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)

Nitric oxide (NO) is postulated to play a role in the pathogenesis of arterial vasodilation in chronic portal hypertension. This present study investigates the relationship between systemic hemodynamics and the vascular production of NO, as estimated by measuring cyclic guanosine monophosphate (cGMP) in aortic tissue in two models of chronic portal hypertension in the rat: the partial portal vein ligation (PVL) model and CCl4-induced cirrhosis. NOS was also examined by Western blotting in aortic and mesenteric vessels. Sham-operated rats and rats given phenobarbital were used as controls. PVL rats and rats with cirrhosis and ascites showed a typical pattern of a hyperdynamic circulatory state, when compared with their respective controls: mean arterial pressure; PVL: 113 +/- 2 versus 124 +/- 2, P < .01 and cirrhotics: 103 +/- 5 versus 130 +/- 4 mm Hg, P < .01. Cardiac index; PVL: 32 +/- 2 versus 26 +/- 1, P < .01 and cirrhotics: 51 +/- 3 versus 30 +/- 1 mL . min-1 . 100 gm-1, P < .0001. Systemic vascular resistance; PVL: 3.7 +/- 0.1 versus 4.9 +/- 0.2, P < .01 and cirrhotics: 2.1 +/- 0.2 versus 4.4 +/- 0.2 mm Hg . min-1 100 g-1, P < .0001. Aortic cGMP was markedly increased in cirrhotic rats with ascites (728 +/- 83 fmol/ mg protein) as compared with phenobarbital-treated controls (244 +/- 31 fmol/mg, P < .001). This increase was abolished by chronic administration of N(omega)-nitro-L-arginine methyl ester. By contrast, PVL rats had an aortic cGMP concentration similar to sham-operated controls (282 +/- 16 fmol/mg vs. 274 +/- 33 fmol/mg, P = not significant) and significantly lower than that found in cirrhotic rats with ascites. Expression of cirrhotic aortic endothelial nitric oxide synthase (eNOS) was increased but PVL aortic eNOS did not differ from that of controls, whereas the mesenteric eNOS was increased in both PVL and cirrhotic rats as compared with the controls. These results suggest that vascular NO production is higher in cirrhotic rats than in PVL rats. This increased production may contribute to the more marked abnormalities in systemic hemodynamics seen in experimental cirrhosis as compared with PVL.
 ...
PMID:Comparison of vascular nitric oxide production and systemic hemodynamics in cirrhosis versus prehepatic portal hypertension in rats. 885 3

Arterial vasodilatation is thought to play a major role in the pathogenesis of systemic hemodynamics and renal disturbances occurring in cirrhotic patients. Recent investigations suggest that an increased vascular nitric oxide (NO) production could be implicated in this abnormality. The current study assessed whether increased expression of inducible and/or endothelial nitric oxide synthase (iNOS and eNOS, respectively) occurs in arterial vessels of cirrhotic rats. The investigation was performed in thoracic and abdominal aortas and mesenteric arteries of 10 control rats and 16 cirrhotic rats with ascites. iNOS and eNOS messenger RNA (mRNA) expression were evaluated by polymerase chain reaction and ribonuclease protection assay, respectively. Endothelial NOS protein expression was assessed by Western blot. No iNOS mRNA was detected in arterial vessels of control rats. In contrast iNOS mRNA was consistently detected in all arteries of cirrhotic rats with ascites, the weakest signal being observed in the thoracic aorta and the strongest in the mesenteric artery. Enhanced eNOS mRNA abundance was found in the aorta of cirrhotic animals as compared with controls. Higher eNOS protein expression was noted in the thoracic aorta of cirrhotic rats. These results indicate the existence of increased eNOS and iNOS expression in arterial vessels of cirrhotic rats, suggesting that transcriptional activation of vascular NOSs and the associated nitric oxide hyperproduction may be of major importance in the pathogenesis of arterial vasodilation in cirrhosis.
 ...
PMID:Increased nitric oxide synthase expression in arterial vessels of cirrhotic rats with ascites. 893 84

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.
 ...
PMID:Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites. 942 86

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

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.
 ...
PMID:Endothelin-1 stimulation of endothelial nitric oxide synthase in the pathogenesis of hepatopulmonary syndrome. 1056 99

Our pilot study disclosed that tryptase-positive mast cells (MC) were densely distributed around the intrahepatic bile ducts (peribiliary MC). In this study, the pathophysiologic roles of these MC were examined with respect to the microcirculation around the bile duct in 71 cases of histologically normal liver, 24 cases of chronic hepatitis, and 45 cases of liver cirrhosis. The tryptase-positive MC were very close to the microvessels of the peribiliary vascular plexus (PVP), which supply the intrahepatic biliary tree. The tryptase-positive MC were frequently found adjacent to vascular smooth muscle cells, including pericytes. The location of the tryptase-positive MC was confirmed by ultrastructural analysis. In cirrhosis, the numbers of both microvessels of PVP and peribiliary MC increased in parallel. Peribiliary MC were immunoreactive for endothelin 1 (ET-1), and were variably immunoreactive for histamine, chymase, inducible nitric oxide synthase (iNOS), and endothelin A and B (ET(A) and ET(B)) receptors, particularly in cirrhotic livers. On vascular endothelial cells of PVP, endothelial nitric oxide synthase (eNOS) and ET-1 were consistently detectable, and ET(A) receptors, ET(B) receptors, and iNOS were variably detectable. Pericytes of PVP expressed ET(A) and ET(B) receptors in addition to ET-1 and iNOS. Biliary epithelial cells also focally expressed iNOS, ET-1, and ET(A) and ET(B) receptors. These vasoactive substances were strongly expressed on the cellular components in cirrhotic liver. By in situ hybridization, iNOS mRNA signals were observed on iNOS-immunoreactive cell components, including peribiliary MC. These morphologic and immunohistochemical findings suggest that the cellular components displaying vasoactive substances in the milieu of the intrahepatic biliary tree are very dynamic in the vasoregulation of PVP in normal livers, even more so in cirrhosis, and that peribiliary MC exert local effects on the microcirculation of PVP, directly and indirectly.
 ...
PMID:Evidence of the participation of peribiliary mast cells in regulation of the peribiliary vascular plexus along the intrahepatic biliary tree. 1090 46

The hepatopulmonary syndrome (HPS) results from pulmonary microvascular dilatation in cirrhosis and is associated with increased pulmonary endothelial nitric oxide synthase (eNOS) levels. In the common bile duct ligation (CBDL) model, endothelin-1 (ET-1) released from the liver contributes to the rise in pulmonary eNOS and intrapulmonary vasodilatation. Whether substances, including ET-1, are found in the biliary tree and selectively enter the circulation after CBDL to influence the pulmonary vasculature is unknown. We assessed if control bile and fluid obtained from the obstructed biliary tree in CBDL animals contains ET-1 and alters eNOS expression and activity in bovine pulmonary artery endothelial cells (BPAECs). Control bile and biliary cyst fluid contained concentrations of ET-1 25- to 42-fold normal plasma levels, and hepatic venous concentrations of ET-1 were selectively increased after CBDL. Biliary cyst fluid caused a dose-dependent induction of eNOS messenger RNA (mRNA) (1.9-fold control), protein (2.5-fold control), and enzyme activity (2.2-fold control) maximal at a 1:10 dilution. The increases were associated with enhanced nitric oxide (NO) production (3.1-fold control) and were inhibitable with an ET(B) receptor antagonist. Bile from sham and portal vein-ligated animals did not increase eNOS expression and at dilutions of 1:100 and 1:10 caused cell toxicity. These results show that bile and biliary cyst fluid contain high concentrations of ET-1 that are specifically increased in hepatic venous blood after CBDL. Biliary cyst fluid increases eNOS expression and activity in an ET(B) receptor-dependent manner in BPAECs. The findings suggest a novel mechanism for the susceptibility of CBDL animals to the HPS.
 ...
PMID:Biliary cyst fluid from common bile duct-ligated rats stimulates endothelial nitric oxide synthase in pulmonary artery endothelial cells: a potential role in hepatopulmonary syndrome. 1123 Jul 54

In carbon tetrachloride-induced liver cirrhosis, diminution of hepatic endothelial nitric oxide synthase (eNOS) activity may contribute to impaired hepatic vasodilation and portal hypertension. The mechanisms responsible for these events remain unknown; however, a role for the NOS-associated proteins caveolin and calmodulin has been postulated. The purpose of this study is to characterize the expression and cellular localization of the NOS inhibitory protein caveolin-1 in normal rat liver and to then examine the role of caveolin in conjunction with calmodulin in regulation of NOS activity in cholestatic portal hypertension. In normal liver, caveolin protein is expressed preferentially in nonparenchymal cells compared with hepatocytes as assessed by Western blot analysis of isolated cell preparations. Additionally, within the nonparenchymal cell populations, caveolin expression is detected within both liver endothelial cells and hepatic stellate cells. Next, studies were performed 4 wk after bile duct ligation (BDL), a model of portal hypertension characterized by prominent cholestasis, as evidenced by a significant increase in serum cholesterol in BDL animals. After BDL, caveolin protein levels from detergent-soluble liver lysates are significantly increased as assessed by Western blot analysis. Immunoperoxidase staining demonstrates that this increase is most prominent within sinusoids and venules. Additionally, caveolin-1 upregulation is associated with a significant reduction in NOS catalytic activity in BDL liver lysates, an event that is corrected with provision of excess calmodulin, a protein that competitively binds eNOS from caveolin. We conclude that, in cholestatic portal hypertension, caveolin may negatively regulate NOS activity in a manner that is reversible by excess calmodulin.
 ...
PMID:Regulation of hepatic eNOS by caveolin and calmodulin after bile duct ligation in rats. 1135 14

Cirrhosis predisposes the liver to secondary stresses such as endotoxemia possibly via dysregulation of the hepatic portal circulation secondary to imbalanced upregulation of vascular stress genes. In this study we determined the effect of cirrhosis on hepatic vasoregulatory gene expression in response to endotoxin (LPS, i.p., 1 mg/kg). Cirrhosis was induced by bile duct ligation (BDL) for 21 days in male Sprague-Dawley rats. Plasma and liver samples were taken 6 h following an injection of LPS for alanine aminotransferase (ALT) assays and RT-PCR analysis of mRNA levels for genes of interest: endothelin (ET-1), its receptors ET(A) and ET(B), endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and heme oxygenase-1 (HO-1). ALT release increased by 5.5-fold in the BDL animals and 9.9-fold in BDL + LPS compared to sham. ET-1 mRNA was increased by either LPS or BDL treatment alone and increased significantly more in BDL + LPS compared to sham + LPS. mRNA levels for ET(B) receptors showed no change, whereas ETA transcripts decreased in BDL animals compared to sham, with no significant difference between the saline and LPS treatment groups. The resultant increased ratio of ET(B) over ET(A) in BDL animals was reflected functionally in the portal pressure responses to ET(A) and ET(B) agonists ET-1 and IRL-1620 (a specific ETB receptor agonist). The pressor response to ET-1 was attenuated, while the response to IRL-1620 was similar in BDL and sham. eNOS mRNA levels did not increase in response to either BDL or LPS or a combination of both compared to sham. The increase in iNOS mRNA was attenuated in BDL + LPS compared to sham + LPS. HO-1 expression increased significantly in sham + LPS, but failed to increase in BDL + LPS. Taken collectively, significantly greater induction of the constrictor ET-1 over the dilation forces (i.e., eNOS, iNOS, and HO-1) was observed in BDL + LPS. This suggests a compromised ability of the cirrhotic liver to upregulate sufficient dilatory forces to counterbalance the constrictive effect of ET-1 upon a secondary insult of endotoxemia. These results may partly explain the increased susceptibility of cirrhotic livers to injury as a result of endotoxemia.
 ...
PMID:LPS-induced imbalanced expression of hepatic vascular stress genes in cirrhosis: possible mechanism of increased susceptibility to endotoxemia. 1195 34

BACKGROUND: In cirrhotic livers, the balance of vasoactive substances is in favour of vasoconstrictors with relatively insufficient nitric oxide. Endothelial dysfunction has been documented in cirrhotic rat livers leading to a lower activity of endothelial nitric oxide synthase but this might not be sufficient to explain the low nitric oxide presence. We compared the amount of all nitric oxide synthase isoforms and other factors that influence nitric oxide bioavailability in livers of two portal hypertensive rat models: prehepatic portal hypertension and carbon tetrachloride induced cirrhosis, in comparison with healthy controls. RESULTS: Endothelial nitric oxide synthase was the solely detected isoform by Western blotting in all livers. In cirrhotic livers, the amount of endothelial nitric oxide synthase protein was lower than in healthy controls, although an overlap existed. Levels of caveolin-1 messenger RNA were within the normal range but endothelin-1 messenger RNA levels were significantly higher in cirrhotic livers (p < 0.05). A markedly lower superoxide dismutase activity was observed in cirrhotic livers as compared to healthy controls (p < 0.05). CONCLUSIONS: In contrast to prehepatic portal hypertension, cirrhotic livers had decreased endothelial nitric oxide synthase protein and enhanced endothelin-1 messenger RNA amount. We hypothesise that a vasodilator/vasoconstrictor imbalance may be further aggravated by the reduced activity of superoxide dismutase. Decreased activity allows enhanced superoxide action, which may lead to breakdown of nitric oxide in liver sinusoids.
 ...
PMID:Low NO bioavailability in CCl4 cirrhotic rat livers might result from low NO synthesis combined with decreased superoxide dismutase activity allowing superoxide-mediated NO breakdown: A comparison of two portal hypertensive rat models with healthy controls. 1257 97


1 2 3 4 Next >>