Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Feeding Sprague-Dawley rats for 3 wk a diet containing 1% by weight of cyclocreatine increased the reservoir of the high-energy phosphate compounds but also caused alterations in the levels of the two key amino acids, aspartate and glutamate. Both were decreased by approximately 50% in the presence of an unaltered content of glutamine. In vitro exposure of these hearts to sequential perfusion, global ischemia, and reperfusion in the absence of added amino acids resulted in changes in aspartate, glutamate, and glutamine that were different from those in hearts from control rats. In the cyclocreatine-fed group, aspartate concentration ([aspartate]) and [glutamate] fell after global ischemia, whereas [glutamine] was unaltered. [Glutamine] decreased, however, in the reperfusion period. In control hearts, the predominant effect was a steady decline in glutamine, which was accompanied by either less than 10% (after global ischemia) or 30-50% fall (after reperfusion) in [aspartate] and [glutamate]. The concentration of tissue Pi was smaller in hearts from cyclocreatine-fed rats and appeared to increase more slowly during ischemia. In the presence of rotenone and aminooxyacetate, heart homogenates catalyzed production of glutamate from glutamine, which was markedly stimulated by Pi and inhibited by H+. It is postulated that 1) phosphate-activated glutaminase is an important enzyme that determines cardiac [glutamate], 2) lower [phosphate] in hearts from rats fed cyclocreatine is responsible for the apparently lesser activity of glutaminase, 3) breakdown of the high-energy phosphate compounds and consequent rise in Pi activates glutaminase, and 4) slow breakdown of glutamine during global ischemia is a result of inhibition of glutaminase by H+.
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PMID:Effect of cyclocreatine feeding on levels of amino acids in rat hearts before and after an ischemic episode. 168 69

The ammonia concentration and changes in the activity of ammonia metabolizing enzymes in the brain tissue during ischemia/reperfusion were investigated in rats. During ischemia (0.5 h) we found a statistically significant increase in brain ammonia concentration and a significant decrease in glutamate dehydrogenase activity. After 1 h of reperfusion, a further accumulation of ammonia concentration was observed. Furthermore, the brain glutamine syntethase and glutamate dehydrogenase were decreased, whereas the brain glutaminase activity was increased. The causes for the changed activities of some ammonia metabolizing enzymes in brain after ischemia/reperfusion have been discussed.
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PMID:Accumulation of ammonia and changes in the activity of some ammonia metabolizing enzymes during brain ischemia/reperfusion injury in rats. 780 37

Alanine transport and the role of alanine amino-transferase in the synthesis and consumption of glutamate were investigated in the preparation of rat brain synaptosomes. Alanine was accumulated rapidly via both the high- and low-affinity uptake systems. The high-affinity transport was dependent on the sodium concentration gradient and membrane electrical potential, which suggests a cotransport with Na+. Rapid accumulation of the Na(+)-alanine complex by synaptosomes stimulated activity of the Na+/K+ pump and increased energy utilization; this, in turn, activated the ATP-producing pathways, glycolysis and oxidative phosphorylation. Accumulation of Na+ also caused a small depolarization of the plasma membrane, a rise in [Ca2+]i, and a release of glutamate. Intra-synaptosomal metabolism of alanine via alanine amino-transferase, as estimated from measurements of N fluxes from labeled precursors, was much slower than the rate of alanine uptake, even in the presence of added oxoacids. The velocity of [15N]alanine formation from [15N]glutamine was seven to eight times higher than the rate of [15N]-glutamate generation from [15N]alanine. It is concluded that (a) overloading of nerve endings with alanine could be deleterious to neuronal function because it increases release of glutamate; (b) the activity of synaptosomal alanine aminotransferase is much slower than that of glutaminase and hence unlikely to play a major role in maintaining [glutamate] during neuronal activity; and (c) alanine amino-transferase might serve as a source of glutamate during recovery from ischemia/hypoxia when the alanine concentration rises and that of glutamate falls.
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PMID:Cerebral alanine transport and alanine aminotransferase reaction: alanine as a source of neuronal glutamate. 790 47

Ischemia-reperfusion injury by free radicals and lipid peroxides is observed in various organs. Ascorbic acid (AsA) or glutathione (GSH) in various doses (AsA:2, 0.5, 0.1 mmol/kg, GSH:2 mmol/kg) was intraperitoneally administered to male Wistar rats. The entire small intestines were resected just before ischemia, after ischemia, and after 20 min of reperfusion (n = 7-10 at each time point). At each time point, the specimens were subjected to assays of lipid peroxides, GSH, and glutaminase activity of the tissues; they were also examined histologically. In the AsA group, the production of lipid peroxides after reperfusion was significantly suppressed in a dose-dependent manner, and the ratio of oxidized GSH to total GSH was also significantly low. Tissue glutaminase activity decreased to a lesser extent, and the degree of injury was apparently less marked in the AsA group. This study indicates that AsA acts as an antioxidant against peroxidative tissue injury, possibly by scavenging radicals, preserving reduced GSH, and reducing the peroxidative reaction.
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PMID:Ascorbic acid prevents ischemia-reperfusion injury in the rat small intestine. 963 56

Ischemia/reperfusion injury (IRI) after free tissue transfer of the small intestine results in transmural tissue damage. This study examined the effects of IRI on the jejunum. Wistar rats served either as controls (N=10) or underwent clamping of the infrarenal aorta for 1 hour followed by 1 hour of reperfusion (N=10). Both ischemia and reperfusion reduced the protein and deoxyribonucleic acid content of the jejunal mucosa (p < 0.05). Myeloperoxidase activity in the jejunal mucosa remained relatively low. The expression of leukocyte function-associated antigen 1 and intercellular adhesion molecule 1 (ICAM-1) on the surface of mucosal cells was not altered significantly by the ischemic insult, but was reduced after the period of reperfusion (p < 0.05). This coincided with an increase in messenger ribonucleic acid (mRNA) for ICAM-1 within isolated mucosal cells (p < 0.05). The specific activity of glutaminase in isolated jejunal mucosal cells was diminished after ischemia and reperfusion (p < 0.05), and this was not associated with an appreciable change in glutaminase mRNA expression. These results have identified some molecular mechanisms underlying IRI of the small intestine that are possible candidates for therapeutic intervention.
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PMID:The influence of ischemia/reperfusion injury on the jejunum. 964 Dec 80

The mitochondrial enzyme glutaminase is a significant contributor to extracellular glutamate after neuronal injury in vitro [R. Newcomb, X. Sun, L. Taylor, N. Curthoys, R.G. Giffard, Increased production of extracellular glutamate by the mitochondrial glutaminase following neuronal death, J. Biol. Chem. 272 (1997) 11276-11282.]. As a step towards characterizing the role of the enzyme in neuronal injury in vivo, glutaminase activity was measured in central and peripheral regions of the ischemic distribution in rat brain at 6, 24, and 48 h after permanent focal ischemia. Although glutaminase activity decreases in the central ischemic area, significant activity remains in peripheral areas of evolving damage, even after 24 and 48 h ischemia. Western blots show no detectable change in glutaminase molecular weight or total immunoreactivity, regardless of the degree of inactivation. Significant amounts of glutamine remain in ischemic tissue at prolonged times after focal ischemia, while reductions in tissue amounts of glutamate are highly correlated with decreases in glutaminase activity. In vivo microdialysis probes were inserted into the ischemic periphery after 24 h focal ischemia. Glutamate is significantly elevated in these dialysates. Perfusion of the glutaminase substrate glutamine and the enzyme activator phosphate results in further and specific elevations in dialysate glutamate. In sum, significant mitochondrial glutaminase activity remains in the periphery of the ischemic lesion at 24 and 48 h, where it can contribute directly to elevated extracellular glutamate. Inactivation of the glutaminase in central areas of the ischemic lesion does not involve significant proteolytic degradation, and likely involves a specific molecular event.
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PMID:Characterization of mitochondrial glutaminase and amino acids at prolonged times after experimental focal cerebral ischemia. 982 79

Glutamate is believed to be an excitatory amino acid neurotransmitter in the retina. Enzymes for glutamate metabolism, such as glutamate dehydrogenase, ornithine aminotransferase, glutaminase, and aspartate aminotransferase (AAT), exist mainly in the mitochondria. The abnormal increase of intracellular calcium ions in ischemic retinal cells may cause an influx of calcium ions into the mitochondria, subsequently affecting various mitochondrial enzyme activities through the activity of mitochondrial calpain. As AAT has the highest level of activity among enzymes involved in glutamate metabolism, we investigated the change of AAT activity in ischemic and hypoxic rat retinas and the protection against such activity by calpain inhibitors. We used normal RCS (rdy+/rdy+) rats. For the in vivo studies, we clamped the optic nerve of anesthetized rats to induce ischemia. In the in vitro studies, the eye cups were incubated with Locke's solution saturated with 95% N2/5% CO2. The activity of cytosolic AAT (cAAT) was about 20% of total activity, whereas mitochondrial AAT (mAAT) was about 75% in rat retina. Ninety minutes of ischemia or hypoxia caused a 20% decrease in mAAT activity, whereas cAAT activity remained unchanged. To examine the contribution of intracellular calcium ions to the degradation of mAAT, we used Ca2+-free Locke's solution containing 1 mM EGTA, ryanodine (Ca2+ channel blocker), and thapsigargin (Ca2+-ATPase inhibitor). In the present study, thapsigargin in Ca2+-free Locke's solution, but not ryanodine in this solution, was found to prevent AAT degradation. AAT degradation was also prevented by calpain inhibitors (Ca2+-dependent protease inhibitor) such as calpeptin at 1 nM, 10 nM, 0.1 microM, 1 microM and 10 microM, and by calpain inhibitor peptide, but not by other protease inhibitors (10 microM leupeptin, pepstatin, chymostatin). Additionally, we determined the subcellular localization of calpain activity and examined the change of calpain activity in ischemic rat retinas. Our results suggest that decreased activity of mAAT in ischemic and hypoxic rat retinas might be evoked by the degradation by calpain-catalyzed proteolysis in mitochondria.
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PMID:Possible mechanism for the decrease of mitochondrial aspartate aminotransferase activity in ischemic and hypoxic rat retinas. 1039 49

Phosphate-activated glutaminase (PAG) activity decreases markedly in the early period of ischemia. The decrease of the enzyme activity is reversible if the ischemic period is relatively short, but it becomes irreversible after 90 minutes of ischemia. The deterioration is a functional damage of the retinas caused by ischemia. We studied effects of growth factors and neurotrophic factors on protection of PAG in the ischemic and reperfused rat retinas. Before ischemia, 1 microl of growth factors or neurotrophic factors (0.1 microg/microl for insulin-like growth factor-I [IGF-I], insulin-like growth factor-II [IGF-II], brain-derived neurotrophic factor [BDNF], nerve growth factor [NGF]; 1 microg/microl for basic fibroblast growth factor [bFGF]) were injected into the vitreous cavity of the left eyes of anesthetized Sprague Dawley rats. As a control, phosphate buffered saline was injected to the right eyes. To induce ischemia, we clamped left eyes for 90 minutes after bulbar conjunctival incision all around limbus. The rat retinas were homogenized with distilled water 1 day after reperfusion and used for PAG assay. Retinal ammonia concentration was also determined as a ischemic marker. About 80% decrease of retinal PAG activity and 50% increase of retinal ammonia concentration were observed after 90 minutes of ischemia and 1 day of reperfusion as compared with unoperated normal eyes. IGF-II, BDNF and NGF had protective effects on the retinal PAG activity, whereas IGF-I, bFGF, stable bFGF were less effective. In addition, IGF-II and BDNF suppressed elevation of retinal ammonia concentration. BDNF, NGF and IGF-II have marked effect on the protection of PAG activity in the ischemic and reperfused rat retinas, whereas bFGF, which is very effective for the protection of ischemic cell death, shows moderate effect.
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PMID:Administration of nerve growth factor, brain-derived neurotrophic factor and insulin-like growth factor-II protects phosphate-activated glutaminase in the ischemic and reperfused rat retinas. 1045 79

An amino acid-based solution has been recently developed and has demonstrated significant protective effects during cold storage of small bowel (SB). This study was designed to examine the role of this novel solution in ameliorating intestinal injury in an in vivo model of ischemia-reperfusion (IR). The impact of luminal treatment with an amino acid-based (AA) solution was assessed throughout reperfusion after 60-min warm ischemia (WI) in rodent SB. Energetics (ATP and total adenylates) remained significantly elevated throughout 60-min reperfusion in AA-treated tissue compared with untreated controls. Increases in end-products (ammonia and alanine) and increases in alanine aminotransferase and glutaminase activity implicated greater amino acid metabolism in AA-treated tissues. After reperfusion, malondialdehyde levels were similar between all groups. Glutathione levels were consistently elevated in AA-treated tissues and by 60 min reperfusion values were sixfold greater than control. AA-mediated protection during IR resulted in reduced neutrophil infiltration suggesting a weaker inflammatory response. Barrier function and electrophysiology parameters exhibited a clear pattern of mucosal preservation in AA-treated tissues; histology supported these findings. This study raises the possibility of a role for a luminal nutrient-rich solution during ischemic storage of small bowel in the clinic.
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PMID:Alleviating ischemia-reperfusion injury in small bowel. 1508 67

Glutamate released by activated microglia induces excito-neurotoxicity and may contribute to neurodegeneration in numerous neurological diseases including ischemia, inflammation, epilepsy, and neurodegenerative diseases. We observed that the gap junction blocker carbenoxolone (CBX) or the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) decreased glutamate release from activated microglia and rescued neuronal death in a dose-dependent manner in vitro. In gerbils, treatment with CBX or DON also prevented the delayed death of hippocampal neurons following transient global ischemia. Thus, blockade of microglial glutamate release may be an effective therapeutic strategy against neurodegeneration after ischemic injury.
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PMID:Blockade of microglial glutamate release protects against ischemic brain injury. 1877 25


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