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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations which occur during ischemia are reviewed. They modify the metabolic status in such a way they prepare the cell to an anomalous response to reoxygenation. The consequence of this disturbance is the generation of oxygen free radicals through several mechanisms, including the mitochondrial oxidative phosphorylation, the arachidonic acid cascade, the activation of xanthine oxidase, activation of phagocytes, iron mobilization, etc. Reduced glutathione is exhausted, proteins are inactivated. Lipid peroxidation induces membrane breakdown and cellular death.
Rev Port Cardiol 1992 Nov
PMID:Ischemia, reperfusion and oxygen free radicals. 129 Jun 47

The aim of this work was to assess the catalytic activity of xanthine oxidase, the level of lipid peroxides and enzymic antioxidant systems in isolated rat heart muscle subjected to a globally partial ischemia followed by varying durations of reperfusion. After 40 min of globally partial ischemia (residual perfusion flow rate: 0.1 ml/min), four different durations of reperfusion were investigated (0, 20, 40, and 60 min). After each experimental ischemia/reperfusion sequence, the heart was frozen in liquid nitrogen. Lipid peroxides were assayed in the cardiac homogenate and the catalytic activity of xanthine oxidase and enzymic antioxidant systems (glutathione peroxidase, superoxide dismutase and catalase) were determined in the centrifuged supernatant. In the different experimental protocols studied in this work, there was no significant increase in the activity of cardiac xanthine oxidase or in the level of lipid peroxides when compared to the non reperfused or to the continuously perfused hearts. Indeed, enzymic antioxidant systems were also not significantly modified in the different periods of reperfusion when compared to control hearts (continuously perfused hearts). These results suggest that xanthine oxidase is apparently not a major source of free radicals in the course of an ischemia-reperfusion sequence in heart muscle, in particular, if we consider the early phases of reperfusion. The process of lipid peroxidation, assessed by assaying thiobarbituric acid reactants, is not a predominant phenomenon of reperfusion-induced injury, at least in the experimental model used here. However, enzymic antioxidant systems investigated in this study do not seem modified. This could mean that the small quantity of oxygen free radicals produced does not overwhelm the enzymic antioxidant systems of myocardium which is in agreement with peroxidatized lipid results.
Basic Res Cardiol
PMID:Ischemia and reperfusion injury in isolated rat heart: effect of reperfusion duration on xanthine oxidase, lipid peroxidation, and enzyme antioxidant systems in myocardium. 146 31

Free oxygen radicals are formed during early reperfusion and are thought to contribute to some types of reperfusion abnormalities, including arrhythmias and myocardial stunning. The purpose of this study was to investigate electrophysiological effects of oxygen free radicals using voltage clamped single ventricular myocytes from guinea-pig hearts. Oxygen free radicals were produced enzymatically by the direct addition of xanthine oxidase (XOD, 0.04 U/ml) in the experimental chamber to a solution containing hypoxanthine (0.96 mM). The generation of oxygen radicals was confirmed by the formation of adrenochrome from adrenaline. Oxygen radicals caused automaticity of isolated myocytes within 20-30 min, followed by later hypercontracture. The percentage of rod-shaped cells declined sigmoidally as a function of time, with a half maximal value at 40.9 +/- 1.6 min, and a Hill slope of -0.10 +/- 0.01 (n = 26). These effects were prevented by a combination of superoxide dismutase (10(5) U/L) plus catalase (10(6) U/L). The rate at which cells underwent morphological shape changes was unchanged by ryanodine (0.5 microM) which is thought to act on the sarcoplasmic reticulum or by the Ca2+ channel blockers nisoldipine (1 microM) or Cd2+ (30 microM). Cellular automaticity and hypercontracture were delayed by variable degrees, and sometimes completely prevented, by zero (1 mM EGTA) extracellular Ca2+, MnCl2 (2 mM) and LaCl3 (50 microM), and amiloride (1 mM). On the other hand, in the presence of a low extracellular Na+ (30 mM) or caffeine (10 mM), hypercontracture occurred at a faster time scale. Whole cell voltage clamping revealed a decrease of the inward rectifying K+ current (IK1), and a decrease of the peak of the L-type Ca2+ current (ICa,L). The total ICa,L during the clamp step was increased, mainly because of an increased time constant of inactivation (47.6 +/- 4.7 ms to 72.7 +/- 15.5 ms after 30 min, n = 4, P less than 0.05). We conclude that oxygen radicals cause automaticity and hypercontracture of isolated myocytes, that these effects may be due to an increased intracellular Ca2+ concentration ([Ca2+]i), and despite an increased ICa,L, that the enhanced Ca2+ influx may occur predominantly via the Na/Ca exchange.
J Mol Cell Cardiol 1992 Jun
PMID:Effects of oxygen free radicals on isolated cardiac myocytes from guinea-pig ventricle: electrophysiological studies. 151 81

Isolated working rat hearts were subjected to aerobic perfusion (25 min), cardioplegic infusion (3 min), global ischemia (30 min at 37 degrees C) and reperfusion (35 min). Measurements of myocardial xanthine oxidase and dehydrogenase activity, together with various adenine nucleotides and metabolites, were made at defined stages of the protocol (n = 6/group). Allopurinol pretreatment (20 mg/kg body wt/day for 3 days) improved the postischemic recovery of cardiac function; thus, aortic flow (a representative index) recovered to 68.8 +/- 4.2% compared with 53.2 +/- 2.3% in untreated controls (p less than 0.05). In fresh tissue, allopurinol pretreatment inhibited xanthine dehydrogenase activity by 73.1% (from 11.9 +/- 0.5 to 3.2 +/- 0.8 mIU/g wet wt: p less than 0.05) and xanthine oxidase activity by 95.2% (from 8.3 +/- 1.2 to 0.4 +/- 0.2 mIU/g wet wt: p less than 0.05); however, this inhibition was not maintained during perfusion. During reperfusion, myocardial xanthine dehydrogenase and oxidase activity was reduced by 40-60% (p less than 0.05) in both allopurinol pretreated and control hearts. Tissue content of creatine phosphate, adenosine triphosphate and catabolites, NAD and inorganic phosphate were not different in allopurinol pretreated or control hearts during either ischemia or reperfusion. This study does not support the concept that allopurinol protects the rat heart during ischemia and reperfusion by inhibition of xanthine oxidase activity or by conservation of purines. It appears that allopurinol achieves its protective effects by some, as yet undefined, mechanism.
Basic Res Cardiol
PMID:Allopurinol-enhanced myocardial protection does not involve xanthine oxidase inhibition or purine salvage. 152 Feb 48

Reperfusion of ischaemic myocardium is necessary to sustain tissue viability (without it the tissue becomes necrotic), but reperfusion, on the other hand, can damage cells which have survived ischaemia. There is now considerable evidence that oxygen radicals, especially hydroxyl radicals produced via the Haber-Weiss and Fenton reactions, are responsible for reperfusion damage. Various investigators have reported that desferal, an iron chelator, has a beneficial effect on the myocardium during ischaemia and reperfusion. The aim of this study was two-fold: i) whether superoxide anions in the absence of LMWI can impair mitochondrial function, and ii) whether the protective effect of desferal on the mitochondrial function persists after withdrawal of desferal. Experiments were done on isolated rat hearts subjected to normothermic ischaemic cardiac arrest (NICA), with or without desferal, followed by 15-min reperfusion with desferal, followed by 15-min perfusion without desferal, or a hypoxanthine/xanthine oxidase medium that generates superoxide anions (with or without desferrioxamine (desferal) in the perfusate). Mitochondrial function (QO2 (state 3), ADP/O and OPR) as well as LMWI were measured. Our results indicated that i) superoxide anions and/or hydrogen peroxide can, independently of LMWI, damage the mitochondria, and ii) withdrawal of desferal after the respiratory burst resulted in the same or more severe mitochondrial damage than without any desferal.
Basic Res Cardiol
PMID:The protective effect of desferal on rat myocardial mitochondria is not prolonged after withdrawal of desferal. 156 53

The metabolic fate of labeled hypoxanthine and inosine, degradation products of adenine nucleotides, was studied in cultured beating cardiomyocytes, in order to assess the physiological significance of their contribution to salvage nucleotide synthesis in the heart. Inosine and hypoxanthine were found to be incorporated into nucleotides by a similar rate, but in the presence of 8-aminoguanosine, a potent inhibitor of purine nucleoside phosphorylase (EC 2.4.2.1), the rate of inosine incorporation into nucleotides was markedly reduced (by 75%), indicating that inosine incorporation to IMP (inosinic acid) occurs following its degradation to hypoxanthine. The proportion of hypoxanthine converted to IMP by hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) is markedly greater than that degraded to xanthine and uric acid by xanthine oxidase (EC 1.3.2.3). However, close to 50% of the IMP formed was degraded to inosine by IMP 5'-nucleotidase (EC 3.1.3.5). The results demonstrate the activity of the following futile cycle in the cardiomyocytes: hypoxanthine----IMP----inosine----hypoxanthine. The rational for the activity of this energy consuming cycle is yet unclear.
J Mol Cell Cardiol 1992 Feb
PMID:Metabolic fate of hypoxanthine and inosine in cultured cardiomyocytes. 158 1

Oxygen free radicals have been shown to play a major role in the development of perfusion abnormalities, contractile dysfunction, and irreversible injury in ischemic-reperfused myocardium. The aim of this study was to assess the direct protective effects of radical scavengers, calcium antagonists, and combination of these substances against free radical induced myocyte damage. Viability (% of rod-shaped cells) and adenine nucleotide content (AdN, high-pressure liquid chromatography) of isolated adult rat cardiomyocytes were measured after exposure to hypoxanthine (2 mM) and xanthine oxidase (25 mU/ml). After 90 min, viability of myocytes decreased to 4.2 +/- 3.4% (mean +/- SEM) of pre-exposure control, and AdN decreased from 28.2 +/- 1.8 to 8.09 +/- 1.1 nmol/mg protein. Addition of catalase (1500 U/ml) resulted in the preservation of viability (77 +/- 6% of pre-exposure control, n = 6, mean +/- SEM), and AdN 84 +/- 6%, p less than 0.001. These values are not significantly different from those measured in myocytes not exposed to free radicals (88 +/- 9% and 79 +/- 6%, respectively). Superoxide dismutase (2400 U/ml), dimethylthiourea (10 mM), and desferrioxamine (1 mM) did not preserve either viability or AdN. The calcium antagonist verapamil (10 microM) also preserved myocyte viability significantly (23 +/- 9.7%, p less than 0.05 vs unprotected cells), but failed to prevent the loss of AdN (13.2 +/- 4%, not significant as compared to unprotected cells). Viability and AdN in myocytes treated with nifedipine (10 microM) or diltiazem (10 microM) were not higher than in unprotected cells. All combined treatment forms which included catalase resulted in the preservation of myocyte viability as well as AdN. These data show that only the hydrogen peroxide scavenger catalase protects isolated cardiomyocytes against free radicals generated in the purine catabolic pathway.
Basic Res Cardiol
PMID:Oxygen free radical damage of isolated cardiomyocytes: comparative protective effect of radical scavengers and calcium antagonists. 159 Jul 37

It has been shown that allopurinol, an inhibitor of xanthine oxidase, may limit the extent of myocardial infarction in dogs. In the present work, we studied the effect of a chronic administration of allopurinol on myocardial infarct size measured histochemically 48 h after in situ left coronary artery ligation in the rat. Our results indicate that allopurinol pretreatment does not produce any limitation of the extent of necrosis, but induces a significant increase in the volume of the non-ischemic portion of the myocardium, accompanied by an increase in protein content. This phenomenon, which could be due to the development of an edema in the non-ischemic portion of the myocardium, may well explain some discrepancies reported in previous experimental studies in which the infarct size was conventionally expressed as a percentage of the total volume of ventricular tissue. We have also shown that allopurinol pretreatment failed to improve the residual cardiac function in rats after left coronary artery ligation. We conclude that the enzyme xanthine oxidase is probably not involved in the pathophysiology of myocardial infarction in the rat because of the absence of collateral vasculature in this species which prevents any oxygen supply to the ischemic zone. In most other mammals such as the dog, the existence of a collateral system maintains a residual blood flow and oxygen supply to the ischemic portion of ligated hearts, allowing the xanthine oxidase-induced production of superoxide anions to be activated, thereby initiating peroxidative lesions in membrane lipids.
Basic Res Cardiol
PMID:Chronic administration of allopurinol fails to exert any cardioprotective effect in rats submitted to permanent coronary artery ligation. 177 86

In the reoxygenated hypoxic heart, hypoxanthine is either oxidized by xanthine oxidase with production of toxic oxygen species or salvaged for the ATP pool by hypoxanthine-guanine phosphoribosyl transferase. To characterize the repartition of hypoxanthine between the two pathways, we have subjected rat hearts to 20 min hypoxia and monitored the recovery (ventricular, end-diastolic and coronary pressures, and the contraction rate) during the reoxygenation (30 min) in the presence of either hypoxanthine or guanine alone, or both. The rate-pressure product recovered 78% of the pre-hypoxia values in hearts reoxygenated with 100 microM hypoxanthine and 80% in hearts reoxygenated with 100 microM guanine, in contrast to 49% in the presence of both hypoxanthine and guanine (100 microM each). Thus, it is likely that hypoxanthine is salvaged when present alone and is oxidized generating the reperfusion injury when the salvage is prevented by guanine that competes with hypoxanthine from the same site of hypoxanthine-guanine phosphoribosyl transferase. The functional impairment was slower when hypoxanthine was replaced by xanthine, and was eliminated by superoxide dismutase and catalase, indicating that the injury is caused by toxic oxygen species generated from hypoxanthine and xanthine oxidase. These data suggest that the salvage pathway may be critical in preventing the reperfusion injury in hypoxic hearts.
J Mol Cell Cardiol 1991 Jan
PMID:Dual role of hypoxanthine in the reoxygenation of hypoxic isolated rat hearts. 203 69

The pathogenesis of post-ischaemic depression of contractility in myocardium was examined in isovolumic rat heart. 31P-NMR was used to monitor changes in ATP, creatine phosphate (CrP), inorganic phosphate (Pi), and [H+] during brief periods of ischaemia and reperfusion with and without allopurinol treatment. During 5, 10, or 15 min of total global ischaemia, the decline in function (rate-pressure product) correlated inversely with [Pi] (r = 0.92, P less than 0.01). Cardiac function exhibited a slow progressive recovery during 20 min of reperfusion, ultimately reaching only 85%, 78%, and 69% of its pre-ischaemic value following 5, 10, and 15 min of global ischaemia respectively. Following each ischaemic period [ATP], [CrP], [Pi], and [H+] all recovered to control levels within 5-10 min of initiating reperfusion. Allopurinol (2 mM) treatment of hearts made ischaemic for 15 min significantly improved contractile recovery to 89 +/- 7%. Allopurinol also exhibited significant anti-arrhythmic activity during the reperfusion period, decreasing the incidence of premature contractions and the duration of tachy-arrhythmias. Allopurinol had no effect on the final repletion of [ATP] and [CrP], or the recovery of [Pi] and [H+], although the rate of ATP repletion was elevated in the initial 5 min of reperfusion. These results show that neither depletion of the cytosolic high-energy phosphate pool, nor sustained elevations in [Pi] or [H+] are important in the production of post-ischaemic contractile impairment. The beneficial action of allopurinol suggests that xanthine oxidase derived oxygen free-radicals may be involved in the sustained contractile dysfunction following brief ischaemic episodes.
J Mol Cell Cardiol 1990 Oct
PMID:Behaviour of energy metabolites and effect of allopurinol in the "stunned" isovolumic rat heart. 209 34


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