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)

The role of nitric oxide (NO) in the changes in blood pressure and plasma levels of nitrate and nitrite (NOx) and alanine aminotransferase (ALT) were determined over a 5-h period in anesthesized rats after intravenous administration of S. typhosa endotoxin (LPS, 4 mg/kg). Rats treated with LPS showed a sustained fall in blood pressure accompanied by an increase in plasma NOx and ALT. Forty percent of these rats died during the experiment. There was no change in blood pressure in rats treated with dexamethasone (1 mg/kg) 1 h before and 2 h after LPS and the increase in NOx and ALT was significantly inhibited. None of the rats in this group died. Administration of 10 mg/kg of NG-monomethyl-L-arginine (L-NMMA) prevented the fall in blood pressure and partially prevented the increase in NOx and ALT. None of the animals in this group died. In contrast, 300 mg/kg of L-NMMA caused an initial increase in blood pressure followed by a rapid fall and enhanced the increase in ALT while abolishing the elevation of NOx. All of these animals died before the end of the experiment. However, when rats treated with high doses of L-NMMA were given a continuous infusion of S-nitroso-N-acetylpenicillamine (SNAP, 300 micrograms/kg/h), the blood pressure was maintained at control levels and no mortality was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of nitric oxide in endotoxic shock: effects of NG-monomethyl-L-arginine. 128 48

Two strains of mice (C57BL/10ScN and C3H/HeJ) that carry the same mutant lipopolysaccharide gene (Lpsd) which makes them resistant to the toxic effects of endotoxin (LPS) are also partially resistant to the hepatotoxic effects of D-galactosamine. As measured by serum alanine aminotransferase, the degree of liver injury induced by D-galactosamine in the LPS-resistant strains is only 10%-30% that of closely related strains of LPS-sensitive mice. Similarly, histopathologic changes are less pronounced in the endotoxin-resistant strains than in LPS-susceptible mice. By transferring spleen cells from LPS-susceptible strains to lethally irradiated, LPS-resistant mice, we established that susceptibility to D-galactosamine is mediated by lymphoreticular cells. Radiation-resistant spleen cells transferred D-galactosamine sensitivity, suggesting a role for macrophages. We did not exclude the possibility that lymphocytes can also transfer the response to D-galactosamine. These results establish that in mice, D-galactosamine sensitivity is associated with endotoxin sensitivity and that the former is mediated by lymphoreticular cells, not by hepatocytes.
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PMID:D-Galactosamine hepatotoxicity is associated with endotoxin sensitivity and mediated by lymphoreticular cells in mice. 388 May 54

The changes of the levels of LTC4, PGI2 and TXA2 in the liver tissue in SD rats with GaIN/LPS-induced acute liver injury was studied with radioimmunoassay (RIA). As a result, 12 h after the administration of GaIN/LPS, serum AST (398 +/- 37 u), ALT (565 +/- 43 u) increased (P < 0.001) and the concentration of TXA2 (12,188 +/- 588 pg/g.w.wt) in liver tissue increased significantly (P < 0.001), while the content of LTC4 (9713 +/- 3557 ng/g.w.wt) and PGI2(1748 +/- 560 pg/g.w.wt) in liver tissue were not obviously changed (P > 0.05) and the inflammatory changes of the pathological findings were observed. The improvement of serum ALT (330 +/- 168 u) (P < 0.05) and AST (273 +/- 124 u) (P < 0.05) and histopathological damage was observed after the administration of diethylcarbamazine (DEC), a LTA4 synthesis inhibitor, the liver TXA2 (12,740 +/- 699) concentration significantly increased (P < 0.001), while the levels of LTC4 (8179 +/- 1653) and PGI2 (2320 +/- 630) were not obviously changed. Serum ALT (536 +/- 74 u) and AST (416 +/- 41 u) (P > 0.05) levels and histopathology did not change with administration of indomethacin, a cyclooxygenase inhibitor, but the liver LTC4 (12,166 +/- 1327) contents increased (P < 0.05) and TXA2 (1868 +/- 791) reduced significantly (P < 0.001). The present study suggests that arachidonic acid metabolism in rats with acute liver injury are significantly abnormal. Leukotrienes and thromboxane are important inflammatory mediators in the liver injury.
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PMID:Arachidonic acid metabolism in galactosamine/endotoxin induced acute liver injury in rats. 780 4

The following study was performed to determine the effects of phosphodiesterase IV (PDE-IV) inhibition and its attenuation of tumor necrosis factor (TNF alpha) production in a rat model of the Adult Respiratory Distress Syndrome (ARDS). Rats were either unexposed (n = 8), pretreated orally with vehicle prior to intratracheal saline exposure (n = 11), pretreated with vehicle prior to 7 mg/kg intratracheal endotoxin (LPS) administration (n = 22), or pretreated with 5 or 50 mg/kg rolipram prior to LPS exposure (n = 6 and 7, respectively). Blood was sampled 1 and 3 hr post LPS exposure and assayed for plasma TNF alpha concentrations. Twenty-four hours after LPS exposure, blood was sampled again for hematologic measurements. The rats were then anesthetized and exsanguinated. Bronchoalveolar lavage (BAL) was performed after the lung of each rat was removed and weighed. Rolipram pretreatment was protective against LPS-induced mortality and also resulted in reduced plasma TNF alpha concentrations. LPS induced pulmonary edema, as indicated by wet/dry lung weight ratio (W/D) and total BAL protein content (TP) was attenuated by rolipram pretreatment. LPS-induced alveolar hemorrhage was reduced by rolipram pretreatment, but LPS-induced pulmonary neutrophilia was not. The hemoconcentration induced by LPS was reduced by rolipram, as was the LPS-induced thrombocytopenia. However, LPS-induced changes in circulating leukocyte populations were actually exacerbated by rolipram. LPS-induced alterations in renal and hepatic function, indicated by increased blood urea nitrogen (BUN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), were inhibited by rolipram.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Therapeutic intervention in a rat model of ARDS: IV. Phosphodiesterase IV inhibition. 838 94

When mice were given an i.v. injection of LPS 7 days after an i.v. injection of Propionibacterium acnes, liver injury and a rapid increase of serum alanine aminotransferase and asparagine acid aminotransferase occurred. The in vivo administration of mAb against LFA-1 on days 1, 2, and 3 after the i.v. injection of P. acnes resulted in a potent inhibition of all these dysfunctions. Using P. acnes and the LPS model, we found that anti-LFA-1 mAb protected the mice from P. acnes and LPS-induced lethal shock. During the course of P. acnes and LPS-induced liver injury, inflammatory cells infiltrated the liver and caused a massive hepatic cell necrosis. Flow cytometry revealed that the liver-infiltrating cells were mainly leukocytes expressing a higher level of LFA-1 antigen than that seen in the normal liver. These results suggested that the LFA-1 molecule on liver-infiltrating leukocytes may play an important role in the induction of inflammatory liver injury.
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PMID:Inhibition of inflammatory liver injury by a monoclonal antibody against lymphocyte function-associated antigen-1. 840 59

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. This study investigates the effects of the non-selective ETA/ETB receptor antagonist, SB 209670, on systemic haemodynamics, renal function, liver function, acid-base balance and survival in a rat model of endotoxic shock. 2. Injection of E. coli lipopolysaccharide (LPS, 10 mg kg-1, i.v.) resulted in increases in the serum levels of tumour necrosis factor-alpha (TNF-alpha, maximum 60 min after LPS), endothelin-1, (ET-1; maximum 120 min after LPS), and interferon-gamma (IFN-gamma, maximum 180 min after LPS). 3. Injection of LPS also resulted in a fall in blood pressure from 113 +/- 3 mmHg (time = 0) to 84 +/- 4 mmHg at 360 min (n = 15) as well as a hyporeactivity to the vasoconstrictor responses elicited by noradrenaline (NA, 1 microgram kg-1, i.v.). Pretreatment of rats with a continuous infusion of SB 209670 (3 mg kg-1, i.v. bolus + 100 micrograms kg-1, i.v. infusion commencing 15 min prior to LPS) significantly augmented the hypotension as well as the vascular hyporeactivity to NA caused by endotoxaemia. 4. Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus given 15 min prior to LPS) or infusion of SB 209670 (bolus dose and infusion as above) resulted in a reduction in 6 h-survival from 71% (control) to 30% and 13%, respectively. 5. Endotoxaemia for 4 h resulted in rises in the serum levels of urea and creatinine (indicators of renal failure), but not in the serum levels of bilirubin, GPT and GOT (indicators of liver dysfunction and/or hepatocellular injury). Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus 15 min prior to LPS) significantly augmented the serum levels of creatinine, bilirubin, GPT and GOT caused by endotoxin. In addition, endotoxaemia caused, within 15 min, an acute metabolic acidosis (falls in pH, HCO3- and base excess) which was compensated by hyperventilation (fall in PaCO2). Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus) significantly augmented the metabolic acidosis caused by LPS. 6. Thus, the non-selective ETA/ETB receptor antagonist, SB 209670, augments the degree of (i) hypotension, (ii) vascular hyporeactivity to noradrenaline, (iii) renal dysfunction and (iv) metabolic acidosis caused by endotoxin in the anaesthetized rat. In contrast to rats treated with LPS alone, LPS-rats treated with SB 209670 exhibited liver dysfunction and hepatocellular injury. We propose that the release of endogenous ET-1 serves to maintain blood pressure and subsequently organ perfusion in septic shock.
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PMID:Effects of the endothelin receptor antagonist, SB 209670, on circulatory failure and organ injury in endotoxic shock in the anaesthetized rat. 873 96

1. We have investigated the effects of (i) several guanidines on the activity of the inducible isoform of nitric oxide (NO) synthase (iNOS) in murine cultured macrophages and rat aortic vascular smooth muscle cells (RASM); and (ii) 1-amino-2-hydroxy-guanidine, the most potent inhibitor of iNOS activity discovered, on haemodynamics, multiple organ (liver, renal, and pancreas) dysfunction and iNOS activity in rats with endotoxic shock. 2. The synthesized guanidine analogues caused concentration-dependent inhibitions of the increase in nitrite formation caused by lipopolysaccaride (LPS, 1 microgram ml-1) in J774.2 macrophages and RASM cells with the following rank order of potency: 1-amino-2-hydroxy-guanidine > 1-amino-2-methyl-guanidine > 1-amino-1-methyl-guanidine > 1-amino-1,2-dimethyl-guanidine. Interestingly, 1-amino-2-hydroxy-guanidine (IC50: J774.2, 68 microM; RASM, 114 microM) was more potent in inhibiting nitrite formation caused by LPS than NG-methyl-L-arginine, but less potent than aminoethyl-isothiourea. 3. In the anaesthetized rat, LPS caused a fall in mean arterial blood pressure (MAP) from 115 +/- 4 mmHg (time 0) to 98 +/- 5 mmHg at 2 h (P < 0.05, n = 10) and 69 +/- 5 mmHg at 6 h (P < 0.05, n = 10). The pressor effect of noradrenaline (NA, 1 mg kg-1, i.v.) was also significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Treatment of LPS-rats with 1-amino-2-hydroxy-guanidine (10 mg kg-1, i.v. plus 10 mg kg-1 h-1 starting at 2 h after LPS) prevented the delayed hypotension and vascular hyporeactivity seen in LPS-rats. However, 1-amino-2-hydroxy-guanidine had no effect on either MAP or the pressor effect elicited by NA in rats infused with saline rather than LPS. 4. Endotoxaemia for 6 h caused a significant rise in the serum levels of aspartate or alanine aminotransferase (i.e. GOT or GPT) and bilirubin, and hence, liver dysfunction. Treatment of LPS-rats with 1-amino-2-hydroxy-guanidine significantly attenuated the liver dysfunction caused by LPS (P < 0.05, n = 10). Injection of LPS also caused a 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 1-amino-2-hydroxy-guanidine (P > 0.05; n = 10). Endotoxaemia also caused a dysfunction of pancreas (rise in serum levels of lipase) as well as a metabolic acidosis (falls in PCO2, HCO3 and base excess). Both pancreatic dysfunction and metabolic acidosis were largely attenuated by treatment of LPS-rats with 1-amino-2-hydroxy-guanidine. In rats infused with saline rather than LPS, 1-amino-2-hydroxy-guanidine had no effect on liver, renal or pancreatic function (n = 4). 5. Endotoxaemia for 6 h resulted in a rise in the serum levels of nitrite (11.0 +/- 0.8 microM, P < 0.01, n = 10), which was significantly reduced by 1-amino-2-hydroxy-guanidine (6.5 +/- 0.7 microM, P < 0.05, n = 10). Endotoxaemia for 6 h was also associated with a significant increase in iNOS activity in lung and liver, which was significantly reduced in lung or liver homogenates obtained from LPS-rats treated with 1-amino-2-hydroxy-guanidine. In addition, endotoxaemia for 6 h resulted in a significant increase in myeloperoxidase activity (MPO), an indicator of neutrophil infiltration, in the liver. Treatment of LPS-rats with 1-amino-2-hydroxy-guanidine did not affect the rise in MPO-activity in the liver caused by endotoxin. 6. Thus, 1-amino-2-hydroxy-guanidine is a potent inhibitor of iNOS activity in macrophages or RASM in culture as well as in rats with endotoxic shock. Inhibition of iNOS activity with 1-amino-2-hydroxy-guanidine prevents the delayed circulatory failure and attenuates the dysfunction of liver, and pancreas, as well as the metabolic acidosis caused by endotoxaemia.
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PMID:Attenuation of endotoxin-induced multiple organ dysfunction by 1-amino-2-hydroxy-guanidine, a potent inhibitor of inducible nitric oxide synthase. 873 25

Radiation protective effects of Gynostemma Pentaphyllum (Gp) were investigated in gamma-irradiated mice. Animals were sacrificed on days 5, 15, 25 and 35 after gamma-irradiation. GOT, GPT, serum IgG and leukocyte counts were measured. Proliferation of splenocytes stimulated by mitogens, such as PHA, Con A, and LPS were detected and compared. The results showed that all parameters measured in this study were decreased and proliferation of splenocytes stimulated by mitogens were repressed in gamma-irradiated mice. Gp helped to recover the decreased leukocyte counts, GOT, GPT and IgG in serum and the proliferation of splenocytes stimulated by PHA, LPS and Con A in the gamma-ray irradiated mice.
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PMID:Protective effects of Gynostemma pentaphyllum in gamma-irradiated mice. 873 85

Reactive oxygen species such as nitric oxide (NO) and/or superoxide have been proposed as mediators in the pathogenesis of reperfusion injury and acute endotoxemia. The purpose of this study was to examine the role of NO in a model of hepatic ischemia-reperfusion with endotoxemia (I/R + LPS). Rats subjected to 30 min of partial hepatic ischemia followed by reperfusion and LPS (Salmonella enteritidis, 1 mg/kg, i.v.,) administration, exhibited a marked, time-dependent increase in plasma alanine aminotransferase (ALT) levels compared to sham controls. An abrupt increase in liver nitrite/nitrate levels was also observed in I/R + LPS rats in association with the increases in plasma ALT. Although liver NO production in I/R + LPS rats increased with time, exacerbation of liver damage was not evident. Administration of L-NAME decreased NO production in plasma and liver but did not affect the liver damage in rats subjected to I/R + LPS. Superoxide levels in livers from I/R + LPS rats increased by threefold after 90 min reperfusion as compared to sham controls but dropped to control levels after 4 hr. There was a significant increase in neutrophils in liver lobes subjected to ischemia-reperfusion and LPS compared to sham controls and to non-ischemic lobes which received LPS. The number of neutrophils in the liver increased further in rats given L-NAME. These results suggest that the progressive injury seen in livers of I/R + LPS rats was possibly due to NO interaction with superoxide forming another reactive oxygen species such as peroxynitrite. However, inhibition of NO synthesis did not ameliorate liver damage, possibly because of an increase in tissue accumulation of activated polymorphonuclear leukocytes (PMN). Lung NO production increased in I/R + LPS rats after 4 hr reperfusion compared to sham controls. Prior administration of L-NAME did not prevent a significant rise in pulmonary NO generation (P < 0.05 at 90 min and 4 hr, compared to sham controls). This unexpected rise of pulmonary NO in the L-NAME treated group of rats was associated with a tendency for increased PMN accumulation (based on myeloperoxidase data) and superoxide generation. The results suggest that endogenous NO protected against excessive neutrophil infiltration in the lung in this model of hepatic ischemia-reperfusion and endotoxemia, and the use of L-NAME, a nonselective NOS inhibitor, may aggravate lung injury.
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PMID:Role of nitric oxide in hepatic ischemia-reperfusion with endotoxemia. 884 95


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