Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The degree of residual liver injury in normal and cirrhotic rats undergoing 70% hepatectomy with hepatic inflow occlusion was examined. The total duration of clamping was 60 min and animals were divided into 3 groups according to the ischemic modality: a 15-min intermittent clamping group (group I); a 30-min intermittent clamping group (group II), and a 60-min continuous clamping group (group III). In normal liver rats, the survival rates after operation in groups I, II and III were 90, 90 and 30%, respectively, compared to 70, 50 and 38%, respectively, in cirrhotic rats. The serum aspartate aminotransferase (AST) level increased markedly with prolongation of each period of clamping in rats with normal liver, showing higher AST levels than those with cirrhotic liver. The liver tissue adenosine-5'-triphosphate (ATP) levels and energy charge (EC) values decreased with prolongation of each period of clamping. Cirrhotic livers showed lower ATP levels and EC values than normal livers. Although there was no significant difference in the mitochondrial function between normal and cirrhotic livers in the group of the same form of ischemia, phosphorylative efficiency of mitochondria was maintained satisfactorily in normal groups I and II and in the cirrhotic group I. Even though cirrhotic livers showed a smaller necrotic response to ischemia than normal livers, they were more vulnerable to ischemia because of an inability to maintain energy metabolism. Therefore, when performing resection of a cirrhotic liver, a 15-min intermittent clamping method should be adopted.
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PMID:Experimental study of liver injury after partial hepatectomy with intermittent or continuous hepatic vascular occlusion. Differences in tolerance to ischemia between normal and cirrhotic livers. 758 3

The liver has been judged relatively resistant to ischemia, but prolonged inflow occlusion at normothermic conditions can produce evidence of reversible or irreversible hepatocellular damage. Cytoprotective agents have been used both experimentally and clinically to afford extended viability of hepatocytes under reduced perfusion. One agent, prostaglandin E1, has been described clinically as effective in sustaining liver function under ischemic conditions. We have sought to verify this observation in an experimental model using prolonged normothermic inflow occlusion. Twenty miniature pigs were anesthetized and subjected to subtotal normothermic hepatic inflow occlusion (portal vein, hepatic artery, choledochal vessels) to allow for sufficient splanchnic decompression. Half of the animals received pretreatment with prostaglandin E1 (alprostadil) 500 micrograms intravenously. Inflow occlusion was maintained for 2 hours followed by reperfusion and killing 24 hours later. As a measure of functional preservation, the tissue adenine nucleotides adenosine monophosphate, diphosphate, and triphosphate (AMP, ADP, ATP) were measured in ischemic liver by freeze-clamping and high-performance liquid chromatography during occlusion and after reperfusion. Cytosolic enzyme determinations (aspartate transaminase, alanine transaminase, lactate dehydrogenase) were also made before occlusion and after reperfusion. As a possible indicator of cellular injury, blood ionized Ca++ was measured before inflow occlusion and after reperfusion. Although no difference was found in levels of AMP and ADP between prostaglandin E1 and control animals, ATP levels rose significantly higher during recovery in prostaglandin E1 animals at 60 minutes and 24 hours after reperfusion (13.97 +/- 1.29 and 13.60 +/- 0.91 mumoles/gm dry weight prostaglandin E1 vs. 9.25 +/- 0.97 and 9.80 +/- 0.85 mumoles/gm dry weight co control, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of prostaglandin E1 on liver adenine nucleotides and cytoplasmic enzymes in a porcine model of normothermic hepatic ischemia. 759 Jun 75

We investigated whether intraportal injection of 150 mg/kg N-acetylcysteine (NAC) into rats reduced hepatic ischemia-reperfusion injury after 48 hours of cold storage and 2 hours of reperfusion. The organ was isolated and perfused to evaluate liver function. The control group received an intraportal injection of 5% dextrose. NAC increased L-cysteine concentrations 15 minutes after injection (1.29 +/- 0.11 mumol/g vs. 2.68 +/- 0.4 mumol/g, P < .05). However, neither treatment modified glutathione liver concentrations relative to preinjection values. After 48 hours of cold storage and 2 hours of reperfusion, livers from NAC-treated rats produced larger amounts of bile than those in the control group (5.04 +/- 1.92 vs. 0.72 +/- 0.37 microL/g liver; P < .05), and showed a significant reduction in liver injury, as indicated by reduced release of lactate dehydrogenase (679.4 +/- 174.4 vs. 1891.3 +/- 268.3 IU/L/g; P < .01), aspartate transaminase (AST) (13.94 +/- 3.5 vs. 38.75 IU/L/g; P < .01), alanine transaminase ALT) (14.92 +/- 4.09 vs. 45.91 +/- 10.58 IU/L/g; P < .05), and acid phosphatase, a marker of Kupffer cell injury (344.4 +/- 89.6 vs. 927.3 +/- 150.8 IU/L/g; P < .01) in the perfusate. Reduced glutathione concentrations in the perfusate were similar in the two groups (805 +/- 69 vs. 798 +/- 252 nmol/L/g), whereas oxidized glutathione (GSSG) concentrations were higher in the control group (967 +/- 137 vs. 525 +/- 126 nmol/L/g; P < .05). Reduced glutathione (GSH) concentrations in liver tissue collected at the end of perfusion were significantly higher in the NAC group (7.3 +/- 0.9 vs. 4.1 +/- 1.0 mumol/g; P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protective effects of N-acetylcysteine on hypothermic ischemia-reperfusion injury of rat liver. 763 22

Previously, pentoxifylline treatment of graft recipients was shown to protect against liver graft failure from storage/reperfusion injury after orthotopic rat liver transplantation. To determine whether pentoxifylline also protects against normothermic ischemia/reperfusion injury to liver, we induced lobar ischemia in rats followed by reflow and partial hepatectomy of the noninvolved liver. In rats receiving pentoxifylline 2 hr before surgery and then twice daily for 5 days, the 1-week survival rate more than doubled from 25% to 67% (P < 0.05). Liver enzymes (alanine transaminase, aspartate transaminase, and lactate dehydrogenase) in the serum and liver necrosis evaluated histologically were also significantly reduced in the pentoxifylline-treated rats (P < 0.01). Hepatic ischemia/reperfusion increased leukocyte infiltration into the lungs, and pentoxifylline tended to reduce this lung injury (P = 0.06). These results show that pentoxifylline treatment reduces hepatic injury and improves survival after normothermic ischemia and reperfusion.
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PMID:Protection by pentoxifylline against normothermic liver ischemia/reperfusion in rats. 777 68

Previous studies have demonstrated a role for both tumor necrosis factor (TNF) and reactive oxygen intermediates (ROI) in hepatic ischemia/reperfusion (I/R) injury. Biologically active TNF was present in liver homogenates in ischemic and nonischemic lobes after 2 h of ischemia but without reperfusion. Using an in situ liver perfusion model, we measured ROI, TNF, and hepatic enzymes in the effluent after 2 h of ischemia. Increased reduction of ferricytochrome C was observed in the hepatic effluent, indicative of the formation of ROI. Treatment of animals with TNF neutralizing antisera significantly reduced both ROI and aspartate aminotransferase (AST). Animals treated with superoxide dismutase (SOD), or SOD + catalase (CAT) had greater TNF in the hepatic effluent compared with I/R alone; however, SOD or SOD + CAT did not cause additional release of AST.SOD + CAT plus anti-TNF serum resulted in significant protection compared with SOD + CAT plus control serum. Reperfusion of ischemic liver with 4 mM H2O2 increased both TNF and AST. Optimal protection of hepatocellular injury from reperfusion injury is achieved with a combination of antioxidants and inhibition of TNF.
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PMID:Hepatic ischemia/reperfusion injury: importance of oxidant/tumor necrosis factor interactions. 781 Jun 59

Glutathione is important in cellular defense against oxidative stress. We postulated that administration of N-acetylcysteine (NAC), a glutathione precursor, might help maintain or replenish hepatic glutathione stores, thereby reducing reperfusion injury in liver grafts after warm ischemia. Eighteen pigs were subjected to 2 hr of warm hepatic ischemia and divided into a control group (group A, n = 6), a preischemia treatment group (group B, n = 6: NAC, 150 mg/kg, continuous i.v. infusion 1 hr before ischemia), and a postischemia treatment group (group C, n = 6: NAC, 150 mg/kg continuous i.v., begun 20 min before reperfusion and continued for 1 hr). At initiation of laparotomy, we measured hepatic levels of reduced glutathione (GSH), its oxidized form (GSSG), ATP, aspartate aminotransferase (AST), and lactate dehydrogenase (LDH). Before reperfusion, after 2 hr of warm ischemia, GSH, GSSG, and ATP were measured. One hour after reperfusion, we measured GSH, GSSG, ATP, AST, and LDH. Bile output was recorded every 10 min. Postoperfusion AST and LDH were significantly lower in both treatment groups than in controls. In group B, hepatic glutathione was maintained at significantly higher levels than in controls, even after ischemia (P < 0.05). In group C, although hepatic GSH levels fell until reperfusion, after administration of NAC, hepatic GSH reached the level of the preischemia treatment group. In both treatment groups, GSH 1 hr after reperfusion was significantly higher than in the controls (P < 0.01): regeneration of glutathione was seen in all 6 animals in group C, compared with 2/6 in group B and none in the control group. ATP recovery, bile output, and survival were all better in the treatment groups than in the control group. Pretreatment with NAC helps maintain hepatic glutathione during warm ischemia; given after ischemia, NAC is effective in replenishing depleted glutathione stores. Adjunctive use of NAC was associated with improved glutathione homeostasis, improved bile output and ATP regeneration, and increased survival.
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PMID:N-acetylcysteine ameliorates reperfusion injury after warm hepatic ischemia. 856 May 64

Alteration of calcium metabolism in cells has been thought to be one of the main factors in ischemia-reperfusion injury. Serial changes in the tissue calcium content of the liver and the correlation between calcium level and liver injury were investigated. Experimental dogs were divided into two groups and subjected to hepatic ischemia of different duration: 60 min in Group A and 120 min in Group B, followed by reperfusion. Serum alanine aminotransferase, as an indicator of liver injury, was more elevated in Group B than in Group A. There was no change in hepatic calcium content during ischemia in either group. Immediately after reperfusion, there was no change in hepatic calcium level in Group A, whereas in Group B it was markedly elevated. The peak value occurred 30 min after reperfusion and gradually decreased thereafter, but did not return to pre-ischemic levels during the observation time. Plasma calcium concentrations in hepatic venous blood were markedly decreased in Group B 30 min and 60 min after reperfusion. These results suggest that calcium accumulation in the liver during the early reperfusion period may be one of the mediators of hepatic injury. To elucidate the mechanisms for elevation of calcium in hepatic tissue, serum malondialdehyde, a product of lipid peroxidation, was measured in hepatic venous blood. No elevation of serum malondialdehyde was observed in either group, indicating that the increases in calcium may not be due to oxidative stress. Serum mitochondrial aspartate aminotransferase and electron microscopic findings were used as indicators of mitochondrial injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in calcium content of the liver during hepatic ischemia-reperfusion in dogs. 789 Aug 88

To clarify the in vivo relevance of leukocyte-endothelial cell interactions in the manifestation of hepatic ischemia-reperfusion (I/R) injury, we studied leukocyte flow behavior in sinusoids and postsinusoidal venules of postischemic hepatic tissue in rats using intravital microscopy. Reperfusion following either 20 min (n = 9) or 60 min (n = 9) of left hepatic lobar ischemia resulted in a significant increase of the number of stagnant leukocytes in sinusoids and adherent cells in postsinusoidal venules compared with sham-operated controls (n = 10). Transmission electron microscopy revealed the extravasation of leukocytes from both sinusoids (into the space of Disse) and postsinusoidal venules. In parallel, hepatic I/R was associated with increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and reduced bile flow. Linear regression estimates revealed significant (P < 0.01) correlations between serum ALT (r = 0.76) and AST (r = 0.65) activities, bile flow (r = -0.62), and the number of adherent leukocytes in postsinusoidal venules. In contrast, parameters of hepatocellular integrity and function did not directly correlate with the number of stagnant leukocytes in liver sinusoids. We conclude that hepatic I/R induces accumulation, adherence, and extravasation of leukocytes in both hepatic sinusoids and postsinusoidal venules. However, the adherence of leukocytes to the endothelial lining of venules, rather than of sinusoids, may determine the manifestation of hepatocellular damage and liver dysfunction.
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PMID:Impact of leukocyte-endothelial cell interaction in hepatic ischemia-reperfusion injury. 797 40

This study investigated the effect of verapamil on prolonged and severe ischemic injury and elucidated the association of the calcium blocking action with cellular injury, assessing changes in hepatic calcium concentrations during ischemia and reperfusion in pigs. Hepatic ischemia was produced for 180 min by clamping both the hepatic artery and portal vein during temporary portacaval shunt performed before the induction of ischemia. Pigs were divided into two groups: the animals in the verapamil group (Group V, n = 6) received continuous administration of 0.025 mg/kg per min of verapamil intraportally for 20 min before ischemia. The control group (Group C) received nothing. A better survival rate was observed in Group V than in Group C (p < 0.01), but serum aspartate aminotransferase was higher in Group V after reperfusion (p < 0.05). There were no significant changes in hepatic calcium concentrations during ischemia in either group, but it increased immediately after reperfusion in both groups. However, no significant difference was found between the two groups. Recovery of the pyruvate/lactate ratio in Group V tended to be better after reperfusion compared to Group C (p = 0.08). These data suggest that the pre-ischemic administration of verapamil produced better survival in animals after prolonged normothermic ischemia. However, the reperfused liver suffered more severe damage in the first 6 h after reperfusion in the verapamil-treated animals. Moreover, there seemed to be very little blocking action of calcium influx. A reduced oxygen requirement may be involved in the protective action of verapamil on animal survival.
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PMID:Effect of verapamil on hepatic reperfusion injury after prolonged ischemia in pigs. 798 12

Hepatic ischemia-reperfusion (I/R) is characterized by circulatory and metabolic derangements, liver dysfunction, and tissue damage. However, little is known about the causative role of I/R-induced microcirculatory disturbance on the manifestation of postischemic reperfusion injury. Therefore, the intention of the study was to assess changes of hepatic microvascular perfusion (intravital fluorescence microscopy) as related to hepatic morphology (light/electron microscopy), hepatocellular integrity (serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities), and excretory function (bile flow). Sprague-Dawley rats were subjected to 20 minutes (group B, n = 9) and 60 minutes (group C, n = 9) of left hepatic lobar ischemia followed by 60 minutes of reperfusion. Sham-operated animals without ischemia served as controls (group A, n = 10). Lobar ischemia for 20 minutes followed by reperfusion resulted in a significant reduction of sinusoidal perfusion rate (93.9 +/- 1.4%; P < 0.05) and a decrease in erythrocyte flux (90.0 +/- 5.6%) when compared with controls (99.4 +/- 0.2 and 97.9 +/- 2.7%). This was accompanied by a significant increase of serum AST and ALT activities (P < 0.05) and a reduction of bile flow (P < 0.05). Prolongation of lobar ischemia (group C, 60 minutes) aggravated postischemic reperfusion injury (sinusoidal perfusion rate: 87.4 +/- 2.9%; erythrocyte flux: 62.1 +/- 8.4%) and was paralleled by severed hepatocellular damage. Electron microscopy of postischemic tissue demonstrated alteration of nonparenchymal cells (swelling of sinusoidal lining cells and widening of Disse's space) and substantial parenchymal cell damage (swelling of mitochondria, disarrangement of rough endoplasmatic reticulum, vacuolization, complete cytoplasmic degeneration). Initial postischemic increase in serum AST and ALT activities and reduction of bile flow directly correlated with the extent of microcirculatory failure (P < 0.01), ie, impairment of sinusoidal perfusion and decrease of erythrocyte flux, indicating the decisive role of microvascular perfusion failure for the manifestation of hepatic tissue damage and liver dysfunction.
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PMID:Hepatic microcirculatory perfusion failure is a determinant of liver dysfunction in warm ischemia-reperfusion. 799 45


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