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)

1. We assessed the effect of polyethylene glycol conjugated superoxide dismutase (PEG-SOD) on myocardial stunning in the rabbit heart in which xanthine oxidase level is extremely low. 2. In open-chest anaesthetized rabbits, the left marginal branch of the coronary artery was occluded for 10 min and then reperfused for 30 min. A group of rabbits (PEG-SOD group) received 1000 units/kg of PED-SOD and another group (control group) was given saline 15 min before the coronary occlusion. 3. Regional systolic thickening fraction (TF) was similarly reduced to approximately -25% of baseline value during ischaemia in both groups. However recovery of TF after reperfusion was significantly better in the PEG-SOD group (n = 9) and TF at 30 min after reperfusion was 70.1 +/- 3.9% of baseline value compared with 44.9 +/- 3.4% in the control group (n = 9; P less than 0.05). Rate-pressure products, left ventricular pressure, and LV dP/dt max were not significantly different between the PEG-SOD treated and untreated control rabbits at any time during the experiment. PEG-SOD did not modify the regional myocardial blood flow (coloured microsphere method) during ischaemia/reperfusion, which was assessed by using separate groups of rabbits. 4. These findings indicate that oxygen free radicals are important in the pathogenesis of myocardial stunning in xanthine oxidase deficient hearts.
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PMID:Superoxide dismutase attenuated post-ischaemic contractile dysfunction in a myocardial xanthine oxidase deficient species. 155 25

In a recent overview on stunning, Bolli listed the three pillars on which theories on stunning rest: its causation by oxygen radicals, the amplification of damage by Ca2+ overload, and the resulting excitation contraction uncoupling. Our own experiments with SOD and catalase do not convince us that stunning is caused by free radicals, because we and others were unable to show improvement. An important pathway of radical generation, i.e., xanthine oxidase, does not exist in the hearts of several families of mammals, but stunning can of course be produced in these species. We agree with Bolli that stunning represents a disturbance of electromechanical coupling, but we acknowledge the controversy that exists with regard to the subcellular seat of the defect. Our results would support hypotheses that pinpoint the defect to the sarcoplasmic reticulum. However, the possibility of multiple defects should also be considered: Our finding of altered Ca2+ ATPase expression and Kusuoka's finding of altered myofibrillar Ca2+ sensitivity are not necessarily mutually exclusive but may be complementary, or may represent different stages of ischemic damage. Our finding of decreased myosin expression may help to explain the long persistence of the contractile defect. From the available evidence, the hypothetial possibility evolves that stunning is not just an injury, but rather the unmasking of a regulatory mechanism to protect the heart against premature or further damage. The observation that coronary occlusion causes both stunning and preconditioning by a parallel, and not by a sequential, mechanism and that a multitude of genes alter their expression in order to protect the myocyte argue for a regulatory change.
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PMID:Molecular mechanisms in "stunned" myocardium. 175 39

1. The delay of ischaemic myocardial necrosis by verapamil has been reported in the dog heart, which contains a high level of xanthine oxidase, a potential source of cytotoxic free radicals. To test whether the retardation of ischaemic myocyte death by verapamil is not an isolated phenomenon in the xanthine oxidase rich heart, we assessed the effect of verapamil in the rabbit heart, which lacks xanthine oxidase. 2. Verapamil (200 micrograms/kg, i.v. bolus plus 40 micrograms/kg per min) was administered in a group of rabbits (n = 5) to test the haemodynamic response to this agent. The heart rate, blood pressure and left ventricular dp/dt max were reduced by 11, 25 and 57%, respectively, and the plasma concentration of verapamil was maintained at 300-400 ng/mL during the infusion. 3. In other groups of rabbits, the effect of the same dosage of verapamil on the size of myocardial infarct after 20 or 30 min ischaemia and 72 h reperfusion was examined. The verapamil was administered for 45 min, starting 15 min prior to ischaemia. The percentage of area at risk infarcted (%I/AAR) was 15.2 +/- 3.9% in the 20 min ischaemia control group and 15.4 +/- 4.5% in the 20 min ischaemia verapamil group, 49.1 +/- 3.4% in the 30 min ischaemia control group and 41.2 +/- 3.3% in the 30 min ischaemia verapamil group. The %I/AAR was significantly smaller in the 20 min ischaemia control groups and 15.4 +/- 4.5% in the 20 min ischaemia there was no difference in %I/AAR between the control and verapamil treated animals in either the 20 or the 30 min ischaemia groups. 4. These results suggest that verapamil does not delay the transition from reversible to irreversible myocardial injury during coronary occlusion in the rabbit, which like the human, lacks myocardial xanthine oxidase.
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PMID:Does verapamil limit myocardial infarct size in a heart deficient in xanthine oxidase? 207 5

Cardioprotection by allopurinol during ischemia is thought to be due to inhibition of xanthine oxidase-derived reactive oxygen intermediates. Previous studies have reported that long pretreatment with allopurinol limits tissue necrosis during acute myocardial ischemia. This study investigated whether a prolonged pretreatment with allopurinol was necessary for cardioprotection. Tissue necrosis was measured in a closed chest canine model of permanent coronary occlusion when the drug was administered post coronary occlusion. In 20 dogs the coronary artery was occluded by an embolus injected into the left coronary artery. Three groups were studied: untreated controls (saline given intravenously post occlusion); allopurinol 1 min post occlusion (25 mg/kg given intravenously, 1 min post occlusion); and allopurinol 30 mins post occlusion (25 mg/kg given intravenously 30 mins post occlusion). Dogs in both drug treatment groups also received allopurinol (25 mg/kg intravenously) every 8 h post coronary occlusion. After 24 h of permanent coronary occlusion tissue necrosis was evaluated using triphenyl tetrazolium chloride staining and was related to major baseline predictors of infarct size, including anatomic risk zone and coronary collateral flow. In control dogs, infarct to risk zone ratio was inversely related to subepicardial collateral flow; analysis of covariance indicated that allopurinol administered post coronary occlusion did not shift this relationship. Treatment with allopurinol within the first minutes after coronary occlusion was ineffective in limiting tissue necrosis in this model of permanent coronary occlusion, therefore, long pretreatment with allopurinol is necessary for cardioprotection.
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PMID:Myocardial salvage with allopurinol during 24 h of permanent coronary occlusion: importance of pretreatment. 322 62

We isolated and purified xanthine oxidase by Sephadex gel filtration and assayed the activity of the enzyme by urate production which we measured by HPLC and UV absorption at 290 nm. We applied this method to extracts of liver and heart of rats, guinea pigs, rabbits, and pigs and to heart of dogs and humans. We found that pig hearts do not exhibit xanthine oxidase activity and that human and rabbit hearts produced small amounts of urate only after hours of incubation. We conclude that xanthine oxidase does probably not play an important part in the mechanisms leading to myocardial infarction using the free radical generating pathway, because it is absent in one species (pig) and barely detectable in two others (rabbit and man) that are known for their rapid and complete infarction following acute coronary occlusion.
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PMID:The activity of xanthine oxidase in heart of pigs, guinea pigs, rabbits, rats, and humans. 342 27

The role of free radicals and the protective action of calcium antagonists have been established in myocardial stunning in canine hearts, which contain a considerable level of xanthine oxidase, a free radical producing enzyme. However, myocardial stunning in hearts which lack xanthine oxidase and its modification by calcium antagonists in vivo remain uncharacterized. The present study examined this issue using open-chest anesthetized rabbits. Myocardial stunning was induced by a 10-min coronary occlusion and reperfusion. Regional systolic thickening fraction (TF) was determined using an epicardial Doppler sensor, together with other hemodynamic parameters. In untreated control rabbits, recovery of TF from the 10 min transient ischemia was 43 +/- 3% of the baseline at 30 min after reperfusion. Administration of verapamil (200 micrograms/kg bolus plus 40 micrograms/kg/min), which was started before the onset of ischemia and continued until 20 min after reperfusion, significantly improved the recovery of TF to 74 +/- 6% (p < 0.05). A similar improvement in post-ischemic contractile function (TF = 77 +/- 10%) was observed when verapamil was injected at the same rate, but the infusion was discontinued 1 min after the coronary occlusion. Myocardial ATP depletion after the 10 min ischemia was significantly less in the verapamil-pretreated rabbits compared with untreated controls (10.1 +/- 1.0 vs. 6.2 +/- 0.7 mumol/g dry wt., p < 0.05). The difference in TF between the rabbit with and without verapamil treatment could not be explained by afterload reduction. When verapamil (100 micrograms/kg bolus plus 20 micrograms/kg/min) was given during the reperfusion period alone, TF recovery was poorer (TF = 22 +/- 8%) than the control value. Thus, it was concluded that verapamil attenuates myocardial stunning in the hearts with trace levels of xanthine oxidase, and that the beneficial effect is achieved only by pretreatment, not by post-ischemic treatment with verapamil.
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PMID:Effects of verapamil on myocardial stunning in xanthine-oxidase deficient hearts: pre-treatment vs. post-ischemic treatment. 801 Sep 31

Indirect evidence suggests that oxygen radicals may contribute to ischemic preconditioning. We directly investigated whether exposure to oxygen radicals per se, in the absence of ischemia, could reproduce the beneficial effects of ischemic preconditioning on infarct size and on postischemic contractile dysfunction. In one branch of the study, isolated rabbit hearts underwent 30 minutes of total global ischemia and 45 minutes of reperfusion (n=6, control group). A second group, before ischemia/reperfusion, was exposed for 5 minutes to a low flux of oxygen radicals generated by purine/xanthine oxidase (P/XO), followed by a 15-minute washout (n=6). Oxygen radical pretreatment significantly improved postischemic recovery of contractile function. We then investigated in another branch of the study whether this preconditioning effect would also reduce infarct size and whether it was mediated by protein kinase C activation. Control hearts were subjected to coronary artery occlusion for 30 minutes, followed by 2.5 hours of reperfusion (n=6). A second group, before coronary occlusion, was exposed to oxygen radicals and washout as described (n=8). A third group was subjected to oxygen radical infusion, but an inhibitor of protein kinase C (polymyxin B, 50 micromol/L) was administered throughout subsequent ischemia (n=7). A fourth group was exposed to oxygen radicals in the presence of scavengers (superoxide dismutase, 250 U/mL; catalase 500, U/mL; n=8). Pretreatment with oxygen radicals markedly reduced infarct size, from 65+/-19% of risk region in controls to 12+/-4% (P<.05). Protein kinase C inhibition significantly attenuated this effect (infarct size, 37+/-9% of risk region; P<.05 versus P/XO; P=NS versus controls). Oxygen radical-induced preconditioning was prevented by scavengers (infarct size, 55+/-14% of risk region; P<.05 versus P/XO; P=NS versus P/XO+polymyxin B). Our data show that in the absence of ischemia, exposure to low concentrations of oxygen radicals can reproduce the beneficial effects of ischemic preconditioning on infarct size and postischemic recovery of left ventricular function. Thus, oxygen radicals might be potential contributors to ischemic preconditioning.
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PMID:Oxygen radicals can induce preconditioning in rabbit hearts. 913 Apr 55

1. The potential for the N-hydroxyguanidine compound PR5 (N-(3, 4-dimethoxy-2-chlorobenzylideneamino)-N'-hydroxyguanidine) as a cardioprotective agent in heart ischaemia and reperfusion injury was investigated using rat models. 2. Administration of 1-10 mg kg-1 of PR5 5 min before 10 min of left coronary artery occlusion, followed by 20 min reperfusion, strongly inhibited reperfusion burst of arrhythmias and markedly improved the survival of the animals (e.g. ventricular fibrillation incidence 93 vs 43% (P<0.05); mortality 47 vs 0% (P<0.05), for controls and for 3 mg kg-1 of PR5, respectively). 3. Administration of 3 mg kg-1 of PR5 1 min before reperfusion to rats subjected to 10 min occlusion, 20 min reperfusion was most effective in reducing arrhythmias and decreasing mortality (43 vs 0%, P<0.05), but effects were also seen when PR5 was administered 0, 1 and 5 min after start of reperfusion. 4. Coronary occlusion/reperfusion (10 - 20 min) increased malondialdehyde (MDA) of rat hearts (0.88+/-0.13 for sham vs 1.45+/-0.12 nmol mg-1 protein for ischaemic; P<0.05). In rats where 3 mg kg-1 PR5 were administered 1 min before reperfusion the increase was attenuated (MDA being 1.04+/-0.12; P<0.05 vs ischaemic). 5. PR5 caused a substantial reduction of the infarction size in rats subjected to 180 min left coronary artery occlusion, followed by 120 min of reperfusion; the necrotic zone being 326+/-32 mg for controls vs 137+/-21 mg for animals treated with 3x3 mg kg-1 of PR5 (P<0.01). 6. PR5 reduced the elevation of the ST-segment of the ECGs, as well as caused pronounced attenuation of the rapid blood pressure drop seen at the start of reperfusion following coronary artery occlusion. 7 We conclude that the N-hydroxyguanidine PR5 provides remarkable protection against ischaemia and reperfusion induced myocardial necrosis and life-threatening arrhythmias. These effects of PR5 are discussed in relation to a recently discovered ability of N-hydroxyguanidines to function as electron acceptors at the xanthine oxidase enzyme.
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PMID:Cardioprotective effects of N-hydroxyguanidine PR5 in myocardial ischaemia and reperfusion in rats. 1055 47

Both free radicals (FRs) and adenosine receptor activation contribute to triggering a mechanism of preconditioning (PC) against infarction. This study examined the possibility that there is some interaction between FRs and adenosine generation during PC. In the first series of experiments, the effects of an FR scavenger, N-2-mercaptopropionyl glycine (MPG), on the interstitial adenosine level during PC and on the infarct size-limiting effect of PC were assessed in the rabbit heart in situ. PC with 5-min ischemia/5-min reperfusion limited infarct size after 30-min coronary occlusion (expressed as a percentage of area at risk, %IS/AR) from 33.2 +/- 4.7% (S.E.) to 10.8 +/- 1.1% (p < 0.05). This cardioprotection was blocked by MPG (1.5 mg/kg/min i.v.) infused before and during PC (%IS/AR = 27.4 +/- 3.6). However, the same dose of MPG did not suppress elevation of the adenosine and inosine levels in the microdialysate from the myocardium during 5-min ischemia/reperfusion. In the second series of experiments, the effect of an FR-generating system (1 mM hypoxanthine and 20 mU/ml xanthine oxidase) on the purine production was compared to that of PC in isolated rabbit hearts. Whereas PC increased the adenosine level in the coronary effluent from 0.17 +/- 0.16 microM under baseline to 1.68 +/- 0.53 microM, infusion of the FR generators over a period of 5 min did not increase the adenosine release. However, infarct size was similarly reduced by PC and by 5-min transient infusion of FR generators, and the cardioprotection by the FR generators was abolished by 300 microM MPG. These results suggest that there is no interaction between free radicals and adenosine during the trigger phase of PC in the rabbit heart.
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PMID:Relationship between free radicals and adenosine in the mechanism of preconditioning: are they interrelated or independent triggers? 1105 47

Nitric oxide (NO) may limit myocardial ischemia-reperfusion injury by slowing the mitochondrial metabolism. We examined whether rat heart contains catalysts potentially capable of reducing nitrite to NO during an episode of regional myocardial ischemia produced by temporary coronary artery occlusion. In intact Sprague-Dawley rats, a 15-min coronary occlusion lowered the nitrite concentration of the myocardial regions exhibiting ischemic glucose metabolism to approximately 50% that of nonischemic regions (185 +/- 223 vs. 420 +/- 203 nmol/l). Nitrite was rapidly repleted during subsequent reperfusion. The heart tissue tested in vitro acquired a substantial ability to consume nitrite when made hypoxic at neutral pH, and this ability was slightly enhanced by simultaneously lowering the pH to 5.5. More than 70% of this activity could be abolished by flushing the coronary circulation with crystalloid to remove trapped erythrocytes. Correspondingly, erythrocytes demonstrated the ability to reduce exogenous nitrite to NO under hypoxic conditions in vitro. In erythrocyte-free heart tissue, the nitrite consumption increased fivefold when the pH was lowered to 5.5. Approximately 40% of this pH-sensitive increase in nitrite consumption could be blocked by the xanthine oxidoreductase inhibitor allopurinol, whereas lowering the Po(2) sufficiently to desaturate myoglobin accelerated it further. We conclude that rat heart contains several factors capable of catalyzing ischemic nitrite reduction; the most potent is contained within erythrocytes and activated by hypoxia, whereas the remainder includes xanthine oxidoreductase and other pH-sensitive factors endogenous to heart tissue, including deoxymyoglobin.
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PMID:Nitrite consumption in ischemic rat heart catalyzed by distinct blood-borne and tissue factors. 1882 31


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