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)

Radicals are species containing one or more unpaired electrons, such as nitric oxide (NO.). The oxygen radical superoxide (O2.-) and the nonradical hydrogen peroxide (H2O2) are produced during normal metabolism and perform several useful functions. Excessive production of O2.- and H2O2 can result in tissue damage, which often involves generation of highly reactive hydroxyl radical (.OH) and other oxidants in the presence of "catalytic" iron or copper ions. An important form of antioxidant defense is the storage and transport of iron and copper ions in forms that will not catalyze formation of reactive radicals. Tissue injury, e.g., by ischemia or trauma, can cause increased metal ion availability and accelerate free radical reactions. This may be especially important in the brain because areas of this organ are rich in iron and CSF cannot bind released iron ions. Oxidative stress on nervous tissue can produce damage by several interacting mechanisms, including increases in intracellular free Ca2+ and, possibly, release of excitatory amino acids. Recent suggestions that free radical reactions are involved in the neurotoxicity of aluminum and in damage to the substantia nigra in patients with Parkinson's disease are reviewed. Finally, the nature of antioxidants is discussed, it being suggested that antioxidant enzymes and chelators of transition metal ions may be more generally useful protective agents than chain-breaking antioxidants. Careful precautions must be used in the design of antioxidants for therapeutic use.
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PMID:Reactive oxygen species and the central nervous system. 140 8

Peroxynitrite (ONOO-), the reaction product of superoxide (O2-) and nitric oxide (NO), may be a major cytotoxic agent produced during inflammation, sepsis, and ischemia/reperfusion. Bovine Cu,Zn superoxide dismutase reacted with peroxynitrite to form a stable yellow protein-bound adduct identified as nitrotyrosine. The uv-visible spectrum of the peroxynitrite-modified superoxide dismutase was highly pH dependent, exhibiting a peak at 438 nm at alkaline pH that shifts to 356 nm at acidic pH. An equivalent uv-visible spectrum was obtained by Cu,Zn superoxide dismutase treated with tetranitromethane. The Raman spectrum of authentic nitrotyrosine was contained in the spectrum of peroxynitrite-modified Cu,Zn superoxide dismutase. The reaction was specific for peroxynitrite because no significant amounts of nitrotyrosine were formed with nitric oxide (NO), nitrogen dioxide (NO2), nitrite (NO2-), or nitrate (NO3-). Removal of the copper from the Cu,Zn superoxide dismutase prevented formation of nitrotyrosine by peroxynitrite. The mechanism appears to involve peroxynitrite initially reacting with the active site copper to form an intermediate with the reactivity of nitronium ion (NO2+), which then nitrates tyrosine on a second molecule of superoxide dismutase. In the absence of exogenous phenolics, the rate of nitration of tyrosine followed second-order kinetics with respect to Cu,Zn superoxide dismutase concentration, proceeding at a rate of 1.0 +/- 0.1 M-1.s-1. Peroxynitrite-mediated nitration of tyrosine was also observed with the Mn and Fe superoxide dismutases as well as other copper-containing proteins.
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PMID:Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. 141 74

Copper(II)2(3,5-diisopropylsalicylate)4 [Cu(II)2(3,5-DIPS)4] has been found to have antiinflammatory, antiulcer, anticancer, anticonvulsant, antimutagenic, antidiabetic, analgesic, and radiation protection and recovery activities. It has also been found to reduce ischemia-reperfusion injury. Because of these activities it was of interest to understand how this compound is transported in the body to affected tissues. Evidence supporting the suggested formation of ternary human serum albumin (HSA)-Cu(II)(3,5-DIPS)2 or Cu(II)2(3,5-DIPS)4 complexes was obtained using ultraviolet spectrophotometry, dialysis, and atomic absorption spectrophotometry or atomic emission spectroscopy. Superoxide dismutase (SOD)-mimetic activity was also determined using the xanthine/xanthine oxidase/cytochrome c system. Ultraviolet spectra of aqueous solution mixtures of Cu(II)2(3,5-DIPS)4 in equilibrium with 2Cu(II)(3,5-DIPS)2 and HSA as well as aqueous solutions of solid Cu(II)2(3,5-DIPS)4 obtained by stirring the solid with an aqueous solution of HSA showed no obvious change in absorbance to indicate ternary complex formation. However, comparison of ultraviolet spectra taken before and after dialysis supports the suggested bonding of Cu(II)(3,5-DIPS)2 or Cu(II)2(3,5-DIPS)4 to HSA. Comparison of copper concentrations before and after dialysis also supports the suggested bonding of Cu(II)(3,5-DIPS)2 or Cu(II)2(3,5-DIPS)4 to HSA. Based upon these data it is plausible that Cu(II)(3,5-DIPS)2 or Cu(II)2(3,5-DIPS)4 form stable ternary complexes with HSA. These stable ternary complexes were also found to have SOD-mimetic activity.
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PMID:Stable superoxide dismutase (SOD)-mimetic ternary human serum albumin-Cu(II)(3,5-diisopropylsalicylate)2/Cu(II)2(3,5-diisopropylsalicylate)4 complexes in tissue distribution of the binary complex. 156 81

Activated neutrophils and possibly xanthine oxidase-derived free radicals are believed to be mediators of ischemia and reperfusion-induced myocardial damage. We studied the cardioprotective effect of the neutrophil stabilizer and xanthine oxidase inhibitor azapropazone in dogs subjected to thrombotic occlusion of the left anterior descending coronary artery (LAD), induced by intracoronary introduction of a copper coil, followed 60 min later by thrombolytic treatment with intracoronary streptokinase and 4-day reperfusion; we then determined infarct size by triphenyltetrazolium stain. Azapropazone [100 mg/kg intravenously (i.v.) followed by a 24-h i.v. infusion of 10 mg/kg/h, n = 8] or vehicle (n = 10) treatments were started immediately before the streptokinase infusion. Steady-state plasma levels of azapropazone ranged from 97 to 163 micrograms/ml during the infusion. Myocardial blood flow and underperfused area at risk were determined using radiolabeled microspheres. Results were as follows (mean +/- SEM): area at risk (percentage of left ventricle) azapropazone 22.7 +/- 3.16 and vehicle 21.8 +/- 4.13; infarct size (percentage of area at risk), azapropazone 45.1 +/- 11.8 and vehicle 75.7 +/- 10.6, p less than 0.03; collateral blood flow (ml/min/g), azapropazone 0.27 +/- 0.02 and vehicle 0.23 +/- 0.02; total ischemic period (min), azapropazone 106 +/- 5.9 and vehicle 91.5 +/- 4.9. Azapropazone had no effects on heart rate (HR), blood pressure (BP), or rate/pressure product (RPP). These dta show that azapropazone limits infarct size in a canine model of coronary thrombosis and long-term reperfusion and that this cardioprotection is independent of cardiovascular parameters.
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PMID:Persistent cardioprotection by azapropazone in a canine model of coronary artery thrombosis and thrombolysis. 171 99

The production of oxygen free radicals can be stimulated by excess iron, cadmium, nickel, and the like. Inversely, copper, zinc, and selenium inhibit production, either via their own action or via antiradical metalloenzymes. The study involved determining the effect of zinc deficiency combined with chronic ethanol administration on the status of blood and tissue free radicals, as well as on cardiac function in isolated, perfused rats' hearts. Animals were fed a basic diet containing residual zinc at 0.2-0.3 ppm. Following a zinc deficiency lasting 5 wk, which during the last 4 wk was accompanied by chronic ethanol administration, hearts were submitted to ischemia for 30 min in vitro, followed by reperfusion. Biochemical analyses (zinc, superoxide dismutase, malondialdehyde, conjugated dienes, and so on) were performed in the blood and in the homogenates of different organs. The experimental zinc deficiency caused a slight decrease of superoxide dismutase activity, accompanied by increased production of peroxidated lipids. Ethanol administration appeared to increase the levels of peroxidated lipids in the heart. Finally, the combination of zinc deficiency and ethanol administration had very harmful effects, especially on lipid peroxidation and contractile function of the isolated, perfused heart in preischemic conditions.
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PMID:Zinc deficiency, ethanol, and myocardial ischemia affect lipoperoxidation in rats. 172 83

It has been proposed that oxygen-derived radicals, superoxide in particular, are involved in the alteration of blood-brain barrier permeability and the pathogenesis of brain edema following trauma, ischemia, and reperfusion injury. Using transgenic mice that overexpress the human gene for copper-zinc-superoxide dismutase, we studied the role of superoxide radicals in the blood-brain permeability changes, edema development, and delayed infarction resulting from cold-trauma brain injury. At 2 hours after a 30-second cold injury, cerebral water and Evans blue contents were reduced, respectively, from 80 +/- 0.2% and 132.7 +/- 12.9 micrograms/gm of dry weight for nontransgenic mice to 78.5 +/- 0.3% and 87.1 +/- 9.9 micrograms/gm of dry weight for transgenic mice. Infarction, as measured by 2,3,5-triphenyltetrazolium chloride staining, was reduced by 52% in transgenic brains. These data indicate that an increased level of superoxide dismutase activity in the brain reduces the development of vasogenic brain edema and infarction. Superoxide radicals play an important role in the pathogenesis of these lesions in cold-traumatized brain.
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PMID:Cold-induced brain edema and infarction are reduced in transgenic mice overexpressing CuZn-superoxide dismutase. 185 79

We studied the role of copper as a potential mediator of postischemic reperfusion injury in the isolated, perfused rat heart. Hearts were equilibrated with Krebs-Henseleit buffer for 10 minutes and then loaded with copper by way of perfusion with buffer containing 20 microM copper(II)-bis-histidial for 30 minutes. Control hearts were perfused with Krebs-Henseleit buffer alone during the loading period. Hearts than were washed with buffer for 10 minutes and subjected to 20 minutes of normothermic global ischemia followed by 30 minutes of reperfusion. Atomic absorption spectroscopy revealed a 67% increase in total copper content in loaded hearts by the end of the wash. By the end of the 30-minute period of reperfusion, control hearts demonstrated a 50-60% recovery of myocardial function as determined by peak systolic pressure, contractility, and heart rate. In contrast, copper-loaded hearts exhibited virtually no functional recovery within the 30-minute time period. Using salicylate as a probe, we determined that peak and duration of .OH formation appears to be increased in copper-loaded hearts during reperfusion. Furthermore, efflux of lactic dehydrogenase was significantly increased in copper-loaded hearts. Our results clearly demonstrate that increasing cardiac content of copper results in enhanced postischemic reperfusion injury associated with increased formation of .OH, thus suggesting an important catalytic role for this transition metal.
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PMID:Copper loading of hearts increases postischemic reperfusion injury. 187 80

Limitation on infarct size, using propionyl-L-carnitine (Sigma-Tau) by itself and with the calcium entry blocker, tiapamil (Hoffmann-LaRoche), was evaluated in two groups of ten dogs each, during chronic (9 days) myocardial infarction. There were eight dogs that served as the control group. A closed-chest model was used to produce the thrombus by placing a helically shaped copper wire in the LAD by catheter technique, under x-ray visualization. Necrotic tissue in serial transventricular sections were delineated by triphenyltetrazolium chloride and measured by computer technique, using an IBM PC interfaced with a digitizing pad, 9 days following occlusion. The mean total amount of necrosis in the propionyl-L-carnitine (7.4%) and the propionyl-L-carnitine/tiapamil (6.7%) groups were significantly less (p less than .01) than found in the control (14.1%) group, reflecting a difference of 50 and 58%, respectively, between the treated groups and control. A number of significant between-group comparisons (p less than .05 to p less than .001), under the same conditions, were found for various ischemia, hemodynamic, and hematologic variables followed before and at 30, 60, 90, 120, and 180 minutes after occlusion, as well as on the second and ninth day. The results of this study strongly suggest that propionyl-L-carnitine and propionyl-L-carnitine with tiapamil has a protective effect on myocardial function, following thrombotic occlusion of the LAD, as well as limiting the resulting infarct size.
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PMID:Effect of propionyl-L-carnitine on experimental myocardial infarction in dogs. 203 76

Free radicals have been incriminated in a variety of injurious processes including the toxicity of the herbicide paraquat and the damage following ischemia and reperfusion of different organs. Based on the assumption that iron and copper could serve as mediators for the transformation of relatively low reactive species (such as superoxide radicals, hydrogen peroxide, ascorbate, and others) to the highly reactive species, in the site-specific metal-mediated mechanism, two new modes for intervention have been tried out. The first is the introduction of specific chelators that "pull" out redox-active and available metals, and by this reduce the apparent damage. Desferrioxamine was shown to protect bacterial cells and mammals against the poisonous effects of paraquat. Using the retrogradly perfused isolated rat heart, we have demonstrated that the chelator neocuproine, which effectively binds both iron and copper provides a major protection against hydrogen peroxide-induced cardiac damage and against ischemia/reperfusion-induced arrhythmias. Likewise, TPEN a heavy metal chelator, provides almost total (greater than 90%) protection against ischemia/reperfusion-induced arrhythmias. The other mode of intervention is the use of redox-inactive metal ions that could compete for the binding sites of iron and copper, and by this "push" these metal ions out, lead to their displacement, and divert the site of free radical attack. Applying Zn(II) complexes provided a marked protection against metal mediated free radical-induced damage in the copper-mediated paraquat toxicity to E. coli, and in the arrhythmias induced by ischemia and reperfusion. It is proposed that the complex zinc-desferrioxamine would be the ultimate protector being effective by both the "pull" and "push" mechanisms.
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PMID:Protection against free radical-induced and transition metal-mediated damage: the use of "pull" and "push" mechanisms. 206 Aug 41

Carrageenan-induced paw edemata of mice and rats were suppressed by 1-4 x 10(3) U/kg intravenous injection of heparin. High doses were less suppressive, corresponding well to the increase in plasma SOD activity. This biphasic dose response curve was also observed in our ischemic paw model of mice. Increased SOD appeared as high molecular EC-SOD C (in mice) and B (in rats) as a result of its sensitivity to a copper chelator and long retention time in the blood stream, compared to the short life of cytosolic Cu, Zn-SOD. EC-SOD C (135 kDa) failed to be detected in the plasma of heparin-injected mice by way of nitroblue tetrazolium staining after PAGE electrophoresis. Instead, SOD activity was found near 270 kDa. An excess heparin-loaded subunit of this enzyme might become inactivated or might not be able to fix to a pocket where EC-SOD eliminates O2-, to protect the endothelium, Electrophoresis dissociates the excess heparin resulting in an active form of the enzyme. Paw edemata of rats were less sensitive because this species lacks the strongly heparin-binding EC-SOD C and has only the weakly heparin-binding EC-SOD B, Ischemia-induced mitochondrial swelling of the paw muscle was observed by electron microscopy and was prevented by heparin injection.
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PMID:Suppression of carrageenan paw oedema in rats and mice by heparin-induced EC-SODs. 207 Oct 31


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