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)

If myocardial ischemia always results from an imbalance between the needs and supplies in oxygen of the myocardium cells, the physiopathology of this process seems today infinitely more complex than the mere diminution or interruption of the output in a coronary artery. The extension of atheromatous lesions, the platelets aggregation, thrombosis, the coronary spasm, the release of products from the arachidonic cascade, the reactivity of the vascular endothelium, the profibrinolytic activity of the tissues are many of the intricate factors inducing myocardial ischemia. Cellular alterations, of which some are triggered by the release of oxygenated free radicals, lead then to an irreversible necrosis. The medications used until now in the treatment of angina are oxygen scavengers and research goes on in this direction with vaso-dilators beta-blockers, prolonged action nitro-compounds (nicorandil) or nitro-compounds with an action reinforced by N-acetyl-cysteine, bradycardiac derivates of alinidine and the new calcium antagonists dihydropyridine. However, the new physiopathological concepts of ischemia have opened new directions for the research: products which modify the arachidonic cascade by increase of synthesis or release of PGI2 (nafazatrom, defibrotide), by inhibition of TXA2 synthesis or blocking of TXA2 receptors, and similar products of PGI2 (iloprost); thrombolytic agents more specific of thrombin (PTA) or fibrinolysis activators (defibrotide), and anticoagulants with extended action; chelating agents of oxygenated free radicals (peroxide dismutase, catalase, peroxidase) or xanthine oxidase inhibitors; platelets anti-aggregates like ticlopidine which blocks the platelets receptors to fibrinogen, or inhibitors of the synthesis of pro-aggregating agents.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Current therapeutic concepts in the treatment of myocardial ischemia. Current and future drugs]. 287 4

Oster has postulated that the enzyme xanthine oxidase in homogenized cow's milk is the cause of myocardial infarction and angina pectoris. This enzyme may be absorbed by ingestion, especially of the small particles of the fat globules, and then carried by lymph streams to the arterial vascular system, where it is deposited into the myocardium. Then it destroys the aldehydes liberated from the cell membrane-based plasmalogens. This results in the intimal damage to the cell membranes of the arterial intima and the myocardium and ultimately in the development of typical atherosclerotic lesions in the arteries. The presented review is a critical approach to this hypothesis. The following factors are discussed: - the influence of conditions prevailing in the intestine and the stomach on the activity of the xanthine oxidase in milk, - the possibility of this enzyme being absorbed in the intestine, - the formation of antibodies against absorbed xanthine oxidase and - the behaviour of xanthine oxidase administered intravenously. Compared with present knowledge, this theory gives little evidence only.
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PMID:[Xanthine oxidase in homogenized cow's milk and Oster's hypothesis: a review]. 636 27

The aim of this study was the elucidation of the role of the xanthine oxidoreductase in the purine metabolism in ischaemic diseases of man. The serum concentrations of hypoxanthine, xanthine, uric acid and allantoin were determined in peripheral blood samples from patients with angina pectoris, cerebral insult and myocardial infarction with thrombolytic therapy and were compared with the concentrations obtained for healthy males and females. No significant differences were observed for the serum hypoxanthine concentrations, xanthine concentrations, the sum (hypoxanthine+xanthine) and the ratio (xanthine/hypoxanthine) between the healthy males, healthy females, the patients suffering from angina pectoris and the patients suffering from cerebral insult. An increase of the serum xanthine concentration in patients with myocardial infarction indicates a significant metabolic involvement of xanthine oxidoreductase in this disease and therefore a possible role in the development of tissue damage in the postischaemic phase due to oxygen radicals generated by the oxidase activity of this enzyme. The serum concentrations of uric acid and allantoin showed no differences between any of the studied groups. Study of the non-enzymatic oxidation of uric acid to allantoin by oxygen radicals, a relevant radical-scavenging mechanism in other diseases, provided no indication of an increased concentration of oxygen radicals due to the xanthine oxidoreductase reaction or other radical-producing mechanisms.
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PMID:A comparative study of the concentrations of hypoxanthine, xanthine, uric acid and allantoin in the peripheral blood of normals and patients with acute myocardial infarction and other ischaemic diseases. 788 80

Activation of cardiac sympathetic afferents during myocardial ischaemia causes angina and induces important cardiovascular reflex responses. Reactive oxygen species (ROS) are important chemical stimuli of cardiac afferents during and after ischaemia. Iron-catalysed Fenton chemistry constitutes one mechanism of production of hydroxyl radicals. Another potential source of these species is xanthine oxidase-catalysed oxidation of purines. Polymorphonuclear leukocytes (PMNs) also contribute to the production of ROS in some conditions. The present study tested the hypothesis that both xanthine oxidase-catalysed oxidation of purines and neutrophils provide a source of ROS sufficient to activate cardiac afferents during ischaemia. We recorded single-unit activity of cardiac afferents innervating the ventricles recorded from the left thoracic sympathetic chain (T1-5) of anaesthetized cats to identify the afferents' responses to ischaemia. The role of xanthine oxidase in activation of these afferents was determined by infusion of oxypurinol (10 mg kg(-1), I.V.), an inhibitor of xanthine oxidase. The importance of neutrophils as a potential source of ROS in the activation of cardiac afferents during ischaemia was assessed by the infusion of a polyclonal antibody (3 mg ml(-1) kg(-1), I.V.) raised in rabbits immunized with cat PMNs. This antibody decreased the number of circulating PMNs and, to a smaller extent, platelets. Since previous data suggest that platelets release serotonin (5-HT), which activates cardiac afferents through a serotonin receptor (subtype 3,5-HT3 receptor) mechanism, before treatment with the antibody in another group, we blocked 5-HT3 receptors on sensory nerve endings with tropisetron (300 microg kg(-1), I.V.). We observed that oxypurinol significantly decreased the activity of cardiac afferents during myocardial ischaemia from 1.5 +/- 0.4 to 0.8 +/- 0.4 impulses s(-1). Similarly, the polyclonal antibody significantly reduced the discharge frequency of ischaemically sensitive cardiac afferents from 2.5 +/- 0.7 to 1.1 +/- 0.4 impulses s(-1). However, pre-blockade of 5-HT3 receptors eliminated the influence of the antibody on discharge activity of the afferents during ischaemia. This study demonstrates that ROS generated from the oxidation of purines contribute to the stimulation of ischaemically sensitive cardiac sympathetic afferents, whereas PMNs do not play a major role in this process.
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PMID:Xanthine oxidase, but not neutrophils, contributes to activation of cardiac sympathetic afferents during myocardial ischaemia in cats. 1218 3

Reactive oxygen species (ROS), as superoxide and its metabolites, have important roles in vascular homeostasis as they are involved in various signaling processes. In many cardiovascular disease states, however, the release of ROS is increased. Uncontrolled ROS production leads to impaired endothelial function and consequently to vascular dysfunction. This review focuses on two clinical conditions associated with elevated ROS levels: ischemia/reperfusion and nitrate tolerance. Injury caused by ischemia/reperfusion is an important limitation of transplantations, and complicates the management of stroke and myocardial infarction. Nitrates, which are used to treat transient myocardial ischemia (angina pectoris), decrease in efficacy in long-term continuous administration. There are several enzyme systems, such as xanthine oxidase, cyclooxygenase, uncoupled endothelial nitric oxide synthase, NAD(P)H oxidase, cytochrome P450 and the mitochondrial electron transport chain, which are responsible for the increased vascular production of superoxide. The contribution of particular ROS producing enzymes and the effect of antioxidant treatment are discussed in both pathological conditions.
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PMID:Endothelial dysfunction and reactive oxygen species production in ischemia/reperfusion and nitrate tolerance. 1563 16

Thirty years ago, Kurt Oster promulgated the avant-garde theory that bovine xanthine oxidase, absorbed intact from homogenized milk, promoted atherogenesis by oxidatively damaging membrane plasmalogens. Under the mistaken impression that folic acid is a xanthine oxidase inhibitor, he administered high-dose folate (80 mg daily) to hundreds of patients afflicted with symptomatic atherosclerosis, and reported marked improvements in angina, intermittent claudication, and wound healing; he also suspected that this regimen was decreasing heart attack risk. The xanthine oxidase theory has since fallen by the wayside, but there is now evidence that folic acid can lessen endothelial oxidative stress by improving the function of "uncoupled" nitric oxide synthase deficient in tetrahydrobiopterin. In light of these new findings, a properly controlled assessment of Oster's mega-dose folate therapy is warranted.
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PMID:Oster rediscovered--mega-dose folate for symptomatic atherosclerosis. 1722 45

Increased production of free radicals under oxidative stress conditions plays a vital role in the impairment of endothelial function and also in the pathogenesis of ischemic heart diseases. Ischemia, followed by reperfusion, leads to the exacerbated formation of oxy- free radicals. These reactive oxygen species through a chain of reactions damage the cardiomyocytes and cause more injury to the myocardium. L-Arginine is reported to act as free radical scavenger, inhibits the activity of pro-oxidant enzymes and thus acts as an antioxidant and these roles of L-arginine are mediated by nitric oxide (NO). In the present study, the effect of oral administration of L-arginine (3 g/day for 7 days) on some antioxidant enzymes, total thiols, lipid peroxidation measured as malondialdehyde (MDA), and plasma ascorbate levels in myocardial ischemic patients was investigated. We observed an increase in the activity of superoxide dismutase (SOD), total thiols (T-SH) and plasma ascorbate levels and a decrease in the activity of xanthine oxidase (XO), MDA levels, carbonyl content and serum cholesterol in the patients on oral administration of L-arginine. The present study demonstrates that L-arginine administration may be beneficial to patients with myocardial ischemic disorders, such as acute myocardial infarction and acute angina.
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PMID:Therapeutic role of L-arginine on free radical scavenging system in ischemic heart diseases. 2036 13

Administration of L-arginine has been shown to control ischemic injury by producing nitric oxide which dilates the vessels and thus maintains proper blood flow to the myocardium. In the present study attempt has been made to determine whether oral administration of L-arginine has any effect on oxidant/ antioxidant homeostasis in ischemic myocardial patients [represented by the patients of acute angina (AA) and acute myocardial infarction (MI)]. L-arginine has antioxidant and antiapoptotic properties, decreases endothelin-1 expression and improves endothelial function, thereby controlling oxidative injury caused during myocardial ischemic syndrome. Effect of L-arginine administration on the status of free radical scavenging enzymes, pro-oxidant enzyme and antioxidants viz. total thiols, carbonyl content and plasma ascorbic acid levels in the patients has been evaluated. We have observed that L-arginine administration (three grams per day for 15 days) resulted in increased activity of free radical scavenging enzyme superoxide dismutase (SOD) and increase in the levels of total thiols (T-SH) and ascorbic acid with concomitant decrease in lipid per-oxidation, carbonyl content, serum cholesterol and the activity of proxidant enzyme, xanthine oxidase (XO). These findings suggest that the supplementation of L-arginine along with regular therapy may be beneficial to the patients of ischemic myocardial syndromes.
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PMID:Oral administration of L-arginine in patients with angina or following myocardial infarction may be protective by increasing plasma superoxide dismutase and total thiols with reduction in serum cholesterol and xanthine oxidase. 2071 9

Cardiovascular disease (CVD) remains the leading cause of death in the United States. There is evidence that shows a direct relationship between an elevated uric acid level and an increased risk of cardiovascular (CV) events, which has set the foundation for the investigation of uric acid-lowering drugs for the treatment of CVD. Although traditionally the cornerstone therapy for gout, allopurinol's ability to be a competitive inhibitor of the key enzyme, xanthine oxidase, needed for uric acid formation, has prompted recent clinical research evaluating allopurinol as a CV drug. Epidemiologic and biochemical studies on uric acid formation have shown that it is not only uric acid itself that leads to worsening prognosis and increased CV events, but also the free radicals and superoxides formed during xanthine oxidase activity. The combination of uric acid formation and formed free radicals could ultimately lead to coronary endothelial dysfunction and worsening of myocardial oxidative stress. Along with preventing uric acid formation, allopurinol also has the ability to behave as a free radical scavenger of the superoxide anions and free radicals released during uric acid formation.Clinical studies have shown that allopurinol improves endothelial dysfunction and subsequently improves the exercise capacity in patients diagnosed with angina pectoris. Allopurinol has also been shown to decrease oxidative stress and ameliorate the morbidity and mortality of congestive heart failure patients by possibly improving mechanoenergetic uncoupling, with the enhancement of myocardial contractility and the left ventricular ejection fraction. This review presents the pharmacologic action of allopurinol on the CV system and describes the effectiveness of allopurinol as a potential drug to treat 2 CVD morbidities: ischemic heart disease and congestive heart failure.
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PMID:Allopurinol as a cardiovascular drug. 2198 13

Glyceryl trinitrate (GTN) has found widespread use for the treatment of angina pectoris, a pathological condition manifested by chest pain resulting from insufficient blood supply to the heart. Metabolic conversion of GTN, a nitric oxide (NO) pro-drug, into NO induces vasodilation and improves blood flow. Patients develop tolerance to GTN after several weeks of continuous use, limiting the potential for long-term therapy. The mechanistic cause of nitrate tolerance is relatively unknown. We developed a cell culture model of nitrate tolerance that utilizes stable isotopes to measure metabolism of ¹⁵N₃-GTN into ¹⁵N-nitrite. We performed global metabolomics to identify the mechanism of GTN-induced nitrate tolerance and to elucidate the protective role of vitamin C (ascorbic acid). Metabolomics analyses revealed that GTN impaired purine metabolism and depleted intracellular ATP and GTP. GTN inactivated xanthine oxidase (XO), an enzyme that is critical for the metabolic bioactivation of GTN into NO. Ascorbic acid prevented inactivation of XO, resulting in increased NO production from GTN. Our studies suggest that ascorbic acid has the ability to prevent nitrate tolerance by protecting XO, but not aldehyde dehydrogenase (another GTN bioactivating enzyme), from GTN-induced inactivation. Our findings provide a mechanistic explanation for the previously observed beneficial effects of ascorbic acid in nitrate therapy.
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PMID:Metabolomics-Driven Elucidation of Cellular Nitrate Tolerance Reveals Ascorbic Acid Prevents Nitroglycerin-Induced Inactivation of Xanthine Oxidase. 3031 19


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