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)

Allopurinol and its metabolite oxypurinol inhibited basal oxidation of ascorbate and exerted comparable concentration-dependent inhibitory effects on the oxidation of ascorbate catalysed by cupric ion, but the stimulation produced by ferric ion was affected minimally. UV spectral analysis suggested the formation of an allopurinol-ascorbate-copper ion complex. The oxidation of erythrocyte membrane lipids by ferric ion and cupric ion-t-butylhydroperoxide was also inhibited by allopurinol and oxypurinol, by the metal chelators EDTA and uric acid, and by the antioxidant butylated hydroxytoluene. The metal chelating actions of allopurinol and oxypurinol may be relevant to their protective actions against ischemia/reperfusion injury.
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PMID:Inhibition of transition metal ion-catalysed ascorbate oxidation and lipid peroxidation by allopurinol and oxypurinol. 211 56

In the presence of O2, Fe(III) or Cu(II), and an appropriate electron donor, a number of enzymic and nonenzymic oxygen free radical-generating systems are able to catalyze the oxidative modification of proteins. Whereas random, global modification of many different amino acid residues and extensive fragmentation occurs when proteins are exposed to oxygen radicals produced by high energy radiation, only one or a few amino acid residues are modified and relatively little peptide bond cleavage occurs when proteins are exposed to metal-catalyzed oxidation (MCO) systems. The available evidence indicates that the MCO systems catalyze the reduction of Fe(III) to Fe(II) and of O2 to H2O2 and that these products react at metal-binding sites on the protein to produce active oxygen (free radical?) species (viz; OH, ferryl ion) which attack the side chains of amino acid residues at the metal-binding site. Among other modifications, carbonyl derivatives of some amino acid residues are formed; prolyl and arginyl residues are converted to glutamylsemialdehyde residues, lysyl residues are likely converted to 2-amino-adipylsemialdehyde residues; histidyl residues are converted to asparagine and/or aspartyl residues; prolyl residues are converted to glutamyl or pyroglutamyl residues; methionyl residues are converted to methionylsulfoxide residues; and cysteinyl residues to mixed-disulfide derivatives. The biological significance of these metal ion-catalyzed reactions is highlighted by the demonstration: (i) that oxidative modification of proteins "marks" them for degradation by most common proteases and especially by the cytosolic multicatalytic proteinase from mammalian cells; (ii) protein oxidation contributes substantially to the intracellular pool of catalytically inactive and less active, thermolabile forms of enzymes which accumulate in cells during aging, oxidative stress, and in various pathological states, including premature aging diseases (progeria, Werner's syndrome), muscular dystrophy, rheumatoid arthritis, cataractogenesis, chronic alcohol toxicity, pulmonary emphysema, and during tissue injury provoked by ischemia-reperfusion. Furthermore, the metal ion-catalyzed protein oxidation is the basis of biological mechanisms for regulating changes in enzyme levels in response to shifts from anaerobic to aerobic metabolism, and probably from one nutritional state to another. It is also involved in the killing of bacteria by neutrophils and in the loss of neutrophil function following repeated cycles of respiratory burst activity.
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PMID:Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences. 228 87

Considerable evidence suggests that free radicals engendered by redox-active metals, particularly iron and copper, are causative agents in reperfusion injury following ischemia. This study demonstrates that perfusion of the isolated rat heart with a buffer containing zinc, a non-redox active metal similar to copper in its coordination chemistry, inhibits the development of ventricular arrhythmias during reperfusion. Zinc was employed as the bishistidine complex, Zn--His2, to maintain solubility and permeability. Zn--His2 exerted an antiarrhythmic activity as hearts spent a longer time in normal sinus rhythm and a shorter time in ventricular fibrillation during reperfusion following 10 min of regional ischemia. However, Zn--His2 also produced a negative inotropic and chronotropic effect, evident during equilibration and ischemia. In the course of experiments which began in Israel and continued in the U.S. it was necessary to use two different sources of rats. Hearts from the two sources manifested different sensitivities to the concentrations of Zn--His2, although their physiological effects were similar. Differential activity responses were noted for antiarrhythmic activity, negative inotropic and chronotropic properties, and toxicity. In both groups of untreated hearts the incidence of ventricular fibrillation after ischemia was 100%. Ventricular fibrillation was reduced to 17% at 37.5 microM Zn--His2 in the U.S.-bred rat hearts and to 9% at 200 microM Zn--His2 in those from Israel. These changes in Zn--His2 treated animals were accompanied by a decrease in lactate dehydrogenase release from the myocardium during reperfusion. None of the protective effects was due to histidine alone. These results indicate that zinc prevents ventricular arrhythmias during reperfusion following regional ischemia and may prevent membrane damage, possibly, by reduction of free radical formation.
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PMID:The effect of zinc on reperfusion arrhythmias in the isolated perfused rat heart. 232 82

The effect of neocuproine on cardiac injury was studied using retrogradely perfused isolated rat hearts in two experimental systems. In the first system, where hydrogen peroxide-induced damage was studied, neocuproine at the range of 40-175 microM provided protection at the level of 70-85%, as demonstrated by the reduced loss in the peak systolic pressure (P), in +dP/dt and in -dP/dt. In the second system, where ischemia/reperfusion-induced arrhythmias were studied, neocuproine (42 microM) provided a marked protection against cardiac injury as demonstrated by the lowering of the incidence in irreversible ventricular fibrillation, by decreasing the duration of ventricular fibrillation and by the concomitant increase of the duration of normal sinus rhythm, and by improving the post-ischemic recovery of P, +dP/dt and -dP/dt. Free radicals have already been implicated as causative agents in cardiac injury resulting from either hydrogen peroxide or ischemia followed by reperfusion. Additionally, iron and copper have already been shown to drastically exacerbate the injurious effects of free radicals. Thus, the results reported here with neocuproine, a highly effective chelator for both iron and copper, as well as with adventitious copper and with the combination of neocuproine and copper, are in accord with the mediatory role of transition metals in enhancing the deleterious effects induced by free radicals.
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PMID:The protective role of neocuproine against cardiac damage in isolated perfused rat hearts. 233 93

Although it has been known for a long time that pronounced hypothermia has a protective effect on the brain during ischemia, and that severe hyperthermia damages neuronal tissue, knowledge of human brain temperature is very limited. The recent findings by two independent research groups, that even small differences in brain temperature significantly influence the degree of neuronal damage following cerebral ischemia, became the incentive for measuring brain temperature in neurosurgical patients. The temperature of the lateral ventricle, epidural space, membrana tympani and rectum were measured with copper-constantan thermocouples. During the implantation of an intraventricular catheter for measuring intracranial pressure, a temperature gradient of 0.4-1.0 degrees C between the lateral ventricle and the epidural space was noted. Continuous measurements for 1-5 days showed that the rectal temperature usually adequately reflects the temperature of the epidural space, although the temperature of the membrana tympani followed changes in epidural temperature more closely. However, at times, and in one patient during most of the time, the temperature of the epidural space was up to 1 degree C above rectal temperature. The relevance of these findings for the care of neurosurgical patients is discussed in relationship to what is known about brain temperature from animal experiments.
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PMID:Epidural temperature and possible intracerebral temperature gradients in man. 233 25

We recently demonstrated in isolated, perfused hearts that radiolabeled pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II) (Cu-PTSM) is well extracted throughout a range of conditions including ischemia, hypoxia, and hyperemia. Once extracted, binding of radioactivity by the isolated heart was essentially irreversible, giving this tracer microspherelike qualities. Because Cu-PTSM can be readily prepared with the generator-produced positron-emitting copper 62 and other gamma- or positron-emitting copper radionuclides, we evaluated its usefulness for measuring regional myocardial and renal blood flow in vivo in intact dogs at rest, after ischemia, or after coronary hyperemia was induced by intravenous administration of dipyridamole. After intravenous administration of radiolabeled Cu-PTSM, the tracer cleared rapidly from the blood. Myocardial uptake of single photon-emitting 67Cu-labeled Cu-PTSM was measured directly in myocardial samples 15 minutes after tracer administration, and it increased proportionally with blood flow throughout the flow range (estimated concomitantly with radiolabeled microspheres) of 0.0-6.0 ml/g/min (n = 340 samples from 17 dogs, r = 0.99, Ycopper radioactivity = 85Xmicrosphere flow -7 chi 2 + 17). Renal uptake of radiolabeled Cu-PTSM was also proportional to blood flow. Positron emission tomography was performed in four intact dogs after intravenous administration of 64Cu-labeled Cu-PTSM (19% positron decay, t1/2 = 12.8 hours). High-quality images of heart and kidney were obtained. Accordingly, radiolabeled Cu-PTSM should be a useful, generator-produced tracer for estimating regional myocardial and renal blood flow with positron emission tomography.
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PMID:Assessment of regional myocardial and renal blood flow with copper-PTSM and positron emission tomography. 239 15

The natural antioxidant beta-carotene which, unlike phenol antioxidants such as dibunol and SPN-6, is capable of exhibiting antioxidative properties under low partial oxygen pressure (ischemia), has been found to increase the activity of antioxidative enzymes in the intact and infarct myocardium and to greatly exert a more antinecrotic action when given orally in a dose of 20 mg/kg in models of rat coronary-occlusion myocardial infarction than the phenol antioxidants mentioned above. Intravenous administration of copper-containing enzymes utilizing O2 superoxide dismutase (SOD), 4 mg/kg, or ceruloplasmin, 50 mg/kg, as with a highly disperse copper powder promoting a substantial increase in antioxidative enzyme activity in the rat myocardium has been demonstrated to reduce the zone of myocardial ischemic lesion in rats and to largely enhance postoperative survival rates in the animals. Three hours following intravenous SOD, an electron microscopic examination of rat ischemic myocardium showed a considerable fall in the structural and functional damages to cardiomyocytes in the periischemic area. The findings suggest that free radical processes make a contribution to ischemic cardiomyocyte lesion and open the way for pharmacological therapy of postischemic abnormalities with enzymatic and non-enzymatic preparations of antioxidants.
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PMID:[The role of free radical inhibitors of lipid peroxidation in protecting the myocardium from ischemic damage]. 255 65

Copper(II) pyruvaldehyde bis(N4-methylthiosemicarbazone) ([Cu]PTSM) has shown potential as a flow tracer and can be labeled with the generator-produced positron emitting radionuclide 62Cu as well as with other copper radioisotopes. To define the myocardial handling of [Cu]PTSM, the externally detected single pass extraction and retention of [67Cu]PTSM was characterized after bolus administration in 12 isolated rabbit hearts perfused with erythrocyte-enriched modified Krebs-Henseleit buffer which permitted physiologic flow rates. The myocardial residual (extraction) fraction at control flow rates (approximately 1.5 ml/g/min) was 45 +/- 7(s.d.)% (n = 12), and was invariate with ischemia (flow = 0.15 ml/g/min, n = 4), hyperemia (flow = 3 ml/g/min, n = 4) or with hypoxia induced by perfusion at control flow rates with hypoxic buffer (n = 4) (residual fraction 45 +/- 20, 43 +/- 8, and 49 +/- 8%, respectively, p = N.S.). Once extracted, the tracer was retained with a biologic t1/2 of greater than 3600 min in all groups. The high single-pass extraction, which is not influenced by flow, and the prolonged retention of this tracer under diverse conditions indicate that [Cu]PTSM could be a useful tracer for measuring blood flow with positron emission tomography.
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PMID:Kinetics of copper-PTSM in isolated hearts: a novel tracer for measuring blood flow with positron emission tomography. 280 49

In the rabbit myocardium, ischemia (produced by ligation of the left circumflex coronary artery) is associated with a reduction in antioxidant capacity. This is reflected by an increased glutathione depletion and production of thiobarbituric acid reactive substances following in vitro oxidative challenge with t-butylhydroperoxide. This effect is greatly intensified by reperfusion following periods of ischemia longer than 20 mins, thereby paralleling the onset of irreversible injury. Chronic allopurinol pretreatment (1 mg/mL in drinking water or approximately 75 mg/kg/day for seven days prior to ligation) provides significant protection of the ischemic/reperfused myocardium to t-butylhydroperoxide induced glutathione depletion and production of thiobarbituric acid reactive substances. This protection was not associated with any significant alterations in levels of tissue ATP or in the activities of the myocardial antioxidant enzymes catalase, copper,zinc-superoxide dismutase or glutathione peroxidase, suggesting that allopurinol may exert its effects by direct radical scavenging or by some other mechanism unrelated to xanthine oxidase inhibition.
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PMID:Altered antioxidant status in the ischemic/reperfused rabbit myocardium: effects of allopurinol. 281 60

Oxygen-derived free radicals and membrane lipid peroxidation have been postulated to be involved in brain edema and cell death, secondary to ischemia and traumatic injury. Using a model of brain edema induced by cold-induced injury, we have demonstrated an early elevation of superoxide radicals followed by permeability changes in the blood-brain barrier and development of edema in injured brain. Intravenous injection of liposome-entrapped copper-zinc-superoxide dismutase 5 minutes before the injury-enhanced entry of the enzyme into endothelial cells of the blood-brain barrier of injured brain reduced the brain level of superoxide radicals and ameliorated blood-brain barrier permeability changes and brain edema. Identical treatment 5 minutes after injury was also effective. These data demonstrate that superoxide radicals play an important role in the delayed development of vasogenic brain edema following brain injury.
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PMID:Protective effects of liposome-entrapped superoxide dismutase on posttraumatic brain edema. 303 89


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