Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well revealed that activation of macrophages stimulated by endotoxin resulted in induction of nitric oxide synthase which catalyze nitric oxide (NO) formation from L-arginine. Consequently, blood concentrations of NO2-/NO3- (NOx-) are shown to increase. We studied on pharmaco/toxicokinetics of NOx- in serum and principal organs in Wistar male rats after i.p. administrations of LPS and NaNO3. The serum levels of NOx- at 1 h and 6 h after nitrate administration (10 mg/kg, i.p.) were 240 and 120 microM, respectively. Tissue levels of NOx- in lung, liver and kidneys were ca.1/2 of the serum level. Those levels in spleen and brain were ca.1/4 and 1/10 of the serum level, respectively. The correlation of NOx- levels in serum and these 5 organ tissues between 1 h and 6 h after administration of nitrate was r = 0.992 suggesting no specific accumulation of NOx- in these organs. The serum level of NOx- at 18 h after LPS treatment (1 mg/kg, i.p.) was 430 microM. The correlation of NOx- levels in serum and 5 organ tissues between LPS and nitrate administrations was shown to be r = 0.851. NOx- levels of serum, lung, kidneys and brain showed good correlation but liver and spleen showed out of the correlation. The liver tissue level of NOx- after LPS treatment was low compared with the expected value from the serum level. The reason may be explained partially by the liver weight increase and the liver toxicity with increased GPT and gamma-GT levels due to LPS. Contrary to this, NOx- level of spleen tissue after LPS treatment was more than 2-fold compared with the expected value from the serum level suggesting NO formation in the spleen. This was supported by the markedly high concentration (73.2 nmol/g tissue) of NO2- in the spleen tissue. NO2- levels in lung (34.5 nmol/g tissue) and brain (14.3) were also found to be significantly high after stimulation with LPS suggesting NO formation in these organs. Increased formation of NO2- in these organs by LPS stimulation suggests the formation of active nitrogen oxides such as N2O3 which is an effective nitrosating agent in non-acidic conditions in vivo.
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PMID:[NO2-/NO3- levels in blood and principal organs in rats treated with lipopolysaccharide]. 1009 17

The aim of our study was to investigate the effect of the 21-aminosteroid U-74389G [21- < 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl-pregna-1,4,9,(11) triene-3,20-dione(z)-2-butenedionate] on the l-arginine-nitric oxide (NO) pathway in a rat model of endotoxin shock. Endotoxin shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg/kg of Salmonella Enteritidis lipopolysaccharide (LPS). Rats were treated with U-74389G (7.5, 15 and 30 mg/kg i.v.) or vehicle (1 ml/kg i.v.) 5 min after endotoxin challenge. Lipopolysaccharide administration reduced survival rate (0%, 72 h after endotoxin administration) decreased mean arterial blood pressure, enhanced plasma concentration of bilirubin and alanine aminotransferase and increased plasma nitrite concentrations. Lipopolysaccharide injection also increased the activity of inducible NO synthase in the liver and in the aorta. Furthermore aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (1 nM-10 microM). In addition lipopolysaccharide (50 microg/ml for 4 h) in vitro stimulation significantly increased nitrite production in peritoneal macrophages harvested from normal rats. Treatment with U-74389G (15 and 30 mg/kg i.v., 5 min after endotoxin challenge) significantly protected against lipopolysaccharide-induced lethality (90% survival rate 24 h and 80% 72 h after lipopolysaccharide injection, respectively, following the highest dose of the drug), reduced hypotension, ameliorated liver function, decreased plasma nitrite levels, restored the hyporeactivity of aortic rings to their control values and inhibited the activity of inducible NO synthase in the liver and in the aorta. Finally, U-74389G in vitro (12.5, 25 and 50 microM) significantly inhibited nitrite production in endotoxin stimulated peritoneal macrophages. The data suggest that U-74389G may exert beneficial effects in an experimental model of septic shock by inhibiting the activity of the inducible NO synthase.
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PMID:The lazaroid, U-74389G, inhibits inducible nitric oxide synthase activity, reverses vascular failure and protects against endotoxin shock. 1020 81

Liver damage induced by lipopolysaccharide (LPS) in actinomycin D-sensitized mice was initiated by a Fas/CD95-independent apoptotic process that produced DNA fragmentation in hepatocytes followed by an increase of plasma ALT. The metabolic inhibitor actinomycin D blocked most of the LPS-induced increase of plasma nitrite/nitrate levels, as did administration of a nitric oxide synthase inhibitor, N(G)-monomethyl-l-arginine, which also promoted LPS-induced apoptotic liver damage. Administration of nitric oxide donors (hydroxylamine, S-nitroso-N-acetylpenicillamine or 2, 2'-(hydroxynitrosohydrazino)bis-ethanamine) resulted in elevation of the plasma nitrite/nitrate level and amelioration of actinomycin D/LPS-induced apoptotic liver damage. The protective effect of nitric oxide against apoptotic liver damage was partially reproduced by a membrane-permeable analog of cyclic GMP. On the other hand, treatment with the soluble guanylate cyclase inhibitor LY83583 overcame the protective effect of nitric oxide against apoptotic liver damage. These results suggest that nitric oxide may regulate programmed cell death in the mouse liver and that induction of genes, including inducible nitric oxide synthase, plays an important role in protecting the liver against LPS-induced apoptotic damage. This effect appears to be mediated, at least in part, via the soluble guanylate pathway.
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PMID:Nitric oxide ameliorates actinomycin D/endotoxin-induced apoptotic liver failure in mice. 1042 31

Aminoguanidine is an inhibitor of the inducible form of nitric oxide synthase (iNOS). In the present study, the effect of aminoguanidine on concanavalin A-induced hepatitis was examined. Treatment of mice with concanavalin A (10 mg/kg, i.v.) induced interferon-gamma and iNOS mRNA expression in the liver before the elevation of plasma alanine aminotransferase activity. Immunohistochemical study showed the induction of iNOS protein expression in the area of necrosis. Aminoguanidine (1, 3 and 10 mg/kg, i.p.) inhibited the concanavalin A-induced elevation of alanine aminotransferase activity. Aminoguanidine (10 mg/kg, i.p.) did not inhibit concanavalin A-induced interleukin-2, interferon-gamma, tumor necrosis factor-alpha or iNOS mRNA expression in the liver. The plasma nitrite/nitrate level was elevated at 6 and 24 h after concanavalin A treatment. The elevation of nitrite/nitrate was inhibited by aminoguanidine (10 mg/kg, i.p.). From these results, we conclude that nitric oxide formed by iNOS may be involved in the development of concanavalin A-induced hepatitis.
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PMID:Aminoguanidine prevents concanavalin A-induced hepatitis in mice. 1082 65

The interferon-gamma (IFN-gamma) transgenic mouse expresses the exogenous IFN-gamma gene in the liver and develops chronic hepatitis. For the present experiment, four IFN-gamma transgene (+) mice of 48 weeks of age and 16 IFN-gamma transgene (+) mice of 8 weeks of age were used. The four IFN-gamma transgene (+) mice of 48 weeks of age showed significantly elevated plasma alanine aminotransferase (ALT) and expressed the inducible form of nitric oxide synthase (iNOS) mRNA in the liver. Of the 16 IFN-gamma transgene (+) mice of 8 weeks of age, iNOS mRNA was expressed in the livers of three. These three mice exhibited higher plasma ALT levels than the other mice of 8 weeks of age. The present results suggest that iNOS mRNA expression in the liver might be correlated with the progression of hepatitis.
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PMID:Expression of the inducible form of the nitric oxide synthase gene in the livers of mice with chronic hepatitis. 1093 96

Lipopolysaccharide (LPS)-induced endotoxemia produces nitric oxide (NO); however, the role of the NO during endotoxemia is still controversial. The aim of this study was to investigate a role of LPS-induced NO during the early phase of endotoxemia. Wistar rats were intraperitoneally injected with saline or LPS at various doses (0.001, 0.01, or 5 mg/kg), and intra-abdominal NO concentration was determined by chemiluminescence before and after LPS administration at indicated times (1, 2, 6, 10, and 18 h). Serum aspartate aminotransferase and alanine aminotransferase levels were determined and histological examination was performed 10 h after LPS administration to assess liver damage. N(G)-nitro-L-arginine-methyl ester (L-NAME), a nonselective inhibitor of NO synthase, was used to investigate the possible roles of NO during LPS-induced endotoxemia. The intra-abdominal NO concentration was elevated within 2 h and reached a maximal level at 10 h after low doses of LPS injection (0.001 and 0.01 mg/kg) while liver damage was not observed. After high-dose LPS (5 mg/kg) administration, liver damage was observed and intra-abdominal NO was elevated continuously until 18 h. A time course study revealed very similar patterns of intra-abdominal NO increase after the three different dose of LPS at each times points during the first 10 h. Pretreatment of L-NAME inhibited the intra-abdominal NO release and aggravated the liver damage caused by low doses (0.001 and 0.01 mg/kg) of LPS as well as high dose (5 mg/kg) of LPS. Therefore, NO, released during the first 10 h after LPS injection, may play a cytoprotective role in the liver.
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PMID:The cytoprotective role of lipopolysaccharide-induced nitric oxide against liver damage during early phase of endotoxemia in rats. 1094 71

The objective of this study was to determine what roles the endothelial cell and inducible isoforms of nitric oxide synthase (eNOS, iNOS) play in ischemia and reperfusion (I/R)-induced liver injury in vivo in mice genetically deficient in each isoform of NOS. We found that 45 min of partial (70%) liver ischemia and 5 h of reperfusion induced substantial liver injury as assessed by the release of large and significant amounts of the liver-specific enzyme alanine aminotransferase (ALT) into the serum of wild-type (wt) mice. The enhanced ALT levels were not due to increased recruitment of potentially damaging PMNs, which could mediate hepatocyte injury, as neither histopathological inspection nor quantitative MPO determinations revealed the presence of PMNs in the liver at this time point. In addition, we observed a significant enhancement in liver injury in eNOS-deficient but not iNOS-deficient mice subjected to liver I/R compared to postischemic wt mice. Taken together, these data suggest that eNOS- but not iNOS-derived NO plays an important role in limiting or downregulating I/R-induced liver injury in vivo following 5 h of reperfusion.
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PMID:Nitric oxide synthase and postischemic liver injury. 1102 58

S-Nitrosylated compounds (nitrosothiols; RS-NOs) function as nitric oxide (NO) reservoirs and preserve the antioxidant activities of NO. We found remarkable cytoprotection by an S-nitrosylated protease inhibitor from human plasma, S-nitroso-alpha(1)-protease inhibitor (S-NO-alpha(1)-PI) that possesses a completely nitrosylated SH group, in hepatic ischemia-reperfusion injuries in rats. Liver ischemia was induced in rats by occluding both the portal vein and hepatic artery for 30 min and was followed by reperfusion. S-NO-alpha(1)-PI and control compounds such as native alpha(1)-PI, an NO synthase (NOS) inhibitor, and standard RS-NOs were given via the portal vein just after reperfusion was initiated. Liver injury was evaluated by measuring the extracellular release of liver enzymes (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase). Infiltration of neutrophils and induction of apoptosis and heme oxygenase-1 (HO-1) in the liver were also examined. Maximal liver injury occurred at 3 h after reperfusion and then decreased gradually. Not only did S-NO-alpha(1)-PI treatment (0.1 micromol; 5.3 mg/rat) greatly reduce elevation of liver enzymes in plasma, as well as neutrophil accumulation and apoptotic change in liver, it also improved the impaired hepatic blood flow as assessed by laser Doppler flowmetry and potentiated the induction of HO-1 in the liver. Although native alpha(1)-PI moderately reduced liver injury, low molecular weight RS-NOs such as S-nitrosoglutathione and S-nitroso-N-acetyl penicillamine produced no obvious protective effect. An NOS inhibitor exacerbated the hepatic ischemia-reperfusion injuries. These results suggest that S-NO-alpha(1)-PI exerts a potent cytoprotective effect on ischemia-reperfusion liver injury by maintaining tissue blood flow, inducing HO-1, and suppressing neutrophil-induced liver damage and apoptosis.
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PMID:Protective effect of S-nitrosylated alpha(1)-protease inhibitor on hepatic ischemia-reperfusion injury. 1108 23

Nitric oxide (NO) has an important role in controlling heart rate and contributes to the cholinergic antagonism of the positive chronotropic response to adrenergic stimulation. Based on evidence of NO overproduction in cholestasis and also on the existence of bradycardia in cholestatic subjects, this study aimed to evaluate the chronotropic effect of epinephrine in isolated atria of cholestatic rats and determine whether alterations in epinephrine-induced chronotropic responses of cholestatic rats are corrected after systemic inhibition of NO synthase (NOS) with N(G)-nitro-L-arginine (L-NNA). Male Sprague-Dawley rats were used. Cholestasis was induced by surgical ligation of the bile duct under general anesthesia and sham-operated animals were considered as control. The animals were divided into three groups, which received either L-arginine (200 mg/kg/day), L-NNA (10 mg/kg/day) or saline. One week after the operation, a lead II ECG was recorded from the animals, then spontaneously beating atria were isolated and chronotropic responses to epinephrine were evaluated in a standard oxygenated organ bath. The results showed that plasma gamma-glutamyl transpeptidase and alanine aminotransferase activity was increased by bile-duct ligation, and that L-aginine treatment partially, but significantly, prevented the elevation of these markers of liver damage. The results showed that heart rate of cholestatic animals was significantly less than that of sham-operated control rats in vivo and this bradycardia was corrected with daily administration of L-NNA. The basal spontaneous beating rate of atria in cholestatic animals was not significantly different from that of sham-operated rats in vitro. Meanwhile, cholestasis induced a significant decrease in chronotropic effect of epinephrine. These effects were corrected by daily administration of L-NNA. Surprisingly L-arginine was as effective as L-NNA and increased the chronotropic effect of epinephrine in cholestatic rats but not in sham-operated animals. Systemic NOS inhibition corrected the decreased chronotropic response to adrenergic stimulation in cholestatic rats, and suggests an important role for NO in the pathophysiology of heart rate complications in cholestatic subjects. The opposite effect of chronic L-arginine administration in cholestasis and in control rats could be explained theoretically by an amelioration of cholestasis-induced liver damage by chronic L-arginine administration in bile duct-ligated rats.
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PMID:The role of nitric oxide in bradycardia of rats with obstructive cholestasis. 1113 68

Recent evidence suggests that the hepatic expression of heme oxygenase-1 (HO-1) may preserve hepatocellular integrity after hemorrhagic shock and resuscitation (HR). Because nitric oxide (NO) has been shown to modulate HO-1 expression in cultured cells in vitro, we determined its potential role in the regulation of HO-1 expression after HR in the rat liver in vivo. HO-1 mRNA and protein were highly induced and HO enzyme activity was higher after HR when compared with time-matched sham controls. Administration of the NO donor, molsidomine (MOL) (3 mg. kg(-1)), during resuscitation attenuated the accumulation of HO-1 mRNA and protein and the rise in HO activity. In addition, MOL prevented the shock-induced increase in DNA binding activity of the transcription factor, activator protein-1 (AP-1), but did not alter the activity of nuclear factor-erythroid 2 related factor (Nrf-2), nuclear transcription factor-kappaB (NF-kappaB), and hypoxia-inducible factor-1 (HIF-1). The suppressing action of MOL was not confined to HO-1, because the hepatic expression of the 70-kd major heat shock protein (HSP) in response to HR was also diminished. Moreover, MOL prevented the HR-induced increase in the serum activity of alanine transaminase (ALT) and alpha-glutathione-S-transferase (alpha-GST) that could otherwise be observed after HR. In contrast, the NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (1 mg.kg(-1)), had either no or only minor effects on the primary experimental endpoints. These findings would be consistent with a reduction of shock-induced liver damage by exogenous NO, which in turn prevents the subsequent activation of injury-sensitive transcription factors, thus attenuating the expression of stress-inducible proteins such as HO-1.
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PMID:Effect of nitric oxide on shock-induced hepatic heme oxygenase-1 expression in the rat. 1128 57


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