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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the study reported here was to explore a new strategy for the aerobic preservation of transplants using stable concentrated fluorocarbon emulsions as an oxygen delivery system. Fluorocarbons (FCs) are synthetic molecules, chemically and biologically inert, with a high oxygen-dissolving capacity. As they do not mix with water, it is necessary to emulsify them for intra-vascular use. Perfluorooctyl bromide (or perflubron) can be emulsifled with egg-yolk phospholipid (EYP), a nontoxic emulsifiant. The recent adjunction of amphiphilic fluorocarbon-hydrocarbon diblock molecules allows the obtaining of stable emulsions. By contrast with hemoglobin, fluorocarbons release oxygen following Henry's linear law rather than Barcroft's sigmoid curve. Release of oxygen by the FCs is only slightly influenced by temperature, which is an advantage for the preservation of organs. We tested a new 90% w/v fluorocarbon stem emulsion (perflubron/EYL/F6H10) diluted to 36% w/v with a hydroelectrolytic solution containing albumin, on four multiple organ blocks (MOBs; heart-lungs, liver, pancreas, kidneys, small intestine) of rats (EMOBs). Five control MOBs were perfused with a 50% v/v mixture of rat-blood and Krebs solution (KBMOBs). The lungs were ventilated with a FiO2 = 100%. In all cases the survival of the MOBs was greater than 210 min, with stable hemodynamics and preserved hydroelectrolytic and acid-base balances. The levels of lactate, amylase, and CK of the EMOBs were inferior (P < 0.05) to those of the KBMOBs between the first and the second hour. The diuresis of the EMOBs was higher (P < 0.05) than that of the KBMOBs (5.65 +/- 1.76 vs 1.21 +/- 0.28 mg/min). The production of bile, and the AST and ALT levels, were not significantly different. The PaO2 of the EMOBs was higher (P < 0.01) than for the KBMOBs. In normothermy, the maintenance of an aerobic metabolism using the FC emulsion caused less damage to the organs. Aerobic preservation of organs using FC emulsions therefore appears to be an attractive alternative to the presently used cold ischemia.
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PMID:Aerobic preservation of organs using a new perflubron/lecithin emulsion stabilized by molecular dowels. 866 Dec 39

Elevated levels of glutamate and aspartate have been implicated in the pathogenesis of neural injury and death induced by ischemia. The mechanism(s) whereby they escape into the extracellular environment have been a subject of controversy. This study evaluated the contribution of phospholipases and protein kinases to ischemia-evoked glutamate and aspartate release from the ischemic/reperfused rat cerebral cortex. Changes in the extracellular levels of these amino acids during four-vessel occlusion elicited global cerebral ischemia were examined using a cortical cup technique. Ischemia-evoked amino acid release was compared in control vs. drug treated animals, in which selective inhibitors of phospholipases and protein kinases were applied topically onto the cerebral cortex. The phospholipase inhibitors tested included 4-bromophenacyl bromide, a non-selective inhibitor; 7,7-dimethyleicosadienoic (DEDA), an inhibitor of secretory type phospholipase A2 (PLA2); AACOCF3, an inhibitor of the Ca2(+)-dependent cytoplasmic form of PLA2, HELSS, which inhibits a Ca(2+)-independent cytoplasmic PLA2, and U73122, a selective inhibitor of phospholipase C (PLC). All five phospholipase inhibitors significantly attenuated glutamate and aspartate release into the extracellular milieu, indicating the possibility that several forms of the enzyme are likely to be involved. The protein kinase C (PKC) inhibitor, chelerythrine chloride, also reduced excitatory amino acid efflux, wheres the PKC activator phorbol 12-myristate 13-acetate (PMA) enhanced their release. The non-selective kinase inhibitor, staurosporine, and H-89, which selectively inhibits protein kinase A, did not reduce ischemia-evoked amino acid efflux. These results suggest that ischemia-evoked release of the excitatory transmitters amino acids is a result, in part, of the activation of phospholipases A2 and C, with PKC involvement in the transduction process. Destabilization and deterioration of the plasma membrane, as a consequence of phospholipid hydrolysis, may allow these transmitter amino acids to diffuse down their concentration gradients into the extracellular fluid.
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PMID:Mechanisms of glutamate and aspartate release in the ischemic rat cerebral cortex. 888 99

The mechanisms of ischemic cell damage are still not fully understood. It has been shown that alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA)/kainate receptor antagonists, such as 6-nitro-7- sulphamoyl-benzo-(f)-quinoxaline-2, 3-dione (NBQX), are neuroprotective in models of transient forebrain ischemia, even when applied during recovery, indicating that nonNMDA receptors may play a pivotal role in ischemic cell damage. In the present series of experiments, we studied whether transient cerebral ischemia causes changes in the extent of mRNA editing of AMPA/kainate receptor subunits, a reaction critical for the control of calcium flux through nonNMDA receptor ion channels. Transient cerebral ischemia was produced in rats using the four-vessel occlusion (4-VO) model. After 30 min of ischemia, brains were recirculated for 4, 8, or 24 h. Total RNA was extracted from the cortex, striatum, and hippocampus in order to analyze the extent of mRNA editing of the glutamate receptor subunits GluR2, GluR5, and GluR6. RNA was converted by reverse transcription into cDNA, which was used as a template for subunit-specific polymerase chain reaction (PCR) to amplify a product across the edited base A (A edited to I in the second transmembrane-spanning regions of GluR2, GluR5, and GluR6). PCR products were analyzed with the restriction enzyme Bbv 1, which recognizes the cDNA sequence GCAGC originating from unedited but not that originating from edited GluR2, GluR5, or GluR6 mRNA (GCGGC, the base I is read as G). Restriction digests were electrophoresed, and the bands visualized with ethidium bromide and then photographed. The extent of mRNA editing of the different subunits was quantified using image analysis and appropriate standards. In all control brains studied, GluR2 mRNA was completely edited and remained so after reversible cerebral ischemia. The extent of GluR5 mRNA editing was significantly upregulated in the striatum (from 39 +/- 6% in controls to 57 +/- 9 and 56 +/- 7 after 4 and 8 h of recovery, respectively, p < 0.05 versus control) but not in the cortex and hippocampus. The extent of GluR6 mRNA editing was significantly reduced after 24 h of recovery: in the cortex, from 92 +/- 1 to 78 +/- 6% (p < 0.01); in the striatum, from 91 +/- 2 to 79 +/- 1% (p < 0.001); and in the hippocampus, from 90 +/- 3 to 80 +/- 2% (p < 0.05). A significant reduction was already apparent in the striatum after 4 h of recovery (p < 0.05). Results indicate that mRNA editing is regulated differently in each of the glutamate receptor subunits GluR2, GluR5, and GluR6 after transient cerebral ischemia. The ischemia-induced upregulation of GluR5 mRNA editing observed in the striatum may be indicative of a higher sensitivity to transient ischemia of neurons that exhibit a large fraction of unedited GluR5 mRNA. This assumption is corroborated by the observation (Mackler and Eberwine, 1993) that GluR5 mRNA is completely unedited in neurons of the hippocampal CA1-subfield, a region most vulnerable to transient cerebral ischemia. Whether the decrease in GluR6 mRNA editing observed in all brain structures after ischemia results from a disturbance of the editing reaction or from glial proliferation will have to be established in further experiments. Studying ischemia-induced changes in mRNA editing of glutamate receptor subunits GluR5 and GluR6 may help to elucidate the molecular mechanisms of ischemic cell damage.
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PMID:RNA editing of glutamate receptor subunits GluR2, GluR5 and GluR6 in transient cerebral ischemia in the rat. 896 93

Few studies have correlated the occurrence of leukocytes with the time course of ischemia-reperfusion (I-R)-induced tissue injury in skeletal muscle. The goal of this study was to test the hypothesis that leukocytes were responsible for not only the onset, but progression of parenchymal cell injury within skeletal muscle following no-flow ischemia. Thirteen male Wistar rats (150-250 g) were randomly allocated to either a control (no I-R; n = 3), I-R (n = 5), or a leukopenic I-R group (n = 5). Under halothane anesthesia, the extensor digitorum longus muscle was prepared for intravital microscopy to allow video recording of microvascular perfusion and leukocyte flow behavior following 3 hr no-flow ischemia of the hindlimb. Tissue injury was assessed as the ratio of ethidium bromide (impermeant dye)-labeled nuclei to bisbenzimide (permeant dye)-labeled nuclei (E/B). During reperfusion, the I-R group showed a progressive decline in the number of perfused capillaries (N(C)) (from 19.37 +/- 0.04 to 3.34 +/- 1.18), while leukopenic and control rats were not significantly different. In the I-R group, the number of rolling leukocytes increased from 4.05 +/- 1.93 to 14.77 +/- 1.33 at the onset of reperfusion and remained stable throughout the reperfusion period. The number of stuck leukocytes, in the I-R group, progressively increased from 1.41 +/- 0.01 prior to ischemia to 4.66 +/- 0.01 at the onset of reperfusion to 11.96 +/- 0.01 after 90 min. The index of tissue injury (EIB) increased asymptotically from 0.60 +/- 0.02 to 0.95 +/- 0.01 after 90 min of reperfusion in the I-R group, while leukopenia significantly reduced both the magnitude of tissue injury (i.e., 35% reduction from untreated I-R group) and the onset of such injury. In spite of the benefit afforded by leukopenia, evidence of tissue injury persisted (20% above control baseline level). We conclude that although leukocytes were responsible for the onset of parenchymal injury in skeletal muscle following 3 hr no-flow ischemia they are not the sole mediators of such injury.
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PMID:Leukocyte activity and tissue injury following ischemia-reperfusion in skeletal muscle. 899 28

Ischemia/reperfusion of the small intestine can lead to metabolic and structural alterations in the mucosa. Cellular dysfunction occurs when mitochondrial metabolism is compromised, which may ultimately lead to impaired organ function. The aims of this study were to assess the suppression of cellular and mitochondrial oxidative metabolism and involvement of mitochondria in the ischemia/reperfusion injury. The mitochondria were prepared from isolated enterocytes obtained from the small intestine of anesthetized adult rats following different time periods of ischemia and ischemia followed by 5 min reperfusion. Cellular and mitochondrial function were assessed using MTT (3-(4,5-Dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide) reduction assay. Ischemia of increasing time periods caused a progressive decrease in cellular and mitochondrial MTT reduction in enterocytes and reperfusion showed further decrease of MTT formazan formation. Inclusion of 1 mM succinate, as respiratory substrate, showed reversal of suppression of mitochondrial function in 30-60 min ischemia whereas 90 min ischemia or short time period ischemia followed by 5 min reperfusion indicated an irreversible damage to mitochondria. This study indicated that mitochondria are a sensitive target of damage due to oxygen deficiency and possibly due to sudden burst of oxygen free radicals. Mitochondria can withstand short periods of ischemia whereas long duration ischemia or reperfusion results in irreversible damage to mitochondrial function.
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PMID:Enterocyte viability and mitochondrial function after graded intestinal ischemia and reperfusion in rats. 905 84

We tested the hypothesis that ischemic preconditioning (PC) of skeletal muscle provided tolerance to a subsequent ischemic event 24 h later, and that such protection was due to nitric oxide (NO). Male Wistar rats, anesthetized with halothane, were randomly assigned to groups: ischemic (no PC; n = 11), PC (n = 11), PC + N-nitro-L-arginine methyl ester (L-NAME; 100 micromol/l; n = 5), PC + N-nitro-D-arginine methyl ester (100 micromol/l; n= 4), PC + aminoguanidine (AMG; 100 micromol/l; n = 4), ischemic + L-NAME (n= 4), or ischemic + AMG (n = 4). PC consisted of 5x 10 min of ischemia and reperfusion, and, 24 h later, 2 h of ischemia were induced by a tourniquet applied to the limb. With the use of intravital microscopy, the number of perfused capillaries (Npc) in the extensor digitorum longus (EDL) muscle was measured over a 90-min reperfusion period. The ratio of ethidium bromide- to bisbenzimide-labeled nuclei was used to estimate tissue injury. PC preserved Npc (23.6 +/- 2.5) following 2 h of ischemia compared with sham muscles (11.5 +/- 5.1), significantly elevating inducible NO synthase (iNOS) activity (81% increase), but did not afford protection to the parenchyma. L-NAME and AMG prevented ischemia-reperfusion-induced reduction in Npc in muscles without PC. However, after 90 min of reperfusion, L-NAME (Npc = 15.0 +/- 1.7), but not AMG (Npc = 22.8 +/- 3.1), significantly reduced the microvascular protection afforded by PC. We conclude that PC of the EDL muscle resulted, 24 h later, in protection to microvascular perfusion only, and that such protection was due to NO from sources other than iNOS.
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PMID:Ischemic tolerance in skeletal muscle: role of nitric oxide. 968

Loss of amino acids into the coronary artery perfusate, which is exacerbated during anoxic stress, may have important implications for the ability of hearts subjected to ischemia or anoxia to recover function during reoxygenation. This work investigates the mechanisms underlying the amino acid efflux. Rat Langendorff heart preparations were used to study amino acid loss into coronary artery perfusates during anoxia or anoxia/reoxygenation sequences. Coronary flow rates, heart rates and intra-aortic pressures were recorded. Changes in myocardial amino acid concentrations were equated with amino acid levels in collected anoxic perfusate. With the exception of taurine, the differences in amino acid levels between normoxic and anoxic hearts were smaller than the amounts lost into the coronary perfusates, indicating ongoing replenishment of most amino acids during the anoxic episode. Fifteen-minute periods of exposure to low oxygen levels (P02 18-20 mmHg) resulted in large percentage increases in perfusate amino acid levels which returned slowly towards control levels upon reoxygenation. Anion channel blockers, anthracene-9-carboxylic acid, furosemide, and 4-acetamido-4-isothiocyanostilbene-2,2'-disulfonic acid (SITS), depressed anoxia-elicited increases in amino acid release. Phospholipase inhibition with quinacrine, 4-bromophenacyl bromide and 7,7-dimethyl-eicosadenoic acid (DEDA) depressed the anoxia-evoked release of amino acids. Combined applications of SITS and DEDA exhibited additive effects, virtually abolishing anoxia-evoked release of all the amino acids. The protein kinase C inhibitor, chelerythrine chloride, and the protein tyrosine kinase inhibitors, genistein and lavendustin A, inhibited anoxia-evoked amino acid release. Polyunsaturated fatty acids, arachidonic and linoleic, reduced anoxia-evoked amino acid release whereas monosaturated (oleic) and saturated (stearic) acids were ineffective. The glutamate transport inhibitor, dihydrokainate, depressed anoxia-evoked glutamate and aspartate release. These results suggest that at least three possible mechanisms for the anoxia-evoked amino acid efflux including (a) diffusional release through volume activated anion channels, (b) leakage across myocyte plasma membranes as a consequence of phospholipase activation and (c) reversal of Na+ dependent high-affinity transporters.
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PMID:Mechanisms of amino acid release from the isolated anoxic/reperfused rat heart. 972 Oct 23

The relationship between bioenergetics and the glutamate system was analyzed in a neuronal model of retinal cells in culture, submitted to glucose deprivation and exposed to glutamate for 2 h, and compared with exposure to glutamate in the presence of glucose. Under glucose deprivation, a reduction (about 1.1-fold) in the energy charge of the cells occurred, probably as a result of a decrement (by about 75%) in the cellular redox efficacy, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test. In the absence of glucose, exposure of retinal cells to 10 microM glutamate potentiated the reduction in the energy charge (by about 1.2-fold) and induced a significant increase in the uptake of 45Ca2+ by the cells (1.3-fold), although no significant changes were observed in the presence of glucose. Under glucose deprivation, 100 microM glutamate caused an irreversible cell membrane damage, as shown by the significant increase in lactate dehydrogenase (LDH) leakage (about 1.8-fold). A significant increase in membrane depolarization, measured by the reduction of [3H]tetraphenylphosphonium+ ([3H]TPP+) uptake, was also observed after glutamate exposure in the absence of glucose. In the presence of glucose, high glutamate concentrations (10 mM) induced a major increase in Ca2+ entry into the cells and membrane depolarization, without affecting the energy charge or cell survival. In contrast, in the absence of glucose, 10 mM glutamate did not alter Ca2+ accumulation by the cells and a smaller decrease in membrane potential occurred, as compared to 100 microM glutamate exposure. Data shown in this study suggest that during a prolonged (2 h) and acute exposure to high glutamate (10 mM), under glucose deprivation conditions, the neuronal systems have "adaptive" mechanisms that allow the survival of cells. These findings may have implications in neuronal degeneration occurring during brain ischemia.
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PMID:Effect of glucose deprivation and acute glutamate exposure in cultured retinal cells. 974 74

1. Cypridina luciferin analogues, 2-methyl-6-(p-methoxyphenyl)-3,7- dihydroimidazo[1,2-a]pyrazin-3-one (MCLD) and 2-methyl-6-phenyl-3,7-dihydroimidazo[1,2-a]pyrazin-3-one(CLA ), react with O2- or 1O2 to emit light in visible region. Such chemiluminescences were used for the detection of O2- or 1O2 in activated leukocyte systems and myeloperoxidase (granulocyte-extract) + Br- + H2O2 systems in vitro. 2. The mechanisms of MCLA (CLA)-dependent luminescence is described in detail. Superoxide generated from sinusoidal cells in acute ethanol intoxication of rats was detected by MCLA-dependent luminescence from the surface of perfused rat liver (organ luminescence). 3. Furthermore, with alive animals, O2- generated in the lung of rats with necrotized pancreatitis and that in the stomach of rats after ischemia/reperfusion were detected by their organ luminescences.
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PMID:Detection of active oxygen species in biological systems. 987 66

The authors hypothesized that augmenting skeletal muscle adenosine 3',5'-cyclic monophosphate (cAMP) levels could reduce tissue inflammation and improve muscle survival in response to ischemia/ reperfusion (I/R) injury. Gracilis muscle flaps in male Wistar rats were subject to 4 hr of ischemia followed by 3 hr of reperfusion, to assess neutrophil accumulation and microvessel tone, or by 24 hr to evaluate percentage of muscle survival. Animals were grouped as follows: positive (saline) or negative (sham) control, or with infused cAMP elevating agents (8 Bromo-cAMP (8 Br-cAMP) or forskolin). Radioimmunoassay demonstrated significant increases in tissue cAMP levels throughout 3 hr of reperfusion with forskolin, while the 8 Br-cAMP-treated group showed only a temporary increase. Compared with vehicle-infused controls, forskolin administered 5 min prior to reperfusion and repeated as an infusion during the first 45 min of reperfusion, resulted in reduced neutrophil adherence and transmigration, and muscle edema with sustained vasodilatation. The percentage of muscle survival using nitro-blue tetrazolium staining demonstrated enhanced muscle-flap preservation with forskolin. There was no beneficial change in the presence of 8 Br-cAMP These observations suggested that sustained elevation of the cAMP pathway may reduce ischemia-reperfusion injury by decreasing neutrophil-mediated injury and improving vessel tone. Elucidation of the cAMP pathway may provide novel opportunities to modulate ischemia/ reperfusion injury.
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PMID:Augmentation of cAMP improves muscle-flap survival and tissue inflammation in response to ischemia/reperfusion injury. 1002 29


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