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

Oxygen-derived free radicals have been implicated in ventricular arrhythmogenesis during coronary reperfusion following an acute ischemic event. We have investigated the possibility that uric acid, a potentially important physiological antioxidant (inhibits lipid peroxidation and scavenges various radical species during oxidation to allantoin), or oxonic acid (inhibitor of uricase enzyme), are able to prevent reperfusion-induced ventricular dysrhythmias in isolated buffer-perfused rat hearts. Rat hearts (n = 12/group) underwent 15 minutes occlusion; arrhythmias were monitored during ischemia and for 10 minutes of reperfusion. There was no difference in the incidence of ventricular fibrillation or ventricular tachycardia in either uric acid or oxonic acid treated hearts compared to untreated controls. Mean duration of ventricular fibrillation appeared to be reduced in hearts treated with 10(-3) and 10(-4) M oxonic acid compared to controls but these data did not achieve a level of statistical significance. These results demonstrate that uric acid and oxonic acid failed to prevent reperfusion-mediated ventricular dysrhythmias in this experimental preparation. Although oxygen-derived free radicals may contribute to the initiation of either ischemia- or reperfusion-induced arrhythmogenesis, our findings provide little support for this hypothesis.
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PMID:Reperfusion-induced arrhythmias are not prevented by uric acid in the isolated rat heart. 193 49

The relationship between nucleotide catabolism and generation of activated oxygen species was investigated in liver, hepatocytes and small intestine of rats. In severe hypoxia nucleotide degradation via xanthine oxidase and urate oxidase requires about half of the oxygen consumed. Data on the changes of nucleobase compounds in rat hepatocytes and small intestine during ischemia and reoxygenation and the effects of allopurinol and oxypurinol thereon are presented. From EPR measurements it is concluded that OH. radicals induce reactions of allopurinol yielding long-living products which are able to react with DMPO-OH with loss of its radical properties.
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PMID:Regulation of purine nucleotide metabolism in hypoxic liver and intestine of rats: radical scavenging effects of allopurinol and oxypurinol. 261 Jan 38

Rat livers were initially perfused and then stored at various temperatures up to 4 h. The intra- and extrahepatic status of glutathione, the accumulation of hydrogen peroxide in the preservation medium, the action of a OH-scavenger and of a xanthine oxidase-inhibitor were investigated as candidates for the assessment of oxidative alterations due to ischemia. Furthermore respiratory functions of mitochondria were measured. The increased efflux of GSSG from the liver tissue, the increase of the GSSGtot/GSHtot-ratio and the favourable effects of formate as OH-scavenger and of allopurinol as xanthine oxidase-inhibitor confirm the hypothesis about the oxidative damage under conditions of oxygen deficiency. The nucleotide degradation, especially the steps catalyzed by xanthine oxidase and uricase, is the main metabolic pathway for the generation of oxygen radicals under ischemic conditions.
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PMID:Status of glutathione in the rat liver. Enhanced formation of oxygen radicals at low oxygen tension. 667 Sep 97

Tyrosine nitration is a common modification to proteins in vivo, but the reactive nitrogen species responsible for nitration are often studied in vitro using just the amino acid tyrosine in simple phosphate solutions. To investigate which reactive nitrogen species could nitrate proteins in a complex biological system, we exposed rat heart and brain homogenates to peroxynitrite, nitric oxide under aerobic conditions, and other putative nitrating agents. Peroxynitrite was by far the most efficient nitrating agent when alternative targets were available to compete with tyrosine. Curiously, proteins in heart homogenates were substantially more resistant to nitration than brain homogenates. Ultrafiltration to remove low molecular weight compounds made the heart proteins equally susceptible as the brain proteins to nitration. Endogenous ascorbate and free thiols had little effect on nitration by peroxynitrite in either heart or brain. However, accumulation of urate formed by the oxidation of hypoxanthine by xanthine dehydrogenase and oxidase in heart appeared to be the major inhibitor of nitration. Heart homogenates treated with uricase, which converts urate to allantoin, showed equivalent nitration as in brain homogenates. Urate, as assayed by HPLC, was 58 +/- 8 microM in heart but only 4 +/- 2 microM in brain homogenates. Although xanthine dehydrogenase conversion to a free radical-producing oxidase can serve as an important source of superoxide and hydrogen peroxide during ischemia/reperfusion, our results suggest that urate formation by xanthine dehydrogenase may provide a significant antioxidant defense against peroxynitrite and related nitric oxide-derived oxidants.
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PMID:Urate produced during hypoxia protects heart proteins from peroxynitrite-mediated protein nitration. 1239 32

Prolonged hyperuricemia is associated with the development of hypertension, renal arteriolosclerosis, glomerulosclerosis, and tubulointerstitial injury. It confers a greater risk than proteinuria for developing chronic renal disease and is associated with the development of hypertension. Mild chronic hyperuricemia without intrarenal crystal deposition was induced in rats by inhibiting uricase with oxonic acid. Hyperuricemic rats developed hypertension, afferent arteriolar thickening, and mild renal interstitial fibrosis. Additionally, hyperuricemia accelerated renal damage and vascular disease in rats undergoing renal ablation. To better understand the role of hyperuricemia in the kidney, micropuncture studies were performed. Hyperuricemia resulted in renal cortical vasoconstriction (single nephron glomerular filtration rate (SNGFR) 35%, P < .05) and glomerular hypertension (P < .05). The possibility that hyperuricemia could modify renal hemodynamic disturbances during progression of renal disease was tested in rats with 5/6 nephrectomy. Hyperuricemia accentuated the renal vascular damage and caused cortical vasoconstriction (SNGFR 40%, P < .05) and persistent glomerular hypertension. In conclusion, hyperuricemia impairs the autoregulatory response of preglomerular vessels, resulting in glomerular hypertension. Lumen obliteration induced by vascular wall thickening results in severe vasoconstriction. The resulting ischemia is a potent stimulus that induces tubulointerstitial inflammation and fibrosis as well as arterial hypertension.
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PMID:Hemodynamics of hyperuricemia. 1566 Mar 30

Since the discovery of hydrogen peroxide in 1819 it was known as a toxic agent for human organs. Due to the recent findings its role should be reevaluated. This review discusses the toxic and physiological roles of hydrogen peroxide and functions of enzyme catalase which is the main regulator of hydrogen peroxide metabolism. The concentration of hydrogen peroxide changes between 0,05 micromol/l and 117 micromol/l in exhaled breath condensate and in human fluids. Hydrogen peroxide is generated by physiological processes such as glycation, phagocytosis, cell metabolism and by pathological changes such as different tumors and side effects of some drugs. The main regulator of toxic concentration of hydrogen peroxide is the enzyme catalase while glutathione peroxidase and hemoglobin has a limited role in this process. Low concentration of hydrogen peroxide plays a role in degradation of some proteins, as a messenger in cell signaling and could contribute to apoptosis. The enzyme catalase, due to its structure and function, is very effective in destroying the toxic concentration of hydrogen peroxide without changing its low, physiologic concentration. Decrease in catalase due to anemia, decreased synthesis and especially to its inherited deficiency may be a risk factor in diabetes, cell damage due to ischemia, in uricase and ascorbic acid treatment as well as in sterilization with hydrogen peroxide. The hydrogen peroxide paradox means that its low concentration is vital for some physiological processes while its high concentration is toxic for human cells. The main regulator of hydrogen peroxide concentration is the enzyme catalase and its deficiency may be a risk factor for some pathological changes.
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PMID:[The hydrogen peroxide paradox]. 1678 44

Neonatal hypoxia ischemia is characterized by inadequate blood perfusion of a tissue or a systemic lack of oxygen. This condition is thought to cause/exacerbate well documented neonatal disorders including neurological impairment. Decreased adenosine triphosphate production occurs due to a lack of oxidative phosphorylation. To compensate for this energy deprived state molecules containing high energy phosphate bonds are degraded. This leads to increased levels of adenosine which is subsequently degraded to inosine, hypoxanthine, xanthine, and finally to uric acid. The final two steps in this degradation process are performed by xanthine oxidoreductase. This enzyme exists in the form of xanthine dehydrogenase under normoxic conditions but is converted to xanthine oxidase (XO) under hypoxia-reperfusion circumstances. Unlike xanthine dehydrogenase, XO generates hydrogen peroxide as a byproduct of purine degradation. This hydrogen peroxide in combination with other reactive oxygen species (ROS) produced during hypoxia, oxidizes uric acid to form allantoin and reacts with lipid membranes to generate malondialdehyde (MDA). Most mammals, humans exempted, possess the enzyme uricase, which converts uric acid to allantoin. In humans, however, allantoin can only be formed by ROS-mediated oxidation of uric acid. Because of this, allantoin is considered to be a marker of oxidative stress in humans, but not in the mammals that have uricase. We describe methods employing high pressure liquid chromatography (HPLC) and gas chromatography mass spectrometry (GCMS) to measure biochemical markers of neonatal hypoxia ischemia. Human blood is used for most tests. Animal blood may also be used while recognizing the potential for uricase-generated allantoin. Purine metabolites were linked to hypoxia as early as 1963 and the reliability of hypoxanthine, xanthine, and uric acid as biochemical indicators of neonatal hypoxia was validated by several investigators. The HPLC method used for the quantification of purine compounds is fast, reliable, and reproducible. The GC/MS method used for the quantification of allantoin, a relatively new marker of oxidative stress, was adapted from Gruber et al. This method avoids certain artifacts and requires low volumes of sample. Methods used for synthesis of MMDA were described elsewhere. GC/MS based quantification of MDA was adapted from Paroni et al. and Cighetti et al. Xanthine oxidase activity was measured by HPLC by quantifying the conversion of pterin to isoxanthopterin. This approach proved to be sufficiently sensitive and reproducible.
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PMID:Biochemical measurement of neonatal hypoxia. 2189 51

Among mammals, there is a positive correlation between serum uric acid (UA) levels and life span. Humans have high levels of UA because they lack a functional urate oxidase (UOX) enzyme that is present in shorter lived mammals. Here, we show that male and female mice with UOX haploinsufficiency exhibit an age-related elevation of UA levels, and that the life span of female but not male UOX+/- mice is significantly increased compared to wild-type mice. Serum UA levels are elevated in response to treadmill exercise in UOX+/- mice, but not wild-type mice, and the endurance of the UOX+/- mice is significantly greater than wild-type mice. UOX+/- mice exhibit elevated levels of brain-derived neurotrophic factor, reduced brain damage and improved functional outcome in a model of focal ischemic stroke. Levels of oxidative protein nitration and lipid peroxidation are reduced in muscle and brain tissues of UOX+/- mice under conditions of metabolic and oxidative stress (running in the case of muscle and ischemia in the case of the brain), consistent with prior evidence that UA can scavenge peroxynitrite and hydroxyl radical. Our findings reveal roles for UA in life span determination, endurance and adaptive responses to brain injury, and suggest novel approaches for protecting cells against injury and for optimizing physical performance.
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PMID:Uric acid enhances longevity and endurance and protects the brain against ischemia. 3057 85

Uric acid (UA) is a product of the catabolism of purine nucleotides, the principal constituents of DNA, RNA, and cellular energy stores, such as adenosine triphosphate. The main properties of UA include scavenging of hydroxyl radicals, superoxide anion, hydrogen peroxide, and peroxynitrite that make this compound to be the most potent antioxidant in the human plasma. As the result of two silencing mutations in the gene of the hepatic enzyme uricase which degrades UA to allantoin, humans have higher levels of UA than most mammals. However, these levels rapidly decrease following an acute ischemic stroke (AIS), and this decrement has been associated to worse stroke outcomes. This review highlights the safety and potential clinical value of UA therapy in AIS, particularly in patients more exposed to redox-mediated mechanism following the onset of ischemia, such as women, hyperglycemic patients, or patients treated with mechanical thrombectomy. The clinical findings are supported by preclinical data gathered in different laboratories, and in assorted animal species which include male and female individuals or animals harboring comorbidities frequently encountered in patients with AIS, such as hyperglycemia or hypertension. A remarkable finding in these studies is that UA targets its main effects in the brain vasculature since available evidence suggests that does not seem to cross the blood-brain barrier. Altogether, the available data with UA therapy extend the importance of vasculoprotection for effective neuroprotection at the bedside and reinforce the role of endothelial cells after brain ischemia for an increased survival of the whole neurovascular unit.
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PMID:Uric acid therapy for vasculoprotection in acute ischemic stroke. 3133 57