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)

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

The role of nitric oxide (NO) in portal hypertension is poorly understood. The role of NO upon hepatic arterial and portal venous vasoconstrictor responses to noradrenaline and ATP in rats with secondary biliary cirrhosis was evaluated. Cirrhosis was induced by bile duct ligation after which livers were excised and dual-perfused in vitro. Concentration-dependent dose-response curves were then constructed to hepatic arterial and portal venous noradrenaline and ATP. Hepatic arterial responses to noradrenaline and ATP were significantly attenuated in cirrhotic rats. 100 microM N(G)-nitro-L-arginine methyl ester (L-NAME) restored attenuated hepatic arterial responses to noradrenaline and ATP in cirrhotic rats. Portal venous responses to noradrenaline in cirrhotic rats were significantly increased compared to controls and were not affected by L-NAME. However, portal venous responses to ATP were significantly attenuated in cirrhotic rats and were also not restored by L-NAME. Hepatic arterial or portal venous responses to noradrenaline did not change after infusion of L-NAME. Hepatic arterial responses to noradrenaline and ATP were significantly attenuated in cirrhotic rats, possibly due to increased production of NO. However, portal venous responses in cirrhotic rats were increased to noradrenaline and attenuated to ATP, and were not related to increased NO production.
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PMID:The action of nitric oxide on hepatic haemodynamics during secondary biliary cirrhosis in the rat. 1256 14

Vascular remodeling is an active process that consists in important modifications in the vessel wall. Endothelium-derived nitric oxide (NO) plays a major role in this phenomenon. We assessed wall thickness (WT), total wall area (TWA), lumen diameter, and total nuclei number/cross-section (TN) in cirrhotic rats with ascites and in control rats. A second group of cirrhotic rats received the NO synthesis inhibitor, L-NAME, or vehicle daily for 11 weeks and systemic hemodynamics, arterial compliance, aortic NO synthase 3 (NOS3) protein expression, and vascular morphology were analyzed. Cirrhotic vessels showed a significant reduction in WT, TWA, and TN as compared to control vessels. Long-term inhibition of NOS activity in cirrhotic rats resulted in a significant increase in WT, TWA, and TN as compared to cirrhotic rats receiving vehicle. NOS3 protein abundance was higher in aortic vessels of nontreated cirrhotic animals than in controls. This difference was abolished by chronic treatment with L-NAME. NOS inhibition in cirrhotic rats resulted in higher arterial pressure and peripheral resistance and lower arterial compliance than cirrhotic rats receiving vehicle. Therefore, vascular remodeling in cirrhosis with ascites is a generalized process with significant functional consequences that can be negatively modulated by long-term inhibition of NOS activity.
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PMID:Nitric oxide synthase 3-dependent vascular remodeling and circulatory dysfunction in cirrhosis. 1275 54

Hepatopulmonary syndrome--a complication of chronic liver disease-is characterised by hypoxaemia, which results from widespread intrapulmonary vascular dilatations. Amplified production of pulmonary nitric oxide is thought to be important in development of this disorder in patients with liver cirrhosis. Here, we report a 64-year-old man with hepatopulmonary syndrome associated with hepatitis-C-virus-related cirrhosis. We gave the patient nebulised N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, which enhanced oxygenation (arterial oxygen pressure increased from 6.98 to 9.45 kPa). After L-NAME, the distance the patient could walk in 6 min rose by 92 m. Administration of L-NAME by aerosol might offer a new approach to treatment of hepatopulmonary syndrome.
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PMID:Effect on dyspnoea and hypoxaemia of inhaled N(G)-nitro-L-arginine methyl ester in hepatopulmonary syndrome. 1285

1. Portal hypertension (PH), a major syndrome in cirrhosis, producing hyperdynamic splanchnic circulation and hyperaemia. In order to elucidate the contribution of heme oxygenase to the vascular hyporeactivity, we assessed the activity of heme oxygenase-1 (HO-1), measured the in vivo pressure response to noradrenaline (NA) and investigated the effects of blocking the carbon monoxide (CO) and nitric oxide (NO) pathways in a prehepatic model of PH in rats. 2. Portal hypertension was induced by partial portal vein ligation (PPVL). Noradrenaline was injected intravenously. Liver, spleen and mesentery homogenates were prepared for measurement of HO-1 activity and expression. Four groups of rats were used: (i) a sham group; (ii) a PPVL group; (iii) a sham group pretreated with Zn-protoporphyrin IX (ZnPPIX); and (iv) a PPVL group pretreated with ZnPPIX. Each group was studied before and after treatment with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). 3. For basal pressures and the pressure response to NA, inhibition of CO and NO pathways by ZnPPIX and L-NAME, respectively, produced an increase in mean arterial pressure (MAP) in sham-operated and in PH rats. Similarly, when both inhibitors were used together in either sham or PPVL rats, a greater increase in MAP was observed. 4. These results, together with the increased HO-1 activity and expression only in the PH group, have led us to suggest that the heme oxygenase/CO pathway is involved in the vascular response to NA in PH rats.
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PMID:Role of heme oxygenase/carbon monoxide pathway on the vascular response to noradrenaline in portal hypertensive rats. 1574 3

Homocysteine (Hcy), an intermediate in methionine metabolism, has been proposed to be involved in hepatic fibrogenesis. Impaired liver function can alter Hcy metabolism. The aim of the present study was to determine plasma Hcy alterations in acute obstructive cholestasis and the subsequent biliary cirrhosis. Cholestasis was induced by bile duct ligation and sham-operated and unoperated rats were used as controls. The animals were studied on the days 7th, 14th, 21st and 28th after the operation. Plasma Hcy, cysteine, methionine, nitric oxide (NO) and liver S-adenosyl-methionine (SAM), S-adenosyl-homocysteine (SAH), SAM to SAH ratio and glutathione were measured. Chronic L-NAME treatment was also included in the study. Plasma Hcy concentrations were transiently elevated by the day 14th after bile duct ligation (P < 0.01) and subsequently returned to control levels. Similar relative fluctuations in plasma Hcy were observed in BDL rats after intraperitoneal methionine overload. Plasma methionine, cysteine and nitrite and nitrate were significantly increased after bile duct ligation. SAM to SAH ratio was diminished by the 1st week of cholestasis and remained significantly decreased throughout the study. These events were accompanied by a decrease in GSH to GSSG ratio in the liver. Chronic L-NAME treatment improved SAM to SAH ratio and prevented the elevation of plasma Hcy and methionine (P < 0.05) while couldn't influence the other parameters. In conclusion, this study demonstrates alterations in plasma Hcy and liver SAM and SAH contents in precirrhotic stages and in secondary biliary cirrhosis, for the first time. In addition, we observed that plasma Hcy concentrations in BDL rats follow a distinct pattern of alteration from what has been previously reported in other models of cirrhosis. NO overproduction may contribute to plasma Hcy elevation and liver SAM depletion after cholestasis.
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PMID:Homocysteine alterations in experimental cholestasis and its subsequent cirrhosis. 1576 80

BALB/c Fech(m1Pas) mice have a mutated ferrochelatase gene resulting in protoporphyria that models the hepatic injury occurring sporadically in human erythropoietic protoporphyria. We used this mouse model to study the development of the injury and to compare the dysfunction of heme synthesis with hepatic gene expression of liver metabolism, oxidative stress, and cellular injury/inflammation. From an early age expression of total cytochrome P450 and many of its isoforms was significantly lower than in wild-type mice. However, despite massive accumulation of protoporphyrin in the liver, expression of the main genes controlling heme synthesis and catabolism (Alas1 and Hmox1, respectively) were only modestly affected even in the presence of the cytochrome P450-inducing CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. In contrast, in BALB/c mice exhibiting griseofulvin-induced hepatic protoporphyria with induction and destruction of cytochrome P450, both Alas1 and Hmox1 genes were markedly up-regulated. Other expression profiles in BALB/c Fech(m1Pas) mice identified roles for oxidative mechanisms in liver injury while modulated gene expression of hepatocyte transport proteins and cholesterol and bile acid synthesis illustrated the development of cholestasis. Subsequent inflammation and cirrhosis were also shown by the up-regulation of cytokine, cell cycling, and procollagen genes. Thus, gene expression profiles studied in Fech(m1Pas) mice may provide candidates for human polymorphisms that explain the sporadic hepatic consequences of erythropoietic protoporphyria.
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PMID:Hepatic gene expression in protoporphyic Fech mice is associated with cholestatic injury but not a marked depletion of the heme regulatory pool. 1579 85

Acceleration of the heart rate in response to catecholamines is impaired in cirrhosis. In this study, we tested the hypothesis that increased formation of reactive nitrogen species in biliary cirrhosis causes nitration of cardiac proteins and leads to impaired chronotropic function. Bile duct-ligated (rats with cirrhosis) or sham-operated rats were injected daily with either saline, N(G)-L-nitro-arginine methyl ester (L-NAME), or N-acetylcysteine for 7 days from week 3 to week 4 after surgery. Cardiac chronotropic responsiveness to beta-adrenergic stimulation was assessed in vitro using spontaneous beating isolated atria. Nitration of cardiac proteins was measured by mass spectrometry and located by immunogold electron microscopy. Marked impairment of chronotropic responses of isolated atria to isoproterenol was seen in rats with cirrhosis, which normalized after the administration of N-acetylcysteine or L-NAME. The levels of protein-bound nitrotyrosine in atrial tissue increased from 16 +/- 1 to 23 +/- 3 pg/microg tyrosine in rats with cirrhosis, and decreased to 15 +/- 1 and 17 +/- 1 pg/microg after treatment with L-NAME and N-acetylcysteine, respectively (P < .05). Immunogold electron microscopy demonstrated increased nitration of mitochondrial proteins in the atria of rats with cirrhosis. The plasma nitrite/nitrate levels were elevated in rats with biliary cirrhosis, and decreased after administration of L-NAME but were unchanged by N-acetylcysteine. In conclusion, abnormal cardiac chronotropic function in cirrhosis is associated with increased nitration of cardiac proteins. Two independent treatments (N-acetylcysteine and L-NAME) that decrease nitration of cardiac proteins led to normalization of cardiac responses. Nitration of critical proteins in cardiac tissue may lead to abnormal cardiac function.
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PMID:Nitration of cardiac proteins is associated with abnormal cardiac chronotropic responses in rats with biliary cirrhosis. 1655 56

It is well known that chronotropic and inotropic responses to beta-adrenergic stimulation are impaired in cirrhosis, but the exact reason is not clear. Considering the inhibitory effect of endogenous opioid peptides and nitric oxide (NO) on beta-adrenergic pathway, we examined their roles in hyporesponsiveness of isolated atria and papillary muscles to isoproterenol stimulation in cirrhotic rats. Cirrhosis was induced by chronic bile duct ligation. Four weeks after ligation or sham operation, the responses of the isolated atria and papillary muscles to isoproterenol stimulation were evaluated in the absence and presence of naltrexone HCl (10(-6) m), N(omega)-nitro-L-arginine methyl ester (L-NAME, 10(-4) m), and naltrexone plus L-NAME in the organ bath. Considering the role of inducible NOS (iNOS) in hemodynamic abnormalities of cirrhotic rats, the chronotropic and inotropic responses of cirrhotic rats to isoproterenol stimulation were also assessed in the presence of aminoguanidine (a selective inhibitor of iNOS, 3 x 10(-4) m). Sham operation had no significant effect on basal atrial beating rate, contractile force, and maximal time derivatives for the development and the dissipation of papillary muscle tension. The basal atrial beating rate of cirrhotic rats did not show any significant difference compared with the sham-operated ones; however, the basal contractile parameters were significantly decreased in cirrhosis. Although the maximum effects of isoproterenol on chronotropic and inotropic responses were significantly reduced in cirrhotic rats, there was no difference in half-maximal effective concentrations of isoproterenol in these concentration-response curves. The basal abnormalities and the attenuated chronotropic and inotropic responses to isoproterenol were completely corrected by the administration of naltrexone, L-NAME and aminoguanidine. Concurrent administration of naltrexone and L-NAME also restored to normal the basal abnormalities and the blunted responses to isoproterenol in cirrhotic rats, and did not show any antagonistic effect. Based on these findings, both the endogenous opioid peptides and NO may be involved in the attenuated chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhosis. It seems that the iNOS activity results in NO-induced hyporesponsiveness to beta-adrenergic stimulation in cirrhosis.
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PMID:Involvement of endogenous opioid peptides and nitric oxide in the blunted chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhotic rats. 1696 16

In liver cirrhosis, elevated levels of NO and ROS (reactive oxygen species) might greatly favour the generation of peroxynitrite. Peroxynitrite is a highly reactive oxidant and it can potentially alter the vascular reactivity and the function of different organs. In the present study, we evaluated whether peroxynitrite levels are related to the progression of renal vascular and excretory dysfunction during experimental cirrhosis induced by chronic BDL (bile-duct ligation) in rats. Experiments were performed at 7, 15 and 21 days after BDL in rats and in rats 21 days post-BDL chronically treated with L-NAME (N(G)-nitro-L-arginine methyl ester). Sodium balance, BP (blood pressure), basal RPP (renal perfusion pressure) and the renal vascular response to PHE (phenylephrine) and ACh (acetylcholine) in isolated perfused kidneys were measured. NO levels were calculated as 24-h urinary excretion of nitrites, ROS as TBARS (thiobarbituric acid-reacting substances), and peroxynitrite formation as the renal expression of nitrotyrosine. BDL rats had progressive sodium retention, and decreased BP, RPP and renal vascular responses to PHE and ACh in the time following BDL. They also had increasing levels of NO and ROS, and renal nitrotyrosine accumulation,especially in the medulla. All of these changes were either prevented or significantly decreased by chronic L-NAME administration. In conclusion, these results suggest that the increasing levels of peroxynitrite might contribute to the altered renal vascular response and sodium retention in the development of the experimental biliary cirrhosis. Moreover, the beneficial effects of decreasing NO synthesis are, at least in part, mediated by anti-peroxinitrite-related effects.
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PMID:Effects of chronic L-NAME on nitrotyrosine expression and renal vascular reactivity in rats with chronic bile-duct ligation. 1818 8


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