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)

This study examines the effect of chronic alcohol consumption on nitric oxide release from the liver of rats with or without lipopolysaccharide (LPS) (Escherichia coli) treatment. Reactive nitrogen intermediates (RNIs) in plasma were monitored with an NOx Analyzer, and nitric oxide (NO) production was measured as nitrite or nitrite + nitrate accumulation in perfusates of the perfused liver, and in supernatants of the freshly isolated hepatic cells after incubation for 3 hr in Hank's balanced salt solution buffer containing 1 mM L-arginine. RNI concentration in plasma of control rats was 32.0 +/- 3.4 microM (mean +/- SE). Livers from diet-fed control rats produced RNIs at the barely detectable rate of 7.8 +/- 1.5 nmol/hr x g wet liver. Six hr after administration of LPS (1 mg/kg, i.v.), plasma RNI levels in diet-fed control rats increased to 426.9 +/- 29.4 microM, and RNI release from the perfused liver was also markedly elevated to 97.7 +/- 7.7 nmol/hr x wet g liver, indicating hepatic NO release as a potentially important source for the increased RNI in plasma. The presence of NG-monomethyl-L-arginine (0.5-1 mM) or the absence of L-arginine in the perfusate inhibited LPS-induced stimulation of RNI release. EGTA (1 mM) had little effect, indicating that the increased RNI release was likely to be due to inducible NO synthase activity. The release of RNIs by freshly isolated Kupffer cells increased 13-fold, and this small cell mass contributed almost half of the hepatic RNI production under these conditions. Plasma ALT concentration was elevated after LPS administration, indicating incipient liver damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Chronic alcohol administration stimulates nitric oxide formation in the rat liver with or without pretreatment by lipopolysaccharide. 754 48

Intravascular coagulation is involved in the development of certain types of liver injury, including that induced by dimethylnitrosamine. Nitric oxide inhibits platelet aggregation and adhesion; however, its role in protecting against intravascular coagulation has not been clarified. We therefore investigated the effect of blocking the production of NO in a dimethylnitrosamine-induced liver injury model. Wistar male rats received dimethylnitrosamine (50 micrograms/kg) intraperitoneally, and were treated with N omega-nitro-L-arginine, an inhibitor of nitric oxide synthase, or N omega-nitro-D-arginine, an inactive isomer. Each arginine derivative (40 mg/kg) was injected intraperitoneally every 6 h. Twenty-four hours after dimethyl-nitrosamine administration, we observed a significant increase in the serum level of alanine aminotransferase in the N omega-nitro-L-arginine group compared with the N omega-nitro-D-arginine group. The N omega-nitro-L-arginine-treated group also exhibited a significant reduction in platelet count, a prolongation of prothrombin time, and an elevation of plasma soluble fibrin monomer complex levels. Sinusoidal congestion, intravascular coagulation, and coagulation necrosis around the central veins were prominent in the N omega-nitro-L-arginine group. In conclusion, the inhibition of nitric oxide production exacerbated the hepatic damage induced by dimethylnitrosamine, mediated by the acceleration of intravascular coagulation.
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PMID:Inhibition of nitric oxide production increases dimethylnitrosamine-induced liver injury in rats. 858 50

Polymorphonuclear leukocytes (PMNS) have been implicated as cellular mediators of hepatic injury in models of inflammation in vivo. In vitro, hepatocyte killing by activated PMNs is mediated in part by proteases, but the role of nitric oxide is unknown. NO is produced by PMNs and hepatocytes and can act either to damage or protect in various models of toxicity. Therefore, we tested the hypothesis that NO is important in PMN-mediated hepatocyte killing in vitro. Freshly isolated hepatocytes from rat liver and PMNs elicited from rat peritoneum were cultured together or alone for 16 hours. Both cell types spontaneously released NO, estimated as its stable breakdown product, nitrite. Accumulation of nitrite in medium from hepatocyte cultures was augmented threefold by incubation with L-arginine and was completely inhibited by treatment with the nitric oxide synthase (NOS) inhibitor NG-methyl-L-arginine (NMA). Nitrite release in PMN cultures was unaffected by L-arginine addition and only partially inhibited by NMA. In PMN:hepatocyte cocultures (10:1), accumulation of nitrite was additive relative to cells cultured separately. Incubation with NMA blocked nitrite production completely in cocultures, whereas L-arginine caused a two-fold increase in nitrite. Addition of PMN stimulants, N-formyl-methionyl-leucyl-phenylalanine (FMLP), or phorbol myristate acetate (PMA), caused increased release of alanine aminotransferase (ALT) activity into medium from hepatocytes cultured with PMNs but not from hepatocytes cultured alone; this indicated that injury to hepatocytes was due to activated PMNS. However, neither FMLP nor PMA significantly altered nitrite release from cocultures. Despite the alterations in NO production induced by addition of NMA or L-arginine, neither agent altered the release of ALT from hepatocytes in coculture with activated PMNs. Thus, PMNs and hepatocytes provided NO in vitro, but neither suppression nor elevation of NO production affected PMN-mediated hepatocyte killing. Accordingly, NO is not involved in the mechanisms by which FMLP-or PMA-stimulated PMNs mediate hepatocyte injury in vitro.
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PMID:Nitric oxide is not involved in hepatocyte killing by neutrophils activated by N-formyl-methionyl-leucylphenylalanine or phorbol myristate acetate in vitro. 866 35

1. We have investigated whether (i) endotoxaemia caused by E. coli lipopolysaccharide in the anaesthetized rat causes a multiple organ dysfunction syndrome (MODS; e.g. circulatory failure, renal failure, liver failure), and (ii) an enhanced formation of nitric oxide (NO) due to induction of inducible NO synthase (iNOS) contributes to the MODS. In addition, this study elucidates the beneficial and adverse effects of aminoethyl-isothiourea (AE-ITU), a relatively selective inhibitor of iNOS activity, and NG-methyl-L-arginine (L-NMMA), a non-selective inhibitor of NOS activity on the MODS caused by endotoxaemia. 2. In the anaesthetized rat, LPS caused a fall in mean arterial blood pressure (MAP) from 117 +/- 3 mmHg (time 0) to 97 +/- 4 mmHg at 2 h (P < 0.05, n = 15) and 84 +/- 4 mmHg at 6 h (P < 0.05, n = 15). The pressor effect of noradrenaline (NA, 1 micrograms kg-1, i.v.) was also significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Treatment of LPS-rats with AE-ITU (1 mg kg-1, i.v. plus 1 mg kg-1 h-1 starting at 2 h after LPS) caused only a transient rise in MAP, but significantly attenuated the delayed vascular hyporeactivity seen in LPS-rats. Infusion of L-NMMA (3 mg kg-1, i.v. plus 3 mg kg-1 h-1) caused a rapid and sustained rise in MAP and attenuated the delayed vascular hyporeactivity to NA. Neither AE-ITU nor L-NMMA had any effect on either MAP or the pressor effect elicited by NA in rats infused with saline rather than LPS. 3. Endotoxaemia for 6 h was associated with a significant rise in the serum levels of aspartate or alanine aminotransferase (i.e. GOT or GPT), gamma-glutamyl-transferase (gamma GT), and bilirubin, and hence, liver dysfunction. Treatment of LPS-rats with AE-ITU significantly attenuated this liver dysfunction (rise in GOT, GPT, gamma GT and bilirubin) (P < 0.05, n = 10). In contrast, L-NMMA reduced the increase in the serum levels of gamma GT and bilirubin, but not in GOT and GPT (n = 5). Injection of LPS also caused a time-dependent, but rapid (almost maximal at 2 h), increase in the serum levels of urea and creatinine, and hence, renal dysfunction. This renal dysfunction was not affected by either AE-ITU (n = 10) or L-NMMA (n = 5). In rats infused with saline rather than LPS, neither AE-ITU (n = 4) nor L-NMMA (n = 4) had any significant effect on the serum levels of GOT, GPT, gamma GT, bilirubin, creatinine or urea. 4. Endotoxaemia for 6 h resulted in a 4.5 fold rise in the serum levels of nitrite (9.13 +/- 0.77 microM, P < 0.01, n = 15), which was significantly reduced by treatment with AE-ITU (6.32 +/- 0.48 microM, P < 0.05, n = 10) or L-NMMA (5.10 +/- 0.40 microM, P < 0.05, n = 5). In addition, endotoxaemia for 6 h was also associated with a significant increase in iNOS activity in lung and liver homogenates, which was significantly reduced in lung or liver homogenates obtained from LPS-rats treated with either AE-ITU or L-NMMA. 5. Thus, AE-ITU or L-NMMA (i) inhibits iNOS activity in LPS-rats without causing a significant increase in MAP in rats infused with saline and, hence inhibition of endothelial NOS activity, and (ii) attenuates the delayed circulatory failure as well as the liver dysfunction caused by endotoxaemia in the rat. Thus, an enhanced formation of NO may contribute to the development of liver failure in endotoxic shock.
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PMID:The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. 868 Jul 15

1. An enhanced production of nitric oxide (NO) from L-arginine, related to the diffuse expression of an inducible NO synthase (iNOS), contributes to the pathogenesis of endotoxic shock. Since iNOS activity depends on extracellular L-arginine, we hypothesized that limiting cellular L-arginine uptake would reduce NO production in endotoxic shock. We investigated the effects of L-lysine, an inhibitor of L-arginine uptake through system y+, on NO production, multiple organ dysfunction and lactate levels, in normal and endotoxaemic rats. 2. Anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 10 mg kg[-1]) received a 5 h infusion of either L-lysine (500 micromol kg(-1) h(-1), n = 12) or isotonic saline (2 ml kg(-1) h(-1), n = 11). In rats treated with saline, LPS produced a large increase in plasma nitrate and L-citrulline concentrations at 5 h, both markers of enhanced NO production. LPS also caused severe hypotension, low cardiac output and marked hyperlactataemia. All these changes were significantly reduced by L-lysine administration. 3. Endotoxaemia also caused a significant rise in the plasma levels of alanine aminotransferase (ALAT), lipase, urea and creatinine, and hence, liver, pancreatic and renal dysfunction. These changes tended to be less pronounced in rats treated with L-lysine, although the differences did not reach statistical significance. 4. Similar experiments were conducted in 10 rats challenged with LPS vehicle in place of LPS and then treated with L-lysine (500 micromol kg(-1) h(-1), n = 5) or saline (2 ml kg(-1) h(-1), n = 5) for 5 h. In these animals, all the haemodynamic and metabolic variables remained stable and not statistically different between both treatment groups, except for a slight rise in ALAT, which was comparable in L-lysine and saline-treated rats. 5. In conclusion, L-lysine, an inhibitor of cellular L-arginine uptake, reduces NO production and exerts beneficial haemodynamic effects in endotoxaemic rats. L-lysine also reduces hyperlactataemia and tends to blunt the development of organ injury in these animals. Contrastingly, L-lysine has no effects in the absence of endotoxin and thus appears to act as a selective modulator of iNOS activity.
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PMID:Effect of L-lysine on nitric oxide overproduction in endotoxic shock. 937 72

The modulating effects of nitric oxide (NO) and reactive oxygen species on cocaine-induced hepatotoxicity were examined by measuring plasma alanine aminotransferase activity and by carrying out histological studies. Liver injury was induced by a single injection of cocaine in adult male ICR mice. Pretreatment with aminoguanidine (an inhibitor of NO synthase), N-methyl-D-glucamine dithiocarbamate complex with iron ion (II) (Fe2+(MGD)2, a trapping reagent of NO) or deferoxamine complex with iron ion (III) (Fe3+-deferoxamine, a scavenger of NO) produced a marked inhibition of the hepatotoxicity induced by cocaine. In addition, pretreatment with allopurinol (an inhibitor of xanthine oxidase) and 1,3-dimethylthiourea (a scavenger of hydroxyl radical) also produced a potent inhibition. These findings suggest that a hydroxyl radical produced by the reaction of NO and superoxide anion (O2-) via peroxynitrite may be involved in the pathogenesis of cocaine hepatotoxicity.
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PMID:Cocaine-induced liver injury in mice is mediated by nitric oxide and reactive oxygen species. 938 53

The role of nitric oxide (NO) and peroxynitrite in the process of neutrophil adhesion and infiltration was investigated in a model of hepatic ischemia-reperfusion. Male Fischer rats were subjected to 30 min of hepatic no-flow ischemia followed by 4 h of reperfusion (I/R). I/R induced liver injury as evidenced by a 13.7-fold increase in plasma alanine aminotransferase activity. Induction of liver injury was associated with an increase in neutrophil accumulation in ischemic lobes of livers [215 +/- 27 polymorphonuclear neutrophil leukocytes/50 high-power field (HPF), P < .05 compared with sham control] and 8-fold augmentation of inducible NO synthase (NOS) activity. However, NO levels in the liver decreased; this decrease may be caused by peroxynitrite formation by the reaction of NO with superoxide. Sections of ischemic lobes of the liver tissue of I/R animals exhibited marked immunoreactivity with anti-nitrotyrosine antibody, which indicates the presence of nitrotyrosine. Administration of Nw-nitro-L-arginine methyl ester (10 mg/kg i.v. before reperfusion) attenuated total and inducible NOS activity in both ischemic and nonischemic lobes of liver, and reduced NO levels in plasma and liver. However, NOS inhibition aggravated liver injury as alanine aminotransferase increased by 61% compared with rats subjected to reperfusion injury. Neutrophil accumulation was enhanced in ischemic (436 +/- 48/50 HPF, P < .05 compared with I/R animal) and nonischemic lobes of livers (34 +/- 3.2/50 HPF, P < .05 compared with sham control). NOS inhibition also attenuated immunohistochemically detected nitrotyrosine formation, but increased superoxide production in the liver. The NO-dependent regulation of neutrophil accumulation in the liver may be linked closely to P-selectin and intracellular adhesion molecule-1 expression because inhibition of NOS resulted in significant increases in gene expression of these two adhesion molecules (determined by reverse transcription-polymerase chain reaction analysis). These results suggest that NO is important in attenuating neutrophil accumulation and liver damage in ischemia-reperfusion injury. Inhibition of NOS activity reduces peroxynitrite formation but aggravates liver injury and increases neutrophil accumulation, which suggests that the anti-inflammatory function of NO is more important than the cytotoxic potential of peroxynitrite in acute inflammation.
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PMID:Inhibition of nitric oxide synthase attenuates peroxynitrite generation, but augments neutrophil accumulation in hepatic ischemia-reperfusion in rats. 949 76

Cross-linked hemoglobin (alphaalpha-Hb) may be a useful red blood cell substitute if it can be administered safely. However, cell-free hemoglobin has inherent properties that may cause oxidant-mediated toxicity. We investigated whether alphaalpha-Hb induces oxidative or inflammatory responses that lead to liver damage. alphaalpha-Hb (0.5 or 1.0 gm/kg) was infused into rats, and indices of liver injury, inflammation, and oxidative stress were examined. Although focal hepatic necrosis was noted at 24 hours, plasma alanine aminotransferase activity was not increased and lesions were resolved by 48 hours. Modest neutrophil accumulation in hepatic vessels, but not sinusoids, occurred at 24 hours. Heme oxygenase-1 (HO-1) protein and activity were induced in a dose- and time-dependent manner, with maximal induction at 24 hours. Plasma tumor necrosis factor-alpha levels were not significantly increased. Additional cytokine- and oxidant-mediated events such as nuclear transcription factor-kappaB activation and nitric oxide synthase induction were not observed. These results suggest that alphaalpha-Hb-derived products such as heme and ferric iron (Fe3+), potent inducers of HO-1, are responsible for increasing HO-1. HO-1 induction may be a protective response by the liver to metabolize excess heme and Fe3+, thereby providing antioxidative products to counter the potentially damaging oxidants produced by Fe3+-catalyzed reactions.
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PMID:Hepatic inflammatory responses to alphaalpha-cross-linked hemoglobin infusion in rats. 960 8

The vasodilator nitric oxide (NO) is involved in the regulation of systemic blood pressure and local organ blood flow. Inhibitors of the constitutively expressed nitric oxide synthase in endothelial cells (eNOS), e.g., Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME), aggravated liver injury in a variety of models. On the other hand, inhibitors of the inducible NOS (iNOS), e.g., 2-aminoethyl-isothiourea (AET), were found to be beneficial during endotoxemia. The aim of this investigation was to study the effect of AET compared with L-NAME on liver microvascular blood flow and injury in more complex models with multiple insults, i.e., ischemia (20 min)-reperfusion (8 h) in combination with .5 mg/kg endotoxin (IRE). Male Fisher rats were treated with 10 mg/kg AET or L-NAME and subjected to IRE. At 8 h, liver injury (plasma ALT: 1320+/-164 U/L) was significantly increased in AET-treated (5,018+/-1,379 U/L) and L-NAME-treated groups (2,429+/-228 U/L). Each inhibitor attenuated microvascular blood flow (assessed by laser Doppler flowmetry) to a similar degree. In striking contrast, AET completely reversed the endotoxin-induced impairment of the microvascular blood flow and significantly protected against an endotoxin-induced liver injury (plasma ALT: 3,007+/-268 U/L (ET); 460+/-39 U/L (ET+AET)). Infusion of endothelin-1 reduced microvascular blood flow by 50-60% and caused liver injury. Our data demonstrated that an inhibitor of eNOS (L-NAME) has a consistent detrimental effect on liver injury during ischemia-reperfusion and endotoxemia mainly because it can cause additional ischemia by reducing the microvascular blood flow. However, selective inhibitors of iNOS (AET) can impair hepatic blood flow and aggravate the injury or improve blood flow and attenuate organ injury depending on the experimental model. These results suggest that iNOS inhibitors may not be universally beneficial and should be tested in a variety of experimental models of sepsis/endotoxemia before used in clinical settings.
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PMID:Differential effect of 2-aminoethyl-isothiourea, an inhibitor of the inducible nitric oxide synthase, on microvascular blood flow and organ injury in models of hepatic ischemia-reperfusion and endotoxemia. 968 86

The aim of this study was to evaluate the protective or deleterious effects of endogenous nitric oxide (NO) on liver cells during hepatic ischemia-reperfusion (IR) in the rat. Injury to hepatocytes and endothelial cells was evaluated by determining cytolysis-marker activity in plasma (alanine transaminase [ALT]; aspartate transaminase [AST]) and plasma hyaluronic acid (HA) concentration. Clamping the hepatic pedicle for 45 minutes caused a significant increase in plasma AST and ALT activity after 30 minutes of reperfusion, which reached a maximum (+270% and +740%, respectively) after 6 hours of reperfusion. Plasma HA concentration was significantly higher (+130%) only after 6 hours of reperfusion. Administration of a nonselective NO synthase (NOS) inhibitor, Nomega-nitro-L-arginine (L-NNA; 10 mg/kg iv), 30 minutes before IR, caused marked aggravation of postischemic liver injury, as shown by plasma ALT and AST activity and HA concentration. This deleterious effect was partially prevented by the simultaneous injection of L-arginine, the endogenous NO precursor (100 mg/kg iv). Interestingly, L-arginine alone limited postischemic damage (AST, -25%; ALT, -45%; HA, -21% vs. untreated IR rats at 6 hours reperfusion). Pretreatment with the Guanosine 3':5'-cyclic monophosphate-independent vasodilator, prazosin, partially reversed L-NNA effects, but it did not protect untreated IR animals. Pretreatment with aminoguanidine, a selective inhibitor of inducible NOS, did not aggravate hepatic IR injury. Thus, endogenous NO, probably produced by an early and transient activation of a constitutive NOS, protects both hepatocytes and endothelial cells against liver ischemia-reperfusion injury, and this effect is not entirely a result of vasorelaxation.
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PMID:Hepatoprotective effect of endogenous nitric oxide during ischemia-reperfusion in the rat. 1005 83


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