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

Hemoglobin solutions were assessed in terms of their ability to promote lipid peroxidation, which was quantitated by measuring the formation of thiobarbituric acid reactive substances (TBARS) under specified conditions in murine brain homogenates. Solutions designed for use in acute treatment of hypovolemic shock and trauma should incorporate ingredients specifically aimed at decreasing oxygen and lipid radical mediated injury occurring secondary to ischemia and reperfusion. A number of strategies aimed at decreasing the oxidant effect of hemoglobin solutions and other blood and plasma substitutes have been evaluated. These include use of the naturally occurring anti-oxidants in human plasma, specifically transferrin and ceruloplasmin. Similarly, certain iron chelators, such as deferoxamine (Desferal, Ciba-Geigy), effectively prevent molecular and cellular damage caused by iron catalyzed formation of oxygen derived radicals.
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PMID:Hemoglobin: a lifesaver and an oxidant. How to tip the balance. 317 98

Brief (15-minute) coronary occlusion and subsequent reperfusion lead to prolonged functional and metabolic abnormalities (stunned myocardium). Previous work suggests that one factor responsible for this phenomenon is oxygen-derived free radicals. The formation of the highly reactive hydroxyl radical requires the presence of metal ions, most importantly iron. In the present study, the effect of the iron-chelator deferoxamine on the recovery of segment shortening (%SS) in the stunned myocardium was compared with a control group in barbital anesthetized dogs. Deferoxamine (500 mg intra-atrially) was administered 15 minutes prior to and throughout 15 minutes of coronary occlusion. %SS, regional myocardial blood flow, hemodynamics, and myocardial high-energy phosphates were measured. Areas at risk, collateral blood flow, and all hemodynamic parameters were similar between control and deferoxamine-treated animals. While deferoxamine did not prevent the loss of systolic wall function that occurred during ischemia, deferoxamine significantly improved the recovery of %SS at all times throughout reperfusion (3-hour %SS of pretreatment: control, 12 +/- 11; deferoxamine, 65 +/- 12), normalized endocardial ATP (percent of nonischemic area: control, 79 +/- 3%, deferoxamine, 93 +/- 6%), attenuated the reperfusion-induced rebound increase in phosphocreatine and prevented the increase in tissue edema at 3 hours after reperfusion. Thus, deferoxamine exhibited a cardioprotective action both metabolically and functionally in the stunned myocardium presumably by decreasing the redox cycling, and hence, the availability of catalytic iron for use in hydroxyl radical formation and for the initiation of lipid peroxidation. These data suggest a possible role for the hydroxyl radical as a mediator of postischemic abnormalities in reversibly injured tissue.
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PMID:Evidence for a role of iron-catalyzed oxidants in functional and metabolic stunning in the canine heart. 339 56

In ischemic acute renal failure oxygen free radicals may mediate injury. In addition, iron appears to play a critical role in hydroxyl radical formation and lipid peroxidation during reperfusion of ischemic kidneys. To determine whether iron may play a similar role in pigment (heme protein)-induced acute renal failure, we studied the effects of the iron chelator deferoxamine in two experimental models of pigment-induced acute renal failure, intramuscular glycerol injection and intravenous hemoglobin infusion without and with concurrent ischemia in the rat. Intramuscular injection of 50% glycerol (5 ml/kg) caused inulin clearance to fall to 0.13 +/- 0.03 (SE) ml/min (normal value, 1.0-1.2 ml/min). Continuous infusion of deferoxamine beginning at the time of glycerol injection significantly attenuated this renal dysfunction. Deferoxamine-treated animals had an inulin clearance of 0.37 +/- 0.06 ml/min (P less than 0.01). Glycerol injection was also associated with significant lipid peroxidation, measured as renal malondialdehyde content. Deferoxamine-treated glycerol-injected rats had renal malondialdehyde content not significantly different from control animals. In another model of heme pigment-induced renal injury, hemoglobin was infused to produce hemoglobinuria. Inulin clearance 1 h after hemoglobin infusion was significantly reduced to 0.84 +/- 0.5 ml/min (P less than 0.025). Infusion of deferoxamine after hemoglobin prevented the hemoglobin-induced decrease in inulin clearance. Thirty minutes of renal ischemia followed by infusion of hemoglobin resulted in more severe renal dysfunction with inulin clearance of 0.54 +/- 0.08 ml/min. Deferoxamine infused at the time of reperfusion attenuated the fall in glomerular filtration rate after ischemia and hemoglobin infusion:inulin clearance 1.04 +/- 0.07 (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity. 341 10

We evaluated whether supplemental pharmacologic interventions that altered formation or degradation of reactive oxygen metabolites, when added to hypothermic crystalloid cardioplegic solution (procaine-free St. Thomas' Hospital solution), alter postischemic function of isolated rabbit hearts. Hypoxic, substrate-free cardioplegic solutions cooled to 27 degrees C were perfused through isolated rabbit hearts for 5 minutes before and after an uninterrupted 2 hour period of global ischemia at 27 degrees C. Hearts were then reperfused with standard buffer for 1 hour at 37 degrees C. In some experiments, the cardioplegic solution was supplemented with the following: superoxide dismutase (30 micrograms/ml; degrades superoxide anion); catalase (1.7 micrograms/ml; degrades hydrogen peroxide); allopurinol (1 mmol/L; inhibits xanthine oxidase); or deferoxamine (Desferal, 0.5 mmol/L; selectively chelates ferric iron). Postreperfusion contractile parameters of supplemented hearts, including left ventricular pressure development and its first derivative, left ventricular compliance, spontaneous heart rate, and coronary vascular resistance, were statistically compared to data obtained from hearts arrested with unsupplemented cardioplegic solution. Catalase supplementation provided statistically significant improvement of most functional parameters; somewhat less protection was obtained with allopurinol. Deferoxamine provided little added protection except for the ability to prevent ischemia-induced increases of coronary vascular resistance. There was no evidence of added protection by superoxide dismutase. The data suggest that an important component of ischemia-induced cardiac cell damage in an asanguineous setting is hydrogen peroxide-dependent, and interventions that either inhibit production of superoxide anion or degrade hydrogen peroxide offer best protection. They may be clinically efficacious additives to crystalloid cardioplegic solutions.
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PMID:Effects of supplementing hypothermic crystalloid cardioplegic solution with catalase, superoxide dismutase, allopurinol, or deferoxamine on functional recovery of globally ischemic and reperfused isolated hearts. 394 95

Activation of cardiac sympathetic afferents leads to excitatory cardiovascular reflexes and pain during myocardial ischemia. We hypothesized that cardiac sympathetic afferents are activated by reactive oxygen species produced during ischemia and reperfusion. Single-unit nerve activity of 55 afferents was recorded from the left paravertebral sympathetic chain (T1-T4) in cats anesthetized with alpha-chloralose. Receptive fields of all afferents were located on the right or left ventricle. Mechanical and chemical sensitivities of each afferent ending were evaluated by von Frey hairs, cardiac distension, and local application of bradykinin (BK, 142 pmol) or H2O2 (7.5-15 mumol) to the receptive field. Thirty-one afferents (56%) were responsive to bradykinin (BK), H2O2, and ischemia (2 or 10 min). Deferoxamine (Def, 10-100 mg/kg), dimethylthiourea (DMTU, 10-100 mg/kg), or iron-loaded Def (10 mg/kg) were employed to evaluate the role of H2O2 and hydroxyl radicals (.OH) in activating these afferents (10A delta and 21C fibers) during ischemia and reperfusion. Treatment with the nonspecific scavenger DMTU (n = 10) significantly diminished the increase in discharge activity evoked by ischemia and reperfusion. Treatment with Def also significantly attenuated the responses during ischemia and reperfusion. Thus reactive oxygen species, particularly .OH, activate a group of cardiac sympathetic A delta- and C-fiber afferents during myocardial ischemia and reperfusion and may play an important role in mediating cardiovascular sympathetic reflex responses and/or pain transmission.
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PMID:Ischemia- and reperfusion-sensitive cardiac sympathetic afferents: influence of H2O2 and hydroxyl radicals. 757 32

Iron chelators have been shown to protect against oxygen free radical injury occurring in association with ischemia/reperfusion (I/R). Tumor necrosis factor alpha (TNF) represents a major mediator of the pulmonary and hepatic injury occurring after hepatic I/R since pretreatment with anti-TNF antibody results in significant protection against both the lung and liver injury following this insult. We were therefore interested in the possible association of the protective actions of deferoxamine (Desferal) following hepatic I/R and subsequent TNF release. A rat model of hepatic I/R was used to evaluate this; four experimental groups were studied. Animals in I/R underwent 90 min of hepatic ischemia with subsequent reperfusion. DES-I/R animals were pretreated with 200 mg of deferoxamine and VEH-I/R rats were given an equivalent amount of vehicle prior to hepatic I/R. SHAM animals underwent sham laparotomy alone. Plasma specimens were obtained and analyzed for TNF using a cytolytic bioassay based on the WEHI 164 subclone 13 cell line. Mean peak TNF levels following deferoxamine pretreatment was 110.38 +/- 24.68 pg/ml, as compared to mean peak TNF levels of 213.64 +/- 38.09 pg/ml in the VEH-I/R group (P < 0.01). Lung injury following hepatic I/R was evaluated by assessment of pulmonary microvascular permeability and by evaluation of pulmonary neutrophil infiltration as measured by pulmonary myeloperoxidase (MPO) content. Pretreatment with deferoxamine resulted in a significant decrease in lung leak as compared to animals pretreated with vehicle prior to I/R (DES-I/R = 0.192 +/- 0.013, VEH-I/R = 0.690 +/- 0.050; P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Desferal attenuates TNF release following hepatic ischemia/reperfusion. 793 22

The endothelial cell is thought to be an important site of free radical generation in ischemic tissues. It has been demonstrated that endothelial cells from several species generate a burst of free radical generation upon reoxygenation; however, it has been suggested that human endothelial cells are not similarly capable of generating free radicals on reoxygenation. In view of the central importance of revascularization with accompanying reoxygenation in the clinical treatment of tissue ischemia/infarction, we have performed studies to determine the presence, mechanism, and kinetics of free radical generation in human endothelial cells. Therefore, we subjected cultured human umbilical vein endothelial cells to anoxia followed by reoxygenation. Cell suspensions of 10(7) cells/ml were subjected to varying periods of anoxia and reoxygenation. On reoxygenation with addition of a 50 mM concentration of the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), after 90 min of anoxia an electron paramagnetic resonance (EPR) signal was observed consisting of 2 components: a quartet 1:2:2:1 DMPO-OH signal, aN = aH = 14.9 G, and a six-peaked DMPO-R signal, aN = 15.6 G aH = 22.9 G, whereas cells in air gave no signal. The observed signal was quenched by superoxide dismutase (SOD) or catalase. Deferoxamine decreased the measured radical signals by 40%. Cyclooxygenase blockers did not decrease radical generation, but the xanthine oxidase blocker oxypurinol did decrease radical generation by 60%.
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PMID:Measurement and characterization of free radical generation in reoxygenated human endothelial cells. 816 33

Fourteen domestic swine were divided into two groups. Group A (n = 7) was the control group, in which no pharmacologic intervention was applied. In group B (n = 7), the ischemic-reperfused spinal cord was treated with the combination of allopurinol (50 mg/kg/day for 3 days before the day of operation) and deferoxamine (Desferal, 50 mg/kg administered intravenously over 3 to 4 hours). The administration of deferoxamine was completed 1 hour before crossclamping. The crossclamp was placed on the descending aorta just distal to the left subclavian artery for 30 minutes. Proximal hypertension was controlled with sodium nitroprusside and volume depletion. Methods of assessment included an evaluation of the neurologic status of the animals by quantitative Tarlov criteria, blood flow by radiolabeled microspheres, and histologic examination of the spinal cord. All animals in the control group, group A, were completely paraplegic with 0% recovery by Tarlov criteria at 24 hours after the removal of the crossclamp. In contrast, all animals in group B, in which the combination of allopurinol and deferoxamine was used, completely recovered (100% recovery by Tarlov criteria), and at 24 hours after the ischemic episode they were able to walk with no difficulty and had intact sensation. Functional parameters of these animals fully correlated with the morphologic findings. Widespread acute neuronal injury and vacuolation of neuropil were observed in the control group of animals. In contrast, animals in group B showed much less pronounced morphologic changes after the same period of ischemia. In summary, the combined use of these agents significantly (p < 0.001) reduced the incidence of paraplegia induced by aortic crossclamping with 82% additivity.
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PMID:Additive effect of allopurinol and deferoxamine in the prevention of spinal cord injury caused by aortic crossclamping. 817 62

The ability of ceruloplasmin, an important serum antioxidant, to reduce the vulnerability of the isolated rat heart to reperfusion arrhythmias has been investigated. Bovine plasma ceruloplasmin was purified by chromatography on aminoethyl-agarose. Isolated rat hearts were submitted to 15 min of regional ischemia and 10 min of reperfusion. The dose-effect relationship and the role of ceruloplasmin conformational integrity in cardioprotection were established by treatment of ischemic hearts with ceruloplasmin at various concentrations (0.25, 0.5, 1, and 2 microM) and at different degrees of conformational integrity (A610/A280 = 0.02, 0.04, and 0.06), 5 min before reperfusion. Deferoxamine (20-500 microM) was used as a positive control. As negative controls we used chemically inactivated ceruloplasmin (1 microM), heat-denatured ceruloplasmin (1 microM), and albumin (1-4 microM). In the control group during the first 5 min of reperfusion, the incidence of total ventricular fibrillation was 100% and of irreversible ventricular fibrillation was 83%. The incidence of reversible and irreversible ventricular fibrillation was significantly decreased in the ceruloplasmin-treated groups in both a dose and molecular integrity dependent manner. Ceruloplasmin had no effect on the incidence of ventricular tachycardia. Deferoxamine reduced the incidence of ventricular fibrillation to the same degree as ceruloplasmin but at concentrations much higher than those of ceruloplasmin. Chemically inactivated ceruloplasmin, heat-denatured ceruloplasmin, and albumin had no protective effects on reperfusion-induced arrhythmias.
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PMID:Antiarrhythmic effects of ceruloplasmin during reperfusion in the ischemic isolated rat heart. 874 74

We studied the role played by prostaglandins and oxygen-derived free radicals in mediating reflex changes in renal sympathetic nerve activity (RSNA) during myocardial ischemia and reperfusion. Ligation of the left coronary artery for 20 min and reperfusion for 10 min were performed in anesthetized rats with sinoaortic denervation and with intact cardiac afferent nerves (control, n = 7), with cardiac sympathetic denervation (SD, n = 6), with vagal denervation (VD, n = 7), and with combined SD + VD (n = 6). In control rats, RSNA decreased by 10 +/- 3% from baseline (P < 0.05) during the first minute of ischemia and increased above baseline after 5 min of ischemia, with the maximum increase at the first minute of reperfusion. In rats with SD, RSNA decreased by 19 +/- 4% from baseline (P < 0.05) at the first minute of ischemia and remained depressed during the entire ischemic and reperfusion periods. In rats with VD, RSNA increased by 26 +/- 5% from baseline (P < 0.05) at the first minute of ischemia, and the increase in RSNA at the end of the ischemic period and at reperfusion was greater than in control rats. No changes in RSNA during ischemia and reperfusion were observed with combined SD + VD. Reflex changes in RSNA that occurred at the onset of ischemia in both VD (n = 7) and SD (n = 7) rats were abolished by indomethacin (5 mg/kg i.v., 20 min before ischemia). Reflex changes in RSNA after prolonged ischemia (> 10 min) and during reperfusion in both VD (n = 7) and SD (n = 7) rats were abolished by the antioxidant deferoxamine (20 mg/kg i.v., 20 min before ischemia). Deferoxamine also diminished the increase of RSNA at the onset of ischemia in VD rats. Thus, in rats, the vagal afferent reflex predominates during early ischemia and the sympathetic afferent reflex predominates during prolonged ischemia and reperfusion. Reflex changes in RSNA that occur at the onset of ischemia are mediated by activation of vagal and sympathetic afferent endings by prostaglandins. Reflex changes in RSNA after prolonged ischemia and during reperfusion are mediated by activation of vagal and sympathetic afferent endings by oxygen-derived free radicals.
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PMID:Renal sympathetic nerve activity during cardiac ischemia and reperfusion in rats. 889 97


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