Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been suggested that cardiac injury by catecholamines may be the result of coronary constriction leading to ischemic damage. Allopurinol (ALLO) has been shown to reduce the extent of myocardial necrosis in various systems. Hence the possibility that ALLO might limit norepinephrine (NE) injury was tested. Rabbit hearts were infused with NE (3 micrograms/min/kg) for 90 minutes, with or without ALLO (50 micrograms/min/kg). Control specimens infused with saline solution plus ALLO were also prepared. Hearts were excised 48 hours later and studied as isovolumic isolated heart preparations. Peak systolic pressure, coronary flow, and myocardial oxygen consumption were significantly reduced in the hearts infused with NE but not in the NE + ALLO hearts. Myocardial adenosine triphosphate and glycogen concentrations were 29% and 26% lower in the NE hearts compared with control hearts. These reductions were absent in the NE + ALLO group. Moreover, rates of creatine phosphokinase and lactic dehydrogenase release were sharply elevated in the NE hearts but not in those also given ALLO. These findings are consistent with the changes observed histologically. The amount of myocardial damage was less in the ALLO + NE group compared with the NE group (p less than 0.02). This appears to be the first report to demonstrate that ALLO reduces myocyte damage by NE. Possible mechanisms include decreased free radical production, scavenging of free radicals, and preservation of the adenine nucleotide pool. Because xanthine oxidase activity is absent in the rabbit, the latter two mechanisms are more likely explanations for the findings.
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PMID:Modulation of catecholamine cardiomyopathy by allopurinol. 206 32

Changes in oxygen radical mechanisms during 6-48 weeks of heart hypertrophy in rats subjected to a narrowing of the subdiaphragmatic aorta were examined. During this period, hypertrophied hearts demonstrated a stable hyperfunction, as indicated by an elevated but stable left ventricular systolic pressure, dP/dt, and aortic pressure and no change in left ventricular end diastolic pressure. Experimental animals showed increased heart-to-body weight ratios; however, the conventional signs of heart failure such as increased wet-to-dry weight ratios of liver and lung, ascites, or pleural effusion were absent. Hearts were examined for superoxide dismutase, glutathione peroxidase, and lipid peroxide activities. The superoxide dismutase activity was significantly higher in hypertrophied hearts at 6 and 12 weeks as compared with sham-operated rats (sham controls), while no difference was seen at 24 and 48 weeks due to a marked increase in the superoxide dismutase activity of sham control hearts in these age groups. During the period studied, glutathione peroxidase activity remained unchanged in controls but was significantly elevated in hypertrophied hearts. Lipid peroxide activity as indicated by the malondialdehyde content was significantly lower in hypertrophied hearts. Perfusion of isolated control and hypertrophy hearts with xanthine-xanthine oxidase, an exogenous source of oxygen radicals, resulted in contractile failure and rise in resting tension. In hypertrophied hearts, however, the contractile force was better maintained and there was a lesser rise in resting tension after exposure to xanthine-xanthine oxidase. The study suggests the development of a higher antioxidative capacity during the stable phase of hypertrophy due to a chronic pressure overload.
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PMID:Higher antioxidative capacity during a chronic stable heart hypertrophy. 252 64

We investigated the effects of the xanthine oxidase inhibitor allopurinol and its metabolite oxypurinol on isolated rabbit hearts. To assess the potential role of these drugs in preventing reperfusion injury, hearts were perfused using Langendorff techniques, held globally ischemic for 3 h at 15 degrees C, and then reperfused. During perfusion, hearts received Krebs-Henseleit solution maintained at 37 degrees C. Aortic perfusion pressure was held constant at 80 cm H2O. Prior to ischemia, hearts were arrested with a constant volume of KCl cardioplegia. Using a left ventricular (LV) balloon, developed pressures were measured prior to and following global ischemia. In addition, coronary circulation (CC) was measured before and after ischemia. All hearts were paced at 260 beats/min. We studied four groups: group 1 received 1 mM allopurinol, group 2 received 1 mM oxypurinol, group 3 received 90 IU/ml superoxide dismutase (SOD) plus 8085 IU/ml catalase (CAT), and group 4 received no treatment and served as a control. Each group consisted of 8 animals. Hearts receiving drug treatment did so during the first 5 min of reperfusion. Displaying all data as a function of LV volume, postischemic values were compared to preischemic values. Multivariate analysis and Tukey tests were used to detect significant differences between groups. When compared to the control group, all drug-treated groups significantly recovered end-diastolic function. Peak systolic pressure decreased significantly in the SOD/CAT group as compared to all other groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prevention of reperfusion injury in ischemic-reperfused hearts by oxypurinol and allopurinol. 262 64

Allopurinol, a competitive inhibitor of xanthine oxidase, has been shown to have a protective effect on ischemic myocardium, but its mechanism of action remains controversial. We used an isolated rat heart preparation to test the hypothesis that allopurinol could restore adenosine triphosphate (ATP) levels and improve the recovery of left ventricular function after global myocardial ischemia. Hearts were equilibrated for 30 min, subjected to 10 min of global, normothermic (37 degrees C) ischemia, and reperfused for 15, 30, and 60 min. Hearts treated with allopurinol (100 microM) exhibited greater ATP levels and improved function during reperfusion than did untreated control hearts. Hearts treated with hypoxanthine (100 microM), the substrate for xanthine oxidase, also showed increased ATP and functional recovery compared with controls. These results suggest that allopurinol may protect the globally ischemic myocardium by enhancing the salvage of hypoxanthine for reincorporation into adenine nucleotides.
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PMID:Allopurinol enhanced adenine nucleotide repletion after myocardial ischemia in the isolated rat heart. 333 32

This study describes the effect of oxygen radicals on the ultrastructure of the isolated Langendorff-perfused rat heart. Oxygen radicals were enzymatically generated by xanthine oxidase (0.025 U/ml) and hypoxanthine (0.96 mM). Hearts were perfusion-fixed for electron microscopy and stereological technique was performed to obtain estimates of volume fractions (Vv) of different tissue components. Perfusion with oxygen radicals resulted in areas with severely damaged myocardial cells. These changes included swelling and cristolysis of mitochondria, disruption of filaments, development of intracellular edema and focal disruption of the sarcolemma. Stereological examination revealed few alterations after 5 min perfusion with oxygen radicals. After 10 min perfusion with oxygen radicals, however, the Vv (myocyte/myocardium) increased from 0.542 +/- 0.042 (mean +/- S.D.) to 0.663 +/- 0.144, and this paralleled the development of Vv (cellular edema/myocyte) being 0.047 +/- 0.028. Vv (capillary wall/capillary) increased from 0.215 +/- 0.046 to 0.411 +/- 0.123 indicating endothelial swelling. Although the mitochondria appeared swollen, Vv (mitochondria/myocyte) remained constant. The effect of a 35 min recovery period on the ultrastructure was minor. The application of SOD and catalase together with xanthine oxidase and hypoxanthine reduced the observed changes significantly, thus proving the participation of oxygen radicals. This study confirms that oxygen radicals can induce major alterations in myocardial ultrastructure.
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PMID:Ultrastructural changes induced in the isolated rat heart by enzymatically generated oxygen radicals. 361 20

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

The effects of a xanthine oxidase-mediated free radical-generating system containing purine and iron-loaded transferrin or solutions containing hydrogen peroxide and iron-loaded transferrin on substrate utilization and high-energy phosphates were evaluated by nuclear magnetic resonance (NMR) spectroscopy in isolated perfused rat hearts. Hearts were supplied with lactate, acetate, and glucose, and the contribution of each substrate to acetyl coenzyme A was measured in control hearts and in the presence of a free radical-generating system. Perfused hearts were monitored by 31P NMR, and tissue extracts were analyzed by 13C NMR. Free radicals decreased the phosphocreatine and beta-ATP peak areas and reduced contractile function. Under control conditions, lactate, acetate, and endogenous sources were the major contributors of acetyl coenzyme A units, with only 5% originating from glucose. In the presence of a xanthine oxidase-mediated free radical-generating system, the glucose contribution increased to 54%, while contributions from acetate and endogenous sources were significantly reduced. Both 13C and 31P NMR analyses showed no significant accumulation of glycolytic sugar phosphates, suggesting little inhibition of glyceraldehyde-3-phosphate dehydrogenase. The increased contribution of glucose to the tricarboxylic acid cycle relative to acetate and endogenous sources is consistent with activation of pyruvate dehydrogenase. In contrast, hearts exposed to a hydrogen peroxide-based free radical-generating system showed an increase in lactate utilization, a decrease in acetate utilization, and no change in glucose utilization compared with control hearts. Glycolytic sugar phosphates were found to accumulate, suggesting possible inhibition of glyceraldehyde-3-phosphate. Thus, different radicals or their metabolites may have varying effects on myocardial metabolism.
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PMID:Effects of oxidant exposure on substrate utilization and high-energy phosphates in isolated rat hearts. 791 69

The effects of allopurinol (AP) on functional and metabolic recovery of the isolated rat heart after global ischemia were studied. Hearts were subjected to aerobic perfusion (30 min), cardioplegic infusion (5 min), normothermic ischemia (37 min), and reperfusion (50 min) which was started with secondary cardioplegic infusion (10 min). AP was injected into rats (44 mg/kg body wt ip 2 h before heart excision) and added to cardioplegic solution (2 mM) prior and after ischemia. AP treatment significantly improved postischemic recovery of the function and reduced the leakage of lactate dehydrogenase from reperfused hearts. These beneficial effects were accompanied by a better preservation of tissue content of ATP, the total adenine nucleotides, phosphocreatine, and the total creatine at the end of reperfusion. Inhibition of xanthine oxidase by AP substantially decreased pre- and postischemic release of xanthine and uric acid and increased postischemic release of hypoxanthine into the coronary effluent. Despite this, AP-treated hearts did not exhibit a reduction in hydroxyl radical adduct formation in the effluents at reperfusion assessed by the spin-trap measurements. The results suggest that AP may protect the heart from ischemia/reperfusion injury due to enhanced energy provision rather than by prevention of oxygen-derived free radical formation.
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PMID:Allopurinol-enhanced postischemic recovery in the isolated rat heart involves repletion of high-energy phosphates. 819 13

The effects of reactive oxygen species (ROS) on myocardial antioxidants and on the activity of oxidative mitochondrial enzymes were investigated in the following groups of isolated, perfused rat hearts. I: After stabilization the hearts freeze clamped in liquid nitrogen (n = 7). II: Hearts frozen after stabilization and perfusion for 10 min with xanthine oxidase (XO) (25 U/l) and hypoxanthine (HX) (1 mM) as a ROS-producing system (n = 7). III: Like group II, but recovered for 30 min after perfusion with XO + HX (n = 9). IV: The hearts were perfused and freeze-clamped as in group III, but without XO + HX (n = 7). XO + HX reduced left ventricular developed pressure and coronary flow to approximately 50% of the baseline value. Myocardial content of hydrogen peroxide (H2O2) and malondialdehyde (MDA) increased at the end of XO + HX perfusion, indicating that generation of ROS and lipid peroxidation occurred. Levels of H2O2 and MDA normalized during recovery. Superoxide dismutase, reduced glutathione and alpha-tocopherol were all reduced after ROS-induced injury. ROS did not significantly influence the tissue content of coenzyme Q10 (neither total, oxidized, nor reduced), cytochrome c oxidase, and succinate cytochrome c reductase. The present findings indicate that the reduced contractile function was not correlated to reduced activity of the mitochondrial electron transport chain. ROS depleted the myocardium of antioxidants, leaving the heart more sensitive to the action of oxidative injury.
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PMID:Exogenous reactive oxygen species deplete the isolated rat heart of antioxidants. 895 32

Oxygen free radicals (OFR) are highly cytotoxic when produced in the myocardium under certain pathological conditions. In isolated rat hearts perfused retrogradely, OFR were generated by electrolysis of the Krebs-Henseleit buffer (two platinum electrodes, DC current, 10 mA, 1 min). In order to find evidence that OFR are produced, we used nitro blue tetrazolium (NBT) a soluble compound which yields a dark blue formazan pigment in the presence of reducing agents. Hearts were subdivided into: control, electrolysed, NBT (3.3 mg/ml) perfusion during electrolysis in the presence or absence of scavengers. The xanthine-xanthine oxidase (XXO) system known to produce superoxide radical was used as a reference. Specimens were fixed with formaldehyde and stained with eosine or Kernechtrot in preparation for light microscopical examination. Several areas of acute necrosis expressed by hyalinisation and loss of striation were observed in electrolysed hearts which present a pattern of wavy disrupted myofibers and an increase in interstitial spaces. A very faint deposition of formazan was observed in some rare areas of NBT perfused heart. Only the electrolysed group perfused with NBT and the one perfused with XXO plus NBT presented an extensive formazan deposition, mostly in the areas of fibre necrosis. Formazan was barely detectable when superoxide dismutase plus catalase were perfused in the XXO system, while it was still apparent when perfused in electrolysed hearts. These results support the hypothesis that electrolysis can be used to generate different species of OFR and to evaluate the protective action of scavenger and antioxidants against OFR-induced myocardial damage.
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PMID:Free radicals generated by electrolysis reduces nitro blue tetrazolium in isolated rat heart. 908 82


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