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)

Although excessive release of the neurotransmitter glutamate contributes to ischemic neuronal damage, immunocytochemical studies have not found a loss of glutamate from ischemic axon terminals. We examined the effects of two components of ischemia, hypoxia and hypoglycemia, on glutamate loss from rat hippocampal slices. In vitro hypoglycemia induced by incubation for 1 h without glucose depleted 50% of glutamate from slices when ATP levels were about 5 nmol/mg protein. Hypoxic slices aerated with N2 reached similar ATP levels without significant glutamate depletion. To induce 50% glutamate losses with chemical hypoxia, ATP had to be depleted to < 1 nmol/mg protein. Immunocytochemical staining indicated that glutamate-like immunoreactivity was reduced throughout slices by hypoglycemia. Hypoxia decreased glutamate-like immunoreactivity in neuronal perikarya and dendrites of pyramidal cells and granule cells. However, in contrast to hypoglycemia, hypoxia maintained or increased glutamate-like immunoreactivity in many terminals. Hypoxia and hypoglycemia induced similar, ATP-dependent releases of glutamate into supernatants, which could account for only part of the hypoglycemic losses. The additional hypoglycemic losses were consistent with increased catabolism of glutamate. Glutamate losses from hypoglycemic terminals were reduced by blockade of aspartate aminotransferase or the tricarboxylic acid cycle. Exogenous glutamate increased glutamate in hypoglycemic slices to hypoxic levels and returned glutamate-like immunoreactivity to terminals, suggesting that terminals maintained glutamate uptake during metabolic insults. Hypoglycemia induces a large loss of glutamate that does not occur during hypoxia. The greater loss of glutamate from terminals during hypoglycemia is consistent with increased metabolism of glutamate via aspartate aminotransferase and not increased release of glutamate. Continued uptake of glutamate by hypoxic terminals may help to maintain their levels of glutamate. Hypoglycemic metabolism of glutamate may decrease pathologic glutamate release and contribute to the prolonged neurologic abnormalities associated with recovery from hypoglycemia.
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PMID:Glutamate in synaptic terminals is reduced by lack of glucose but not hypoxia in rat hippocampal slices. 1057 5

BACKGROUND: The metabolic and hemodynamic effects of nisoldipine supplementation in cardioplegia after ischemic injury were investigated in 13 isolated rabbit hearts. Group 1 consisted of 6 hearts, which received St. Thomas II cardioplegic solution. In group 2, nisoldipine was added to the cardioplegic solution at a concentration of 0.1 mg/kg in 7 hearts. METHODS: The explanted hearts were suspended from Langendorff apparatus and were perfused with Krebs-Henseleit solution. Left ventricular pressure, heart rate, malondialdehyde, glutathione peroxidase, glutathione reductase, reduced glutathione, oxidized glutathione, creatine kinase MB, (CK-MB), aspartate transaminase, and lactate dehydrogenase (LDH) were measured before and after 60 minutes of ischemia. Peak generated pressure after ischemia was significantly higher in group 2 versus group 1 while end-diastolic pressure was significantly lower in group 2 after ischemic arrest (P <.05). RESULTS: Malondialdehyde levels were lower in group 2 (P <.05). Glutathione peroxidase and glutathione reductase levels were significantly higher in group 2 (P <.05). The only enzymatic significant difference was observed between the preischemic and postischemic levels of aspartate transaminase in group 2 (P <.05). CONCLUSIONS: These findings show beneficial effects of nisoldipine cardioplegia, although its use as a cardioplegic additive is not yet possible. We believe, however, the effects of oral nisoldipine before cardiac surgery can be studied in a clinical setting.
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PMID:Nisoldipine Cardioplegia in the Isolated Rabbit Heart. 1068 69

The protective effect of O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime (BGP-15) against ischemia-reperfusion-induced injury was studied in the Langendorff heart perfusion system. To understand the molecular mechanism of the cardioprotection, the effect of BGP-15 on ischemic-reperfusion-induced reactive oxygen species (ROS) formation, lipid peroxidation single-strand DNA break formation, NAD(+) catabolism, and endogenous ADP-ribosylation reactions were investigated. These studies showed that BGP-15 significantly decreased leakage of lactate dehydrogenase, creatine kinase, and aspartate aminotransferase in reperfused hearts, and reduced the rate of NAD(+) catabolism. In addition, BGP-15 dramatically decreased the ischemia-reperfusion-induced self-ADP-ribosylation of nuclear poly(ADP-ribose) polymerase(PARP) and the mono-ADP-ribosylation of an endoplasmic reticulum chaperone GRP78. These data raise the possibility that BGP-15 may have a direct inhibitory effect on PARP. This hypothesis was tested on isolated enzyme, and kinetic analysis showed a mixed-type (noncompetitive) inhibition with a K(i) = 57 +/- 6 microM. Furthermore, BGP-15 decreased levels of ROS, lipid peroxidation, and single-strand DNA breaks in reperfused hearts. These data suggest that PARP may be an important molecular target of BGP-15 and that BGP-15 decreases ROS levels and cell injury during ischemia-reperfusion in the heart by inhibiting PARP activity.
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PMID:BGP-15, a nicotinic amidoxime derivate protecting heart from ischemia reperfusion injury through modulation of poly(ADP-ribose) polymerase. 1069 58

Hepatic allografts from donors who have suffered a brief cardiopulmonary arrest may sustain ischemic damage before organ procurement. However, there is no reported correlation between donor cardiopulmonary arrest and hepatic allograft dysfunction. On the other hand, brief ischemia-reperfusion injury has been shown experimentally to result in protection in several organ models. Induction of ischemic tolerance has been called ischemic preconditioning. Our objective was to study the influence of brief donor cardiopulmonary arrest on hepatic allograft outcome in human liver transplantation. Between May 1997 and July 1998, 181 consecutive orthotopic liver transplant (OLT) cases were divided into 2 groups based on the occurrence of donor cardiopulmonary arrest. Group A consisted of 37 donors who suffered a cardiopulmonary arrest. Group B consisted of the remaining 144 patients. Liver graft survival within 90 days of OLT and early postoperative graft function were analyzed. Although there was significant liver damage resulting from circulatory failure during cardiopulmonary arrest before organ procurement in group A, graft survival was not affected. After OLT, the mean peak aspartate transaminase and alanine transaminase concentrations in group A (1, 444.1 and 718.2 U/L) were significantly lower than those in group B (2,382.8 and 1,507.3 U/L) (P <.05). Experiences of brief cardiopulmonary arrest in organ donors did not affect post-OLT hepatic allograft survival and function. Although the liver function tests are elevated in an organ donor, the hepatic allograft is suitable for OLT if the liver damage is induced by brief donor cardiopulmonary arrest.
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PMID:Influence of donor cardiopulmonary arrest in human liver transplantation: possible role of ischemic preconditioning. 1070 45

Although adenosine has been postulated to inhibit ischemia-reperfusion injury in various tissues, its in vivo cytoprotective mechanism is not fully known. The aim of this study was to determine the effect of intraportally infused adenosine on reperfusion injury in the canine liver. Two h ischemia and reperfusion of the liver were induced in beagle dogs by clamping the portal triad. Either adenosine or saline was infused in the portal vein after reperfusion for 60 min. Levels of serum aspartate aminotransferase and alanine aminotransferase and the survival of animals were examined. Hepatic levels of protein carbonyls and glutathione were also measured, as markers of oxidative stress. One h after reperfusion, the liver was perfused with nitroblue tetrazolium and the formation of formazan was observed to evaluate superoxide formation. Twenty-four h after reperfusion, 100% of animals in the adenosine group and 33% of animals in the control group survived. Adenosine significantly decreased the reperfusion-induced increase in serum levels of aspartate aminotransferase and alanine aminotransferase. Adenosine also suppressed the formation of protein carbonyls and the decrease in glutathione levels. Histologically, neutrophil infiltration, superoxide formation, and apoptosis were decreased by adenosine. These results suggest that intraportally infused adenosine attenuates reperfusion injury of the liver, presumably by suppressing the activation of neutrophils and oxidative stress.
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PMID:Post-ischemic intraportal adenosine administration protects against reperfusion injury of canine liver. 1098 96

Distal pancreatectomy with resection of the celiac axis can increase resectability of carcinoma of the body and tail of the pancreas. We performed reconstruction of the hepatic artery to avoid complications caused by a decrease in hepatic arterial flow. We carried out distal pancreatectomy with resection of the celiac axis for carcinoma of the body and tail of the pancreas in four patients. When pulsation in the proper hepatic artery was weak after occlusion of the celiac axis, we performed reconstruction of the hepatic artery, using the splenic artery, which had been taken beforehand from the resected specimen. In two patients, we performed reconstruction of the hepatic artery. These two patients underwent reconstruction of the portal vein combined with prolonged clamping of the portal vein. Levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were elevated just after the operation, but recovered to normal levels within 10 days. No complications related to hepatic ischemia were observed. These results suggested that reconstruction of the hepatic artery allowed us to safely perform distal pancreatectomy with resection of the celiac axis for carcinoma of the body and tail of the pancreas.
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PMID:Distal pancreatectomy with resection of the celiac axis and reconstruction of the hepatic artery for carcinoma of the body and tail of the pancreas. 1098 11

The protective effect of N-[(3, 5-di-tertiobutyl-4-hydroxy-1-thiophenyl)]-3-propyl-N'-(2,3, 4-trimethoxybenzyl)piperazine (S-15176) on liver injury induced by warm ischemia-reperfusion was investigated using a rat model. Animals were subjected to 2 h of ischemia followed by different reperfusion times. Hepatocyte integrity was assessed by measuring plasma alanine and aspartate aminotransferase activities, and by determining reduced and oxidized glutathione in plasma and bile. Hepatocyte function was quantitated by determining bile flow and liver ATP content. Ischemia-reperfusion resulted in severe hepatic injury involving a huge increase in alanine and aspartate aminotransferase activities, a drop in ATP content, and a decrease in bile flow. Plasma and bile reduced (GSH) and oxidized (GSSG) glutathione concentrations were inversely related: plasma levels increased when biliary levels decreased. This was associated with a decrease in animal survival (-34%). S-15176 pretreatment (1.25, 2.5, 5 or 10 mg kg(-1) day(-1)) improved the survival rate and limited tissue damages in a dose-dependent manner. The pretreatment also reduced the aminotransferase leakage from hepatocytes and the increase in plasma glutathione levels. In addition, normalization of the plasma GSSG/GSH ratio, a good index of an oxidative stress, was observed in groups treated with the higher dosage, suggesting that the antioxidant properties demonstrated for the compound in vitro (IC(50)=0.3 microM towards lipid peroxidation) could play a role in its protective effect. S-15176 pretreatment also protected the organ from the drop in ATP levels. At the higher dose, ATP content was maintained at a level almost 86% of the sham-operated group after 60 min of reperfusion. This was associated with a restoration of the biliary flow. These data suggest that S-15176 may be a useful drug in liver surgery to prevent ischemia-reperfusion injury.
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PMID:S-15176 reduces the hepatic injury in rats subjected to experimental ischemia and reperfusion. 1102 Apr 92

Hepatic ischemia-reperfusion (I/R) is an important cause of organ dysfunction in the critically ill. With reperfusion, Kupffer cells release pro-inflammatory cytokines that promote endothelial cell (EC) expression of adhesion molecules such as intercellular adhesion molecule (ICAM)-1, facilitating neutrophil (PMN) infiltration. Studies suggest hypertonic saline (HTS) might exert beneficial effects on development of organ injury following shock on the basis of reduced PMN-EC interactions. We hypothesized that HTS alters expression of EC ICAM-1 and thus minimizes PMN-mediated injury. To test our hypothesis, we used an in vivo model of hepatic I/R and an in vitro model of activated EC. Rats underwent 30 min of hepatic ischemia after pretreatment with HTS (7.5% NaCl, 4cc/kg ia) or normal saline (NS). At 4 h reperfusion, plasma was taken for aspartate aminotransferase (AST) and liver tissue was harvested for assessment of hepatic ICAM-1 mRNA by Northern blot analysis. Human umbilical vein endothelial cells (HUVECs) were activated by lipopolysaccharide (LPS) and exposed to hypertonic medium (350-500 mOsM). HUVEC ICAM-1 protein was measured by cell ELISA and ICAM-1 mRNA by Northern blot analysis. HTS prevented hepatic I/R injury as measured by AST. AST of shams was 282.6+/-38.1 IU/L. I/R following NS pretreatment caused significant injury (AST 973.8+/-110.9 IU/L) compared to sham (SM) (P < 0.001). Pretreatment with HTS exerted significant protection following I/R with an AST of 450.9+/-56.3 IU/L (P < 0.05). There was no significant difference in AST levels between SM and HTS groups. Reduced hepatic injury after HTS and I/R was accompanied by inhibition of I/R-induced hepatic ICAM-1 mRNA expression compared to NS treated animals (P < 0.01). Similarly, hypertonicity inhibited HUVEC LPS-induced ICAM-1 protein (LPS: 1.86+/-0.19 absorbance units; 400 mOsM +/- LPS: 1.45+/-0.14 absorbance units; 450 mOsM + LPS: 1.02+/-0.19 absorbance units, P < 0.001) and mRNA expression. Thus, hypertonicity modulates endothelial ICAM-1 expression as one possible protective mechanism against I/R injury.
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PMID:In vivo and in vitro modulation of intercellular adhesion molecule (ICAM)-1 expression by hypertonicity. 1102 65

Previous morphological studies failed to show appreciable injury of biliary epithelial cells (BEC) after cold ischemia of rat liver, although recent evidence indicated that BEC integrity and function were impaired in this model. We tested the hypothesis that analysis of bile for enzymes, such as lactate dehydrogenase (LDH), alanine transaminase (ALT), and aspartate transaminase (AST), can be used for assessing cold ischemic injury of BEC. Furthermore, we examined whether biliary gamma-glutamyltransferase (GGT) reflects warm ischemic injury of BEC and whether normothermic reperfusion aggravates the negative effect of cold ischemia on BEC integrity and function. Rat livers were reperfused after different periods of cold or warm ischemia using a blood-free perfusion model. Compared with controls, perfusate LDH, ALT, and AST levels and parameters of hepatocyte function, including hepatocyte tight junction permeability, were not significantly altered by 18-h cold ischemia. On the other hand, 9-h cold ischemia markedly increased biliary LDH, ALT, and AST levels. However, only LDH release into the bile was strongly dependent on the time of cold storage. Biliary GGT, LDH, and glucose levels decreased during the reperfusion period following 18-h cold ischemia. The results suggest that biliary LDH can be used for assessing injury of BEC in cold-preserved livers and that normothermic reperfusion does not aggravate preservation-induced injury of BEC after cold ischemic storage.
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PMID:Bile analysis as a tool for assessing integrity of biliary epithelial cells after cold ischemia--reperfusion of rat livers. 1103 93

One of the changes produced by ischemia and reperfusion is endothelin (ET)-mediated constriction of the hepatic vascular bed. This leads to microcirculatory disturbances and reduced blood flow, thereby causing local hypoxia and liver damage. Our aim was to induce stepwise changes of microvascular vessel diameters so as to define the best protective vessel width that could be produced by drug therapy and thereby to minimize ischemia/reperfusion injury. The mixed ET receptor antagonist bosentan was used in different dosages in a rat liver ischemia/reperfusion model with splenocaval shunt. In vivo microscopy was performed 30-90 min after reperfusion and local hepatic tissue pO2 was determined, together with aspartate aminotransferase/alanine aminotransferase (AST/ALT). After ischemia, sinusoidal diameters were significantly reduced to 76 +/- 7% of those in the control group. After the administration of bosentan in dosages of 0.1, 1, and 10 mg/kg body weight iv and 10 mg/kg body weight intraportally we found diameters of 83 +/- 4, 98 +/- 2, 109 +/- 6, and 137 +/- 19%, respectively. Perfusion rate and leukocyte-endothelium interactions showed dependence on sinusoidal diameters, with the best results in the group where preischemic sinusoidal vessel width had been maintained. Local tissue pO2 and transaminase levels also showed that oxygen supply was sufficient and that hepatocellular injury was most minimized in this group. Graduated blocking of ET receptors allows stepwise regulation of sinusoidal and postsinusoidal venular vessel width and offers a treatment strategy for pathophysiological situations that are associated with ET-induced vasoconstriction. The results suggest that maintenance of preischemic microvascular diameter is the best therapeutic approach.
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PMID:Controlled vasoregulation of postischemic liver microcirculation--a therapeutic approach. 1107 63


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