UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
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Excessive or prolonged stimulation of N-methyl-D-aspartate (NMDA) receptors appears to play an important role in many neurodegenerative processes in brain through a process known as excitotoxicity. This study examined the effects of ethanol on NMDA receptor-mediated excitotoxicity in primary neuronal cultures obtained from embryonic rat whole brain. Neurotoxicity was quantitated by measuring the amount of lactate dehydrogenase released into the media during a 20-hr time period following NMDA washout. Exposure of 12- to 14-day-old cultures to NMDA in Mg(2+)-free HEPES buffer (pH 7.4) for a 25-min period resulted in a concentration-dependent toxicity (EC50 = 54 microM). Time-course experiments showed that exposure to NMDA for as little as 5 min was excitotoxic and reached a plateau after a 20-min exposure period. Preincubation of the cultures with ethanol (25 to 200 mM) resulted in a concentration-dependent inhibition of NMDA-mediated toxicity with approximately 38% inhibition produced by 25 mM ethanol and essentially complete inhibition at 200 mM ethanol (IC50 = 60 mM). Increasing the glycine concentration to 100 microM did not potentiate NMDA neurotoxicity or antagonize the neuroprotective effect of ethanol. NMDA-Mediated excitotoxicity was reduced by approximately 50% by the glycine antagonist 7-chlorokynurenate (50 microM). Ethanol (50 mM) reduced NMDA neurotoxicity similar to 7-chlorokynurenate, and the two together produced greater inhibition than either alone. These results show that intoxicating concentrations of ethanol can potently inhibit NMDA receptor-mediated excitotoxicity and may have important implications in terms of ethanols interactions with brain trauma, ischemia, and other neuropathologies associated with NMDA receptor-mediated neurotoxicity.
Alcohol Clin Exp Res 1993 Feb
PMID:Ethanol inhibits NMDA receptor-mediated excitotoxicity in rat primary neuronal cultures. 838 26

We employed hyperosmotic concentrations of penetrating cryoprotective agents (CPA) to store the isolated rat hearts unfrozen at subzero temperatures. The effect of acute exposure to CPA was assessed by flushing the hearts with CP-14, a cardioplegic solution, containing methanol (MeOH), ethanol (EtOH), ethylene glycol (EG), or propylene glycol (PG) for 2 min and reperfusing immediately with Krebs-Henseleit buffer in a working-heart model. The maximal doses that did not cause irreversible suppression of heart function were: MeOH, 1.78 M; EtOH, 1.27 M; EG, 0.84 M; and PG, 0.87 M. For nonfreezing storage, the hearts were flushed with CP-14 containing the highest tolerable concentrations of MeOH, EtOH, EG, or PG, stored for 6 h at -3.7, -2.8, and -1.4 degrees C, respectively, and then reperfused. Control cardiac output (CO) was 76.2 +/- 1.8 ml/min. Post-reperfusional recovery of CO was 86% in MeOH hearts, 82% in EtOH hearts, 76% in EG hearts, and 79% in PG hearts. Thus MeOH offered not only the least cardiac-suppressing effect but the lowest nonfreezing storage temperature. When storage time was extended, recovery and myocardial ATP level decreased with time in hearts flushed with CP-14 + 1.78 M MeOH and stored at -3.7 degrees C. The decay of function was faster than the decay of ATP level, suggesting energy was better preserved than function. The low return of function, however, may be related to CPA toxicity, osmotic stress, and ischemia/reperfusion injury. Nonfreezing storage at subzero temperatures using these CPAs may provide a novel approach to long-term cardiac preservation.
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PMID:Subzero nonfreezing storage of the mammalian cardiac explant. I. Methanol, ethanol, ethylene glycol, and propylene glycol as colligative cryoprotectants. 840 87

Peroxide production in cultures of Saccharomyces cerevisiae was measured using the H2O2-sensitive fluorescent probe 2',7'-dichlorofluorescein diacetate (DCFH-DA) and flow cytometry. Aeration of cultures of S. cerevisiae exposed to a period of hypoxia was found to induce elevated levels of peroxide that were 100-fold higher than the levels observed in cultures maintained under exclusively aerated or hypoxic conditions. Simultaneous viability analysis, using the fluorescent DNA-intercalating dye propidium iodide, indicated that the increase in peroxide generation preceded cell damage and death. Various agents were found to influence the effect of peroxides on cell viability. The addition of ethanol to hypoxic stationary cultures dramatically increased the rate of cell death without further increasing the amount of peroxide produced, while glucose inhibited peroxide production and decreased the rate of cell death. Surprisingly, elevated peroxide levels of hypoxic/reaerated cultures were maintained upon addition of KH2PO4, although the cells remained viable for extended periods of time when compared to control and other test cultures. Similarities between our observations and those of other investigators using anoxic/reperfused organs suggest that hypoxic/reaerated yeast cultures may be a useful model system to study ischemia-dependent tissue destruction of mammals.
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PMID:Characterization of hypoxia-dependent peroxide production in cultures of Saccharomyces cerevisiae using flow cytometry: a model for ischemic tissue destruction. 847 5

Although accounting for 2% of body weight, brain has one of the greatest metabolic rates compared with other organs and systems. The energy metabolic consum is expended mainly in the maintenance of ionic gradient, essential to neuronal activity. Brain receives energy substrates from circulation, with interference of blood brain barrier (BBB). Glucose is the main substrate and has a metabolic rate so high as 150 g/day (0.7 mM/G/min). At cellular level, metabolism of glucose seems to be controlled by phosphofructokynase. If the cellular level were high enough, manose and other products like fructose 1,6 biphosphate, pyruvate, lactate and acetate can be used in the place of glucose. Lactate, when oxyded, consums at least 21% of the cerebral needs of O2. In ischemia and inflammatory infections, brain tissue produces lactate instead of use it. Ketone bodies reduce cerebral needs of glucose; in view of the disturbances that occur in cerebral production of succinyl CoA and guanosine 3 phosphate (GTP), they must be considered as complementary substrate but not as an alternative one. Although they can be metabolized, there are no evidences that brain could produce energy from systemic free fatty acids, even when hypoglicemia is present. Ethanol and glycerol are considered only at experimental level. Brain uptake of aminoacids occur better for long chain aminoacids, specially valine. The aminoacids that are synthetised in the brain (aspartate, gluconate and alanine) show the lower absortion rates. All aminoacids should be oxided to CO2 and H2O. Even when glucose consum is reduced to 30%, aminoacid accounts for only 10% of the energetic expenditure of the brain. To maintain cerebral glucose and oxygen supply to the brain, blood flow must be at least 800 ml/min. The regulation of supply and consumption of energy substrate by the brain is changed in few situations. Among them, are included the oxidation of lactate immediately before milk diet early in development and utilization of ketone bodies at the beginning of lactation. This review includes a brief discussion about the relevance of glucose as the main energy substrate for cerebral tissue in different ages and ischemia or hypoxia.
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PMID:[Control of supply and use of energy substrates in the encephalon]. 858 33

This study determined the role that oxygen-derived free radicals played in the production of gastric injury in rats challenged orally with concentrated ethanol or subjected to vascular compromise. In the ethanol study, rats were pretreated with a variety of free radical scavengers or enzyme inhibitors prior to exposing the stomach to 100% ethanol. At sacrifice, the degree of macroscopic damage to the glandular gastric mucosa was quantified. In separate studies, the effects of ethanol on gastric mucosal levels of enaldehydes (malondialdehyde and 4-hydroxynonenal) were examined as an index of lipid peroxidation. Superoxide dismutase and catalase pretreatment were without benefit in reducing injury in our ethanol model, excluding potential contributory roles for the superoxide anion or hydrogen peroxide, respectively. Dimethyl sulfoxide and desferoxamine were likewise without protective capabilities, eliminating a role for the hydroxyl radical. Allopurinol, a xanthine oxidase inhibitor, provided no protection under acute conditions, even though partial protection was noted when administered chronically. Further, enaldehyde levels were not increased over control levels in alcohol-exposed mucosa, indicating no enhanced lipid peroxide formation. In contrast, in animals in which ischemia to the stomach was induced followed by reperfusion, marked gastric injury was observed in combination with enhanced enaldehyde levels. Prevention of enaldehyde formation by a 21-aminosteroid concomitantly prevented injury induced by ischemia-reperfusion. These findings support the conclusion that ischemia-reperfusion injury to the stomach is an oxygen-derived free radical process whereas ethanol-induced injury clearly involved some other process. Although allopurinal was partially protective against ethanol damage when administered chronically, observations in other models of injury suggest that this action is independent of its inhibitory effect on xanthine oxidase.
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PMID:Gastric injury induced by ethanol and ischemia-reperfusion in the rat. Differing roles for lipid peroxidation and oxygen radicals. 865 47

The purpose of this study was to evaluate the protective effect of a new endotoxin analogue, monophosphoryl lipid A (MLA) in a rabbit model of myocardial ischemia/reperfusion and to show if this protection was mediated via synthesis of 70 kDa heat shock protein (HSP 70). Three groups of New Zealand White rabbits underwent 30 min coronary occlusion, followed by 4 hours reperfusion. First group of rabbits (n = 6) were treated with 0.35 ml vehicle (40 % propylene glycol, 10 % ethanol in water). The second and third group of rabbits (n = 6-8) were treated with MLA (35 micrograms/kg, i.v.) 12 and 24 hours prior to ischemia and reperfusion. MLA treatment either 12 or 24 h prior to ischemia/reperfusion demonstrated significantly reduced infarct size (12.5 +/- 1.7 and 14.7 +/- 2.1% for 12 and 24 h) when compared with vehicle control (40.4 +/- 8.6%, mean +/- S.E.M, p < 0.05). No significant differences in the infarct size was observed between the 12 and 24 h MLA treated groups. The area at risk was not significantly different between the three groups. Baseline values of heart rate, systolic and diastolic blood pressure were not significantly different between the control and MLA treated groups. However, the systolic as well as diastolic blood pressure during reperfusion were significantly lower in rabbits treated with MLA. Western blot analysis of the protein extracts of the hearts (n = 2/group) demonstrated no increase in the expression of the inducible form of HSP 70 following treatment with MLA. We conclude that MLA has significant anti-infarct effect in rabbit which is not mediated by the cardioprotective protein HSP 70. The anti-infarct effect of this drug is superior to the reported protective effects of delayed ischemic or heat stress preconditioning. We hypothesize that the pharmacologic preconditioning afforded by MLA is accomplished via a unique pathway that bypasses the usual intracellular signaling pathways which lead to the myocardial protection with the expression of heat shock proteins.
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PMID:Monophosphoryl lipid A induces pharmacologic 'preconditioning' in rabbit hearts without concomitant expression of 70-kDa heat shock protein. 870 70

Inactivation of lipoamide dehydrogenase (LipDH) by the Cu(II)/H2O2 Fenton system (SF-Cu(II): (5.0 microM Cu(II), 3.0 mM H2O2) was enhanced by catecholamines (CAs), namely, epinephrine, levoDOPA (DOPA), DOPAMINE, 6-hydroxyDOPAMINE (OH-DOPAMINE) and related compounds (DOPAC, CATECHOL, etc.). After 5 min incubation with the Cu(II)/H2O2/CA system (0.4 mM CA), the enzyme activity decayed as indicated by the following percentage values (mean +/- S.D.; in parenthesis, number of determinations): SF-Cu(II) alone, 43 +/- 10 (18); SF-Cu(II) + epinephrine, 80 +/- 9 (5); SF-Cu(II) + DOPA, 78 +/- 2 (4); SF + Cu(II) + DOPAMINE, 88 +/- 7 (5); SF-Cu(II) + OH-DOPAMINE 87 +/- 6 (7); SF-Cu(II) +/- DOPAC, 88 +/- 3 (6); SF-Cu(II) + catechol, 85 +/- 6 (5). In all cases P < 0.05, with respect to the SF-Cu(II) control sample. CAs effect was concentration-dependent and at the 0-100 microM concentration range, it varied with the CA structure. Above the 100 microM concentration, CAs were equally effective and produced 90-100% enzyme, inactivation (Figure 2). In the absence of oxy-radical generation, the enzyme specific activity (mean +/- S.D.) was 149 +/- 10 (24) mumol NADH/min/mg protein. Assay of HO. production by the Cu(II)/H2O2/CA system in the presence of deoxyribose (TBA assay) yielded values much greater than those obtained omitting CA. Hydroxyl radical production depended on the presence of Cu(II) and H2O2 and significant H. values were obtained with OH-DOPAMINE, DOPAC, epinephrine, DOPAMINE, DOPA and catecol supplemented systems (Table 2). LipDH (1.0 microM) inhibited 50-80% deoxyribose oxidation, the inhibition depending on the CA structure (Table 2). Native catalase (20 micrograms/ml) and bovine serum albumin (40 micrograms/ml) effectively prevented LipDH inactivation by the Cu(II)/H2O2/CA system; denaturated catalase, SOD, 0.3 M mannitol, 6.0 mM ethanol and 0.2 M benzoate were less effective or did not protect LipDH (Table 3). Incubation of CAs with the Cu(II)/H2O2 system produced a time and Cu(II)-dependent destruction of CAs, the corresponding o-quinone, production as illustrated with epinephrine (figures 6 and 7), as illustrated with epinephrine and DOPAMINE (Table 4). These results support LipDH inactivation by (a) reduction of Cu(II) to Cu(I) by CAs followed by Cu-catalyzed production of HO. from H2O2; (b) CA oxidation followed by the corresponding o-quinone interaction with LipDH. CAPTOPRIL, N-acetylcysteine, mercaptopropionylglycine and penicillamine prevented to various degree LipDH inactivation by the Cu(II)/H2O2/CA systems (Table 1). The former was the most effective and 0.4 mM CAPTOPRIL prevented about 95-100% the effect of Cu(II)/H2O2/CA systems supplemented with epinephrine, DOPAMINE and OH-DOPAMINE (Figures 3 and Table 1). LipDH increased and CAPTOPRIL inhibited epinephrine oxidation by Cu(II)/H2O2 (Figures 4 and 5). Since un-physiological concentrations of CAs and Cu(II) may be released in the myocardium after ischemia-reperfusion, the summarized observations may contribute to explain myocardial damage in that condition.
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PMID:[Inactivation of the myocardial lipoamide dehydrogenase by catecholamines. Prevention by captopril and other thiol compounds]. 872 69

Ischemia and reperfusion cause the production of oxygen free radicals. These damage grafts or disrupt normal vascular homeostatic mechanisms, with a parallel reduction in endothelial nitric oxide and adenosine 3',5'-cyclic monophosphate levels. We hypothesized that lung preservation failure may be related to these events. To improve lung preservation, we prepared a new ET-Kyoto solution, which contains N-acetylcysteine (a radical scavenger), nitroglycerin (to elevate the nitric oxide level), and dibutyryl adenosine 3',5'-cyclic monophosphate (to elevate the adenosine 3',5'-cyclic monophosphate level) and examined its efficacy in a canine single-lung transplantation model. Lungs were flushed with new ET-Kyoto solution (group I, n = 9), basal ET-Kyoto solution (group II, n = 6), basal ET-Kyoto solution plus ethanol and propylene glycol (solvents of nitroglycerin; group III, n = 6), or low-potassium dextran glucose solution (group IV, n = 6), and stored at 4 degrees C for 30 hours. After left single-lung transplantation, the right main bronchus and right pulmonary artery were ligated and the functions of the transplanted lung were assessed for 6 hours. Arterial oxygen tension was significantly higher in group I than in groups II, III, and IV (p < 0.05). Peak inspiratory pressure and wet-to-dry lung weight ratio were significantly lower in group I than in groups II and IV (p < 0.01). Histologic and ultrastructural studies showed better preservation in group I than in groups II, III, and IV. We conclude that the new ET-Kyoto solution provides enhanced 30-hour lung preservation.
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PMID:A newly developed solution enhances thirty-hour preservation in a canine lung transplantation model. 880 Jan 41

The purpose of this study was to evaluate the protective effect of a new endotoxin analogue, monophosphoryl lipid A (MLA) in a rabbit model of myocardial ischemia/reperfusion and to show if this protection was mediated via synthesis of 70 kDa heat shock protein (HSP 70). Three groups of New Zealand White rabbits underwent 30 min coronary occlusion, followed by 4 hours reperfusion. First group of rabbits (n = 6) were treated with 0.35 ml vehicle (40% propylene glycol, 10% ethanol in water). The second and third group of rabbits (n = 6-8) were treated with MLA (35 micrograms/kg, i.v.) 12 and 24 hours prior to ischemia and reperfusion. MLA treatment either 12 or 24 h prior to ischemia/reperfusion demonstrated significantly reduced infarct size (12.5 +/- 1.7 and 14.7 +/- 2.1% for 12 and 24 h) when compared with vehicle control (40.4 +/- 8.6%, mean +/- S.E.M, p < 0.05). No significant differences in the infarct size was observed between the 12 and 24 h MLA treated groups. The area at risk was not significantly different between the three groups. Baseline values of heart rate, systolic and diastolic blood pressure were not significantly different between the control and MLA treated groups. However, the systolic as well as diastolic blood pressure during reperfusion were significantly lower in rabbits treated with MLA. Western blot analysis of the protein extracts of the hearts (n = 2/group) demonstrated no increase in the expression of the inducible form of HSP 70 following treatment with MLA. We conclude that MLA has significant anti-infarct effect in rabbit which is not mediated by the cardioprotective protein HSP 70. The anti-infarct effect of this drug is superior to the reported protective effects of delayed ischemic or heat stress preconditioning. We hypothesize that the pharmacologic preconditioning afforded by MLA is accomplished via a unique pathway that bypasses the usual intracellular signaling pathways which lead to the myocardial protection with the expression of heat shock proteins.
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PMID:Monophosphoryl lipid A induces pharmacologic 'preconditioning' in rabbit hearts without concomitant expression of 70-kDa heat shock protein. 881 12

DL-1,3-butanediol (DL-BD) is an ethanol dimer which affords cerebral protection in various experimental models of hypoxia and ischemia but its mechanism of action is unknown. DL-BD is a ketogenic alcohol and it has been proposed that its protective effect was accomplished through cerebral utilization of ketone bodies. Since DL-BD is a racemic, its metabolic effects could be due to D, L or both isomers. The effects of equimolar doses of DL-, D- and L-BD (25 mmol/Kg) on cerebral metabolism were studied by measuring the cortical levels of the main glycolytic (glycogen, glucose, glucose 6-phosphate, fructose 1,6-diphosphate, pyruvate and lactate) and citric acid cycle (citrate, alpha-ketoglutarate and L-malate) intermediates. The two BD isomers exerted different effects on cerebral metabolism. Unlike L-BD, D- and DL-BD treatments resulted in a slight (+10%) but significant increase in citrate level whereas L-BD treatment led to significant reduction in pyruvate (-12%) and lactate (-24%) levels. These effects were apparently not linked to hyperketonemia, since DL-BHB treatment, which mimicked hyperketonemia induced by DL-BD, had no effect on cerebral metabolites but might be due to intracerebral metabolism of BD.
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PMID:Effect of D- and L-1,3-butanediol isomers on glycolytic and citric acid cycle intermediates in the rat brain. 884 93

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