls (28.3% +/- 14% in cirrhotics and 26% +/- 11% in controls), but the degree of aa-induced changes in ERPF was more marked in patients with liver cirrhosis (31.8% +/- 17% vs. 18.6% +/- 12%, P = .02). Plasma levels of NOx and cGMP were similar in either group at baseline and during aa infusion, whereas NOx and cGMP excretion in cirrhotics was constantly 14% to 24% lower than in the control group. We conclude that patients with compensated liver cirrhosis and portal hypertension already have an impaired kidney function. In addition our data suggest a cirrhosis-related dissociation between ERPF and GFR during aa stimulation. Further studies are warranted to find out whether a local imbalance between vasoconstrictors and vasodilators, e.g., decreased local NO formation, plays a key role for this phenomenon.
 ...
PMID:Renal functional reserve and nitric oxide in patients with compensated liver cirrhosis. 932 5

Plasma alpha 1 antitrypsin (alpha 1 AT) is the major serine protease inhibitor (Pi) in plasma. It is a glycoprotein, which presents many molecular variants. Allelic phenotypes are classified alphabetically according to their electrophoretic mobility in the Pi (Proteases inhibitor) system. More than 75 distinct protease inhibitor subtypes have been identified using isoelectric focusing (IEF). The major interest for detecting its microheterogeneity is the rare possibility of deficient alleles, which are responsible of low amounts in the alpha IAT production. The clinical use of the alpha 1AT phenotyping is the diagnosis of hereditary alpha 1AT deficiencies. The most common normal phenotype is MM; the major deficient phenotypes are MS, MZ, SS, SZ and ZZ. Hereditary deficiencies of the Pi, the most common inborn error in European people, lead to pulmonary emphysema in young adults or liver cirrhosis in children. IEF on polyacrylamide gels is the reference method for alpha 1AT phenotyping, but is very difficult to standardize. In the present study, we have developed IEF on agarose gels for Pi subtyping within a number of technical improvements. A 0.5 mm thin agarose gel (1.6%) is cast on polyester film; focusing is performed using carrier ampholines (pH = 4.2-4.9), using a very high voltage. Staining is done with a simplified silver nitrate method. The patterns of the different Pi phenotypes obtained with our technique are very attractive. The common subtypes corresponding to the alleles M1, M2, M3, S, Z are univocally demonstrated. Agarose gel allows the advantage of using a non toxic substance. Further the gels are easy to produce and the method is accessible to all clinical laboratories.
 ...
PMID:[Determination of alpha 1 antitrypsin phenotypes in plasma using isoelectric focusing on this agarose gel]. 976 31

The aim of this study is to ascertain whether the formation of nitric oxide is argumented in patients with liver cirrhosis and its mechanism. 38 cirrhotic patients and 15 normal controls were studied. Higher plasma levels of NO2-/NO3- (stable end products of nitric oxide), endotoxin, tumor necrosis factor alpha (TNF alpha) and cyclic guanosine monophosphate (cGMP) were observed in patients with cirrhosis than in normal controls (P < 0.01, 0.01, 0.01, 0.05). The higher Child-Pugh, the higher plasma NO2-/NO3- level. The concentration of NO2-/NO3- had a positive correlation with that of endotoxin and TNF alpha (r = 0.481, P < 0.01; r = 0.351, P < 0.05). It is suggested that the production of nitric oxide is augmented and could be induced by endotoxin and TNF alpha. Execessive formation of nitric oxide may be related to hyperdynamic circulation in cirrhosis.
 ...
PMID:[Nitric oxide levels in cirrhotic patients]. 981 57

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.
 ...
PMID:Lipoic acid prevents development of the hyperdynamic circulation in anesthetized rats with biliary cirrhosis. 1021 16

The characteristic cardiovascular changes in liver cirrhosis are vasodilatation and increased cardiac output. Augmented activity of the vasorelaxant factor, nitric oxide (NO), stimulated by cytokines, have been suggested to play a role in the pathogenesis, but previous studies show conflicting results. We therefore aimed to evaluate the entire pathway from cytokines to the final metabolites, nitrate/nitrite. The levels of serum Tumor Necrosis Factor-alpha (TNFalpha) and nitrate/nitrite (NOx) were measured, and aorta content of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) mRNA and protein were determined by reverse-transcription polymerase chain reaction and Western blotting in rats with cirrhosis due to chronic bile duct ligation and sham-operated controls. Compared to control rats, serum TNFalpha levels were significantly elevated in cirrhotic rats (48.4+/-21.1 vs 16.8+/-9.0 pg/ml, p<0.01); iNOS mRNA was detectable whereas it was absent in controls, and eNOS mRNA levels was significantly higher in aortae of cirrhotic rats. Aortic eNOS protein content was significantly higher in cirrhotic rats, but iNOS protein was undetectable by Western blotting in both groups. Serum NOx concentrations in the cirrhotic group were significantly higher than those in controls (3.5+/-1.0 vs 2.3+/-0.5 microM, p<0.01). These results suggest that NO activity in cirrhosis is increased, and is predominantly due to eNOS since the detectable iNOS mRNA does not seem to be expressed as protein. The increased NOS activity in the arterial system may play a role in the systemic hemodynamic changes occurring in cirrhosis.
 ...
PMID:Increased nitric oxide synthase expression in aorta of cirrhotic rats. 1035 29

High levels of nitric oxide are thought to be the cause of some of the complications associated with decompensated end-stage liver disease. To assess nitric oxide metabolism in cirrhotic patients, we measured the levels of nitric oxide metabolites (nitrosohemoglobin, methemoglobin, nitrate, and nitrite) in normal subjects, in patients with decompensated cirrhosis, in patients with renal failure (model for impaired NO metabolites excretion), and in patients with mononitrates-treated anginal syndrome (model for exogenous nitric oxide). When compared to controls, patients with decompensated cirrhosis exhibited elevated levels of nitrate only. A significant increase of nitrate was also noted in patients receiving exogenous nitrates, whereas patients with impaired excretion had significantly elevated levels of both nitrite and nitrate. In conclusion, nitric oxide metabolism in patients with decompensated cirrhosis is similar to that of patients receiving nitric oxide from an exogenous source. Renal impairment, whether alone or associated with cirrhosis, causes a change in nitric oxide metabolism. These findings may have clinical implications for nitrates treatment in patients with decompensated cirrhosis.
 ...
PMID:Nitric oxide metabolites in decompensated liver cirrhosis. 1048 15

Sepsis is a common complication of cirrhosis with a high mortality. In this study, we have investigated some of the pathways that may be involved in tissue injury and death. Bile duct-ligated (BDL) cirrhotic and control rats were challenged with lipopolysaccharide (LPS). Sensitivity to LPS was markedly enhanced in the BDL group, and was associated with increased liver injury and mortality. There was a 5-fold constitutive activation of nuclear factor kappa B (NFkappaB) in the liver of BDL rat controls (P <.001), and this was activated further, but to a similar extent, in the liver of both sham and BDL rats after injection of LPS. Plasma tumor necrosis factor alpha (TNF-alpha) increased more markedly in the BDL cirrhotic rats (2,463 +/- 697 pg/mL in BDL rats versus 401 +/- 160 pg/mL in the controls at 3 hours; P <.01). Plasma nitrite/nitrate concentrations were increased in the BDL controls at baseline, and increased further after LPS (P <.05), but did not differ from sham controls at 6 hours. Plasma F(2)-isoprostanes increased 6-fold in the cirrhotic rats and 2-fold in the controls (P <.01) indicative of lipid peroxidation. Esterified F(2)-isoprostanes in the liver increased 2- to 3-fold at 1 hour in control and BDL rats, but returned to baseline levels by 3 hours. Esterified F(2)-isoprostanes in the kidney increased by 2-fold in the BDL rats after LPS administration, but remained unchanged in sham controls. We conclude that there is a marked increase in sensitivity to LPS in BDL cirrhotic rats. This is associated with an enhanced TNF-alpha response and increased lipid peroxidation. These may be directly and causally related to mortality.
 ...
PMID:Increased sensitivity to endotoxemia in the bile duct-ligated cirrhotic Rat. 1053 41


<< Previous 1 2 3 4 5 6 Next >>