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)

Copper Fenton systems (Cu(II)/H2O2 and Cu(II)/Asc) inactivated the lipoamide reductase and enhanced the diaphorase activity of pig-heart lipoamide dehydrogenase (LADH). Cupric ions alone were less effective. As a result of Cu(II)/H2O2 treatment, the number of titrated thiols in LADH decreased from 6 to 1 per subunit. NADH and ADP (not NAD+ or ATP) enhanced LADH inactivation by Cu(II). NADH also enhanced the effect of Cu(II)/H2O2. Dihydrolipoamide, dihydrolipoic acid, Captopril, acetylcysteine, EDTA, DETAPAC, histidine, bathocuproine, GSSG and trypanothione prevented LADH inactivation. 100 microM GSH, DL-dithiothreitol, N-(2-mercaptopropionylglicine) and penicillamine protected LADH against Cu(II)/Asc and Cu(II), whereas 1.0 mm GSH and DL-dithiothreitol also protected LADH against Cu(II)/H2O2. Allopurinol provided partial protection against Cu(II)/H2O2. Ethanol, mannitol, Na benzoate and superoxide dismutase failed to prevent LADH inactivation by Cu(II)/H2O2 or Cu(II). Catalase (native or denaturated) and bovine serum albumin protected LADH but that protection should be due to Cu binding. LADH inhibited deoxyribose oxidation and benzoate hydroxylation by Cu(II)/H2O2. It is concluded that site-specifically generated HO, radicals were responsible for LADH inactivation by Cu(II) Fenton systems. The latter effect is discussed in the context of ischemia-reoxygenation myocardial injury.
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PMID:Inactivation of heart dihydrolipoamide dehydrogenase by copper Fenton systems. Effect of thiol compounds and metal chelators. 775

The brain mitochondrial NAD+/NADH ratio, as a reflection of the oxidation-reduction (redox) state of cellular compartment, was determined under conditions of hypoxia, anoxia, hypoxia-ischemia, complete ischemia and hypoglycemia in immature rats. NAD+/NADH ratios were calculated from changes in the concentrations of specific oxidative substrates and calculated intracellular pH during cerebral metabolic stress. The results suggest that the use of the acetoacetate/beta-hydroxybutyrate substrate couple provides a more accurate prediction of the mitochondrial redox state under adverse conditions than use of the alpha-ketoglutarate/glutamate couple. It is possible that the mitochondrial oxidation seen with the latter substrate couple during cerebral metabolic stress might reflect a population of cells (neurons or glia) which are substrate-deprived relative to the rest of the brain in the setting of metabolic stress produced by oxygen deficiency.
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PMID:Cerebral mitochondrial redox states during metabolic stress in the immature rat. 798 46

Ischemia/reperfusion (IR) damage is a major cause of dysfunction in transplanted organs. The objective of the present study was to correlate in vivo measurements of respiratory chain (RC) function with histological and physiological parameters. Non-invasive in situ (surface fluorescence) measurements of mitochondrial NADH and near infrared spectroscopic measurements of cyt aa3 were made in unstored (Group 1) and 72 hour stored (1 to 2 degrees C) (Group 2) autografted rabbit kidneys. The effect of sodium pentobarbitone on NADH levels was investigated. In Group 1, there was a significant change in the redox state of cyt aa3 in all (N = 6) kidneys on reperfusion which correlated with organ viability and increased NADH oxidation and minimal edema on histological examination. In Group 2 there was no significant change in cyt aa3 compared to baseline, and this correlated with poor long term organ viability, slower NADH oxidation, and severe cortical edema. Pentobarbitone inhibition of the RC resulted in rapid and complete reduction of NAD+ in Group 1, but none or only a slight reduction in Group 2. The results demonstrate that it might be possible in future to predict organ viability and histological changes by non-invasive measurements of RC dysfunction in the clinical transplant situation.
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PMID:Non-invasive measurement of respiratory chain dysfunction following hypothermic renal storage and transplantation. 807 62

Warm ischemia of the intestine is a medical emergency which results from mesenteric vascular occlusion. In addition, intestinal transplantation techniques will also inevitably result in intestinal ischemia. The recovery of organ function following ischemia depends on the extent of irreversible damage produced by the ischemia and the extent of reflow upon reperfusion. In some organs energy homeostasis has been found to correlate with organ recovery and graft survival following ischemia-reperfusion. Investigating the usefulness of the determination of adenine and pyridine nucleotides as indicators of the extent of ischemic injury in intestinal segments, we found that after an initial 40% decrease in ATP following 30 min of ischemia there was no further decrease despite increasing the ischemia period to 120 min. Similarly, the decrease in NAD+ and NADP which occurred after 30 min of ischemia did not decrease further after 60, 90, or 120 min of ischemia. Xanthine was the only biochemical where an increase appeared to correlate with ischemia duration while energy charge was of no value in indicating injury extent. Additionally, after reperfusion there was at best a poor correlation between recovery of ATP content and the duration of ischemia. Microcirculation reflow after reperfusion indicated ischemia time-related endothelial cell injury. Thus, the measurement of high-energy phosphates in intestinal segments is not of value as an indicator of the extent of intestinal ischemic injury.
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PMID:Adenine nucleotides of ischemic intestine do not reflect injury. 841 29

Diabetes increases the incidence of cardiovascular disease as well as the complications of myocardial infarction. Studies using animal models of diabetes have demonstrated that the metabolic alterations occurring at the myocyte level may contribute to the severity of ischemic injury in diabetic hearts. Of the several mechanisms being investigated to understand the pathogenesis of diabetic complications, the increased metabolism of glucose via the polyol pathway has received considerable attention. Deviant metabolic regulation due to increased flux through aldose reductase in diabetic hearts may influence the ability of the myocardium to withstand ischemia insult. To determine if aldose reductase inhibition improves tolerance to ischemia, hearts from acute type I diabetic and nondiabetic control rats were isolated and retrograde perfused. Each group was exposed to 1 micromol/l zopolrestat, a specific inhibitor of aldose reductase, for 10 min, followed by 20 min of global ischemia and 60 min of reperfusion in the absence of zopolrestat. Zopolrestat reduced sorbitol levels before ischemia in diabetic hearts. The cytosolic redox state (NADH/NAD+), as measured by lactate-to-pyruvate ratios, was significantly lowered under baseline, ischemic, and reperfusion conditions in diabetic hearts perfused with zopolrestat. In these diabetic hearts, ATP was significantly higher in zopolrestat hearts during ischemia, as were phosphocreatine and left ventricular-developed pressure on reperfusion. Zopolrestat provided similar metabolic and functional benefits in nondiabetic hearts. Creatine kinase release was reduced by approximately 50% in both nondiabetic and diabetic hearts treated with zopolrestat. These data indicate that inhibition of aldose reductase activity preserves high-energy phosphates, maintains a lower cytosolic NADH/NAD+ ratio, and markedly protects both diabetic and nondiabetic hearts during ischemia and reperfusion.
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PMID:Aldose reductase inhibition protects diabetic and nondiabetic rat hearts from ischemic injury. 900 Jul 7

The therapeutic potential of alpha-lipoic acid (thioctic acid) was evaluated with respect to its influence on cellular reducing equivalent homeostasis. The requirement of NADH and NADPH as cofactors in the cellular reduction of alpha-lipoic acid to dihydrolipoate has been reported in various cells and tissues. However, there is no direct evidence describing the influence of such reduction of alpha-lipoate on the levels of cellular reducing equivalents and homeostasis of the NAD(P)H/NAD(P) ratio. Treatment of the human Wurzburg T-cell line with 0.5 mM alpha-lipoate for 24 hr resulted in a 30% decrease in cellular NADH levels. alpha-Lipoate treatment also decreased cellular NADPH, but this effect was relatively less and slower compared with that of NADH. A concentration-dependent increase in glucose uptake was observed in Wurzburg cells treated with alpha-lipoate. Parallel decreases (30%) in cellular NADH/NAD+ and in lactate/pyruvate ratios were observed in alpha-lipoate-treated cells. Such a decrease in the NADH/NAD+ ratio following treatment with alpha-lipoate may have direct implications in diabetes, ischemia-reperfusion injury, and other pathologies where reductive (high NADH/NAD+ ratio) and oxidant (excess reactive oxygen species) imbalances are considered as major factors contributing to metabolic disorders. Under conditions of reductive stress, alpha-lipoate decreases high NADH levels in the cell by utilizing it as a co-factor for its own reduction process, whereas in oxidative stress both alpha-lipoate and its reduced form, dihydrolipoate, may protect by direct scavenging of free radicals and recycling other antioxidants from their oxidized forms.
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PMID:Modulation of cellular reducing equivalent homeostasis by alpha-lipoic acid. Mechanisms and implications for diabetes and ischemic injury. 906 43

To investigate the basis of neuronal vulnerability we studied mitochondrial redox changes in gerbil hippocampus before and after 5 minutes forebrain ischemia. The brain was frozen by in situ funnel freezing method, and grinned off coronally until exposure of hippocampus. Relative value of regional redox ratio (NAD+/NADH) was obtained from fluorescence signals of intrinsic fluorochromes, i.e., NADH (PN) and flavoproteins (Fp), using a high resolution fluorometer. We calculated a modified redox ratio MRR = FP/(Fp + PN). Each point is displayed in gray scales ranged 16 degrees corresponding to the MRR value of the point; black represents a low MRR value (reduced) and white represents a high value (oxidized). Pyramidal cell layers and the granule cell layers were seen as linear areas of high MRR. The stratum radiatum and stratum orience of the CA 1 subfield showed low MRR compared with other hippocampal regions. During ischemic period, MRR in all subfield of hippocampus had decreased but the decrease was more severe in CA 1 region than in another. Just after recirculation, MRR decreased transiently in dentate and CA 3 areas but was fully recovered in all hippocampal areas with the exception of CA 1 region, where the MRR decreased again 12 hours after recirculation. These results suggest that CA 1 area suffers more pronounced hyoxic condition (state V) than other less vulnerable regions during 5 minutes ischemia. The irreversible reduction of MRR in CA 1 area may result from continuing mitochondrial dysfunction, and this may cause lasting energy shortage in CA 1 neurons that eventually results in slowly progressive cell death.
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PMID:[Mitochondrial redox change in gerbil hippocampus before and after transient ischemia]. 939 29

In a previous report, we have demonstrated that simultaneous inhibition of nucleoside transport and adenosine deaminase accumulates endogenous adenosine and protects the myocardium against stunning. The differential cardioprotective effects of erythro-9(2-hydroxy-3-nonyl)-adenine (EHNA), a potent inhibitor of adenosine deamination but not transport, and p-nitrobenzylthioinosine (NBMPR), a selective blocker of adenosine and inosine transport, are not known. Thirty-seven anaesthetized adult dogs were instrumented to monitor left ventricular performance using sonomicrometery. Dogs were randomly assigned into four groups. The control group (n = 8) received only the vehicle solution. Treated groups received saline containing 100 microM EHNA (EHNA-group, n = 7), 25 microM NBMPR (NBMPR-group, n = 7), or a combination of 100 microM EHNA and 25 microM NBMPR (EHNA/NBMPR-group, n = 10). Hearts were subjected to 30 min of normothermic global ischaemia and 60 min of reperfusion while on bypass. Adenine nucleotides, nucleosides, oxypurines and NAD+ were determined in extracts of transmural myocardial biopsies using HPLC. TTC staining revealed the absence of necrosis in this model. Drug administration did not affect myocardial ATP metabolism and cardiac function in the normal myocardium. Ischemia caused about 50% ATP depletion and accumulation of nucleosides. The ratio between adenosine/inosine at the end of ischemia was 1:10, 1:1, 1:1 and 10:1 in the control, EHNA-, NBMPR- and EHNA/NBMPR-group, respectively. Upon reperfusion, both nucleosides washed out from the myocardium in the control and EHNA-group while retained in the myocardium in the NBMPR and EHNA/NBMPR groups. Ventricular dysfunction 'stunning' persisted in the control group (52%) and in the EHNA-treated group (32%) after 30 min of reperfusion. Significant improvement of function was observed in the EHNA group only after 60 min of reperfusion. LV function recovered in the NBMPR- and EHNA/NBMPR-treated groups during reperfusion. ATP recovery occurred only when animals were pretreated with the combination of EHNA/NBMPR and remained depressed in the control group and EHNA and NBMPR-treated groups. At post mortem, TTC staining revealed the absence of myocardial necrosis. Superior myocardial protection was observed with inhibition of nucleoside transport by NBMPR alone or in combination with inhibition of adenosine deaminase by EHNA. Selective blockade of nucleoside transport by NBMPR is more cardioprotective than inhibition of adenosine deaminase alone in attenuating myocardial stunning. It is not known why EHNA partially inhibit adenosine deaminase, in vivo.
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PMID:Differential cardioprotection with selective inhibitors of adenosine metabolism and transport: role of purine release in ischemic and reperfusion injury. 954 45

Several studies have shown that maintenance of glycolysis limits the metabolic and functional consequences of low-flow ischemia. Because diabetic animals are known to have impaired glycolytic metabolism coupled with increased flux through the aldose reductase (AR) pathway, we hypothesized that inhibition of AR would enhance glycolysis and thereby improve metabolic and functional recovery during low-flow ischemia. Hearts (n = 12) from nondiabetic control and diabetic rats were isolated and retrograde perfused using 11 mM glucose with or without the AR inhibitor zopolrestat (1 microM). Hearts were subjected to 30 min of low-flow ischemia (10% of baseline flow) and 30 min of reperfusion. 31P NMR spectroscopy was used to monitor time-dependent changes in phosphocreatine (PCr), ATP, and intracellular pH. Changes in the cytosolic redox ratio of NADH to NAD+ were obtained by measuring the ratio of tissue lactate to pyruvate. Effluent lactate concentrations and oxygen consumption were determined from the perfusate. AR inhibition improved functional recovery in both control and diabetic hearts, coupled with a lower cytosolic redox state and greater effluent lactate concentrations during ischemia. ATP levels during ischemia were significantly higher in AR-inhibited hearts, as was recovery of PCr. In diabetic hearts, AR inhibition also limited acidosis during ischemia and normalized pH recovery on reperfusion. These data demonstrate that AR inhibition maintains higher levels of high-energy phosphates and improves functional recovery upon reperfusion in hearts subjected to low-flow ischemia, consistent with an increase in glycolysis. Accordingly, this approach of inhibiting AR offers a novel method for protecting ischemic myocardium.
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PMID:Metabolic effects of aldose reductase inhibition during low-flow ischemia and reperfusion. 968 14

Brain ischemia initiates a complex cascade of metabolic events, several of which involve the generation of nitrogen and oxygen free radicals. These free radicals and related reactive chemical species mediate much of damage that occurs after transient brain ischemia, and in the penumbral region of infarcts caused by permanent ischemia. Nitric oxide, a water- and lipid-soluble free radical, is generated by the action of nitric oxide synthases. Ischemia causes a surge in nitric oxide synthase 1 (NOS 1) activity in neurons and, possibly, glia, increased NOS 3 activity in vascular endothelium, and later an increase in NOS 2 activity in a range of cells including infiltrating neutrophils and macrophages, activated microglia and astrocytes. The effects of ischemia on the activity of NOS 1, a Ca2+-dependent enzyme, are thought to be secondary to reversal of glutamate reuptake at synapses, activation of NMDA receptors, and resulting elevation of intracellular Ca2+. The up-regulation of NOS 2 activity is mediated by transcriptional inducers. In the context of brain ischemia, the activity of NOS 1 and NOS 2 is broadly deleterious, and their inhibition or inactivation is neuroprotective. However, the production of nitric oxide in blood vessels by NOS 3, which, like NOS 1, is Ca2+-dependent, causes vasodilatation and improves blood flow in the penumbral region of brain infarcts. In addition to causing the synthesis of nitric oxide, brain ischemia leads to the generation of superoxide, through the action of nitric oxide synthases, xanthine oxidase, leakage from the mitochondrial electron transport chain, and other mechanisms. Nitric oxide and superoxide are themselves highly reactive but can also combine to form a highly toxic anion, peroxynitrite. The toxicity of the free radicals and peroxynitrite results from their modification of macromolecules, especially DNA, and from the resulting induction of apoptotic and necrotic pathways. The mode of cell death that prevails probably depends on the severity and precise nature of the ischemic injury. Recent studies have emphasized the role of peroxynitrite in causing single-strand breaks in DNA, which activate the DNA repair protein poly(ADP-ribose) polymerase (PARP). This catalyzes the cleavage and thereby the consumption of NAD+, the source of energy for many vital cellular processes. Over-activation of PARP, with resulting depletion of NAD+, has been shown to make a major contribution to brain damage after transient focal ischemia in experimental animals. Neuronal accumulation of poly(ADP-ribose), the end-product of PARP activity has been demonstrated after brain ischemia in man. Several therapeutic strategies have been used to try to prevent oxidative damage and its consequences after brain ischemia in man. Although some of the drugs used in early studies were ineffective or had unacceptable side effects, other trials with antioxidant drugs have proven highly encouraging. The findings in recent animal studies are likely to lead to a range of further pharmacological strategies to limit brain injury in stroke patients.
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PMID:Oxidative stress in brain ischemia. 998 55


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