allopurinol and Arteriosclerosis

Hyperuricemia is defined as serum uric acid values greater than 6 mg/dl and could occur either due to hyperproduction or as a result of reduced renal excretion, which exceeds gut compensation. In Italy, prevalence is around 12% of the general population and increases in renal disease up to 60%. Recent experimental studies demonstrated a role of uric acid in the development of arterial hypertension and systemic arteriosclerosis, with an increase in cardiovascular risk. It also appears from observational studies that high uric acid is an independent risk factor associated with de novo onset of chronic kidney disease after adjustment of main confounding variables. Hyperuricemic subjects treated with febuxostat, a selective inhibitor of xantino-oxidase, showed in RCTs a better control of hyperuricaemia in comparison with those receiving allopurinol. Moreover, observational studies indicate that urate lowering treatment could be helpful in reducing cardiovascular events as well as in slowing the progression of chronic kidney disease; randomized controlled studies, designed to assess as primary outcome the nephroprotective effect of urate lowering treatment, are in progress.

Topics: Allopurinol; Arteriosclerosis; Disease Progression; Febuxostat; Humans; Hypertension; Hyperuricemia; Observational Studies as Topic; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Risk Factors

Topics: Allopurinol; Arteriosclerosis; Benzbromarone; Enzyme Inhibitors; Gout; Humans; Hyperuricemia; Kidney Diseases; Probenecid; Prognosis; Risk; Uricosuric Agents; Urinary Calculi; Xanthine Oxidase

Topics: Allopurinol; Animals; Antioxidants; Arteriosclerosis; Enzyme Inhibitors; Free Radical Scavengers; Gout; Humans; Oxidative Stress; Reactive Oxygen Species; Uric Acid; Xanthine Oxidase

Xanthine oxidase (EC 1.1.3.22) and xanthine dehydrogenase (EC 1.1.1. 204) are both members of the molybdenum hydroxylase flavoprotein family and represent different forms of the same gene product. The two enzyme forms and their reactions are often referred to as xanthine oxidoreductase (XOR) activity. Physiologically, XOR is known as the rate-limiting enzyme in purine catabolism but has also been shown to be able to metabolize a number of other physiological compounds. Recent studies have also demonstrated its ability to metabolize xenobiotics, including a number of anticancer compounds, to their active metabolites. During the past 10 years, evidence has mounted to support a role for XOR in the pathophysiology of inflammatory diseases and atherosclerosis as well as its previously determined role in ischemia-reperfusion injury. While significant progress has recently been made in our understanding of the physiological and biochemical nature of this enzyme system, considerable work still needs to be done. This paper will review some of the more recent work characterizing the interactions and the factors that influence the interactions of XOR with various physiological and xenobiotic compounds.

Topics: Animals; Arteriosclerosis; Gene Expression Regulation, Enzymologic; Humans; Inflammation; Purines; Substrate Specificity; Xanthine Dehydrogenase; Xanthine Oxidase; Xenobiotics

The theory that consumption of homogenized milk containing active xanthine oxidase is a causative factor in development of atherosclerosis is reviewed. Biologically available xanthine oxidase in consumed milk products may be absorbed in the small intestine and enter the blood stream. However, there appears to be no unequivocal evidence that the absorbed enzyme has any pathological effects that may contribute to development of atherosclerotic heart disease.

Topics: Allopurinol; Angina Pectoris; Animals; Aorta; Arteriosclerosis; Cattle; Food Handling; Humans; Hydrolysis; Intestinal Absorption; Liposomes; Milk; Myocardium; Phospholipases A; Plasmalogens; Rabbits; Rats; Xanthine Oxidase

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.

Topics: Absorption; Angina Pectoris; Animals; Antibody Formation; Arteriosclerosis; Cattle; Food Handling; Gastric Mucosa; Humans; Hydrogen-Ion Concentration; Intestinal Mucosa; Milk; Milk, Human; Myocardial Infarction; Xanthine Oxidase

Although hyperlipidemia, high blood pressure, and diabetes increase the risk of arteriosclerosis, it is not clear whether hyperuricemia increases the risk of arteriosclerosis or not. We examined the effects of uric acid and curative drugs for hyperuricemia on atherosclerosis-susceptible C57BL/6J apolipoprotein E-deficient (apoE(-/-)) mice. Male apoE(-/-) mice (age: 6 weeks) were fed a normal diet (normal diet group) or a uric acid-enriched diet. Mice fed the uric acid-enriched diet were divided into three groups and administered a drinking vehicle (high uric acid diet group), allopurinol (20 mg·kg(-1)·d(-1)), or benzbromarone (20 mg·kg(-1)·d(-1)) for 10 weeks. Serum uric acid concentrations were higher in the high uric acid diet group than in the normal diet group, and concentrations in the allopurinol and benzbromarone groups were lower than in the high uric acid diet group. Serum total cholesterol and triglyceride levels were lower in the allopurinol group than in the high uric acid diet group. Oxidative stress was lower in the benzbromarone group than in the high uric acid diet group. Atherosclerotic lesion areas were smaller in the allopurinol and benzbromarone groups than in the high uric acid diet group. Thus, hyperuricemia may not be an independent risk factor for arteriosclerosis; however, the administration of allopurinol and benzbromarone prevented the development of atherosclerosis in apoE(-/-) mice fed a uric acid-enriched diet. The anti-atherosclerotic effect was in part due to lower total cholesterol and oxidative stress in the serum. Other possible mechanisms underlying this effect should be investigated.

Topics: Aging; Allopurinol; Animal Feed; Animals; Apolipoproteins E; Arteriosclerosis; Benzbromarone; Diet; Gene Expression Regulation; Gout Suppressants; Hyperuricemia; Male; Mice; Mice, Knockout; Risk Factors; Uric Acid; Uricosuric Agents

Effects of ingesting garlic extract on plasma and erythrocyte antioxidant parameters of atherosclerotic patients were investigated in this study. Eleven patients with atherosclerosis participated in the study. They ingested a dose of 1 ml/kg body weight of garlic extract daily for 6 months (study period). Before and after this period, fasting blood samples were obtained, and oxidant (malondialdehyde, MDA and xanthine oxidase, XO) and antioxidant (superoxide dismutase, SOD and glutathione peroxidase, GSH-Px) parameters were studied in plasma and erythrocytes obtained from the patients. Blood samples obtained from 11 healthy subjects served as the controls. Plasma XO activity and MDA levels were higher, but plasma and erythrocyte GSH-Px activities were lower, in patients with atherosclerosis relative to those of the control group. Our results showed that ingestion of garlic extract leads to significantly lowered plasma and erythrocyte MDA levels in the patients even in the absence of changes in antioxidant enzyme activities. Our results also demonstrated the presence of oxidant stress in blood samples from patients with atherosclerosis, but ingesting garlic extract prevented oxidation reactions by eliminating this oxidant stress. Thus, it is possible that reduced peroxidation processes may play a part in some of the beneficial effects of garlic in atherosclerotic diseases.

Topics: Aged; Arteriosclerosis; Erythrocytes; Female; Garlic; Glutathione Peroxidase; Humans; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Plant Extracts; Statistics, Nonparametric; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Xanthine Oxidase

The effects of the xanthine oxidase/hypoxanthine free radical generating system on endothelium dependent and independent relaxation were compared in aortic rings from New Zealand white rabbits and heterozygous Watanabe heritable hyperlipidemic (WHHL) rabbits with mild atherosclerosis. Studies were carried out in young (3 months) and mature (18 months) animals. Plasma cholesterol levels were significantly higher in both 3 and 18 month WHHL animals. Endothelium independent relaxation to SNP did not differ between groups. However, the attenuation of relaxation to carbachol after xanthine oxidase/hypoxanthine treatment tended to be less in WHHL. This reached significance at 18 but not 3 months. We propose that this could be due to increases in levels of endogenous scavenger enzymes in these WHHL rabbits.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Carbachol; Cholesterol; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Free Radicals; Hyperlipidemias; Hypoxanthine; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Rabbits; Xanthine Oxidase

Tissue destruction in atherosclerosis is partly due to uncontrolled protease and oxygen radical release. In this study we investigated the release of elastase and myeloperoxidase, as well as the production of reactive oxygen species by polymorphonuclear leukocytes (PMNLs) obtained from patients with obliterative atherosclerotic of the lower legs. In addition we measured the plasma concentration of xanthine oxidase. PMNLs of atherosclerotic patients have a greater ability to increase elastase and myeloperoxidase release after their stimulation with formyl-methionin-leucyl-phenylalanin (fMLP) and calcium ionophore, A23187, independently of their age, than PMNLs of healthy middle-aged subjects. Similarly to healthy elderly subjects there was an increased superoxide anion (O2-) production under basal condition in both atherosclerotic patient age-groups. The activation of PMNLs with fMLP and A23187 enhanced O2- formation both in healthy subjects and in patients with atherosclerotic disease of the lower legs, however the increase was significantly less in the latter group. No biochemical parameters showed significant correlation with patient's risk factors, however myeloperoxidase production was significantly higher in less severe stage of the disease (P < 0.05). We found that patients with atherosclerotic disease of the lower legs have higher plasma xanthine oxidase level than control subjects. This study indicates an other piece of evidence suggesting the activation and involvement of neutrophils in the pathogenesis of atherosclerosis of the lower legs. The similar tendencies in the reactivity of neutrophils during aging and in atherosclerosis suggest that atherosclerosis may be an early aging process.

Topics: Adult; Aged; Arteriosclerosis; Calcimycin; Cell Degranulation; Elastin; Humans; Hydrogen Peroxide; Ionophores; Leukocyte Elastase; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pancreatic Elastase; Peroxidase; Respiratory Burst; Superoxides; Xanthine Oxidase

Topics: Adult; Aged; Aortic Aneurysm, Abdominal; Arteriosclerosis; Carotid Stenosis; Chromatography, High Pressure Liquid; Humans; Middle Aged; Uric Acid; Xanthine Oxidase

Low density lipoproteins are highly sensitive to oxidation by copper salts, and such peroxidation is accompanied by macrophage scavenger receptor recognition. This study shows that fresh human atherosclerotic material (aneurysms and endarterectomies) can contain detectable amounts of redox active iron and copper that is chelatable from tissue homogenates. Such material is often prooxidant towards lipid peroxidation and deoxyribose degradation. Aneurysms and endarterectomies contain ferroxidase 1 activities, whereas only in aneurysms could caeruloplasmin be immunologically detected. Ferroxidase 2 activity, characteristic of a copper-oxidised lipoprotein complex, could not, however, be detected in any of the atherosclerotic samples. A third ferroxidase activity, attributable to xanthine oxidase, was present in several aneurysms and endarterectomies.

Topics: Arteriosclerosis; Azides; Ceruloplasmin; Chelating Agents; Copper; Humans; Iron; Oxidation-Reduction; Reactive Oxygen Species; Xanthine Oxidase

Oxidised low-density lipoprotein (LDL) produced by the action of arterial cells, including macrophages, has been implicated in atherosclerosis. We have investigated the effect of inhibitors of various cellular free-radical generating enzymes on macrophage-mediated LDL oxidation. Xanthine oxidase and nitric oxide synthase are not responsible for LDL modification by resident mouse peritoneal macrophages. Eicosatetraynoic acid, a lipoxygenase inhibitor, produced a dose-dependent irreversible inhibition of macrophage modification of LDL, but at concentrations rather close to those toxic to the cells. Diphenyl and diphenylene iodonium, NADPH oxidase and mitochondrial electron transport inhibitors, inhibited macrophage oxidation of LDL, at concentrations that were not obviously toxic. This suggests that NADPH oxidase, or some other flavin nucleotide-dependent process, may be involved in LDL oxidation by macrophages. Wortmannin and thiopropionic acid dilauryl ester did not inhibit LDL oxidation, suggesting that inhibition of NADPH oxidase may not be the means by which the iodonium compounds inhibit LDL oxidation. Macrophages from C3H/HeJ mice, which lack receptors for lipopolysaccharide, modified LDL normally, suggesting that the inadvertent priming of resident macrophages by traces of lipopolysaccharide bound to LDL was not involved in LDL oxidation.

Topics: Amino Acid Oxidoreductases; Animals; Arteriosclerosis; Enzyme Inhibitors; Female; Free Radicals; Lipoproteins, LDL; Lipoxygenase Inhibitors; Macrophages, Peritoneal; Mice; Mice, Inbred C3H; NADH, NADPH Oxidoreductases; NADPH Oxidases; Nitric Oxide Synthase; Oxidation-Reduction; Superoxide Dismutase; Xanthine Oxidase

Topics: Aged; Animals; Arteriosclerosis; Drug Synergism; Epoprostenol; Fibrinolytic Agents; Humans; In Vitro Techniques; Male; Middle Aged; Molsidomine; Neutrophils; Plasma; Platelet Aggregation; Rats; Xanthine; Xanthine Oxidase; Xanthines

A segment of fresh rabbit thoracic aorta (RbA) was turned inside out and superfused (1.5 ml/min) with citrated (3.8%) or heparinized (10 U/ml) blood of rabbit and the superfusate was discarded. RbA gained in weight due to deposition of thrombi on its endothelial surface. These thrombi were mainly composed of platelets. The interaction between platelets and endothelium was augmented in RbAs from animals with atherosclerosis and in RbAs pretreated with aspirin (110 microM) or 15-HPETE (150 microM) or by the enzymatic system generating oxygen free radicals (xanthine:xanthine oxidase - 100 microM: 0.1 U/ml). On the other hand, this interaction was impaired by superoxide dismutase (20 U/ml) or catalase (0.2 U/ml). Finally, the dissipation of thrombi by thromboxane A2-synthetase inhibitor--dazoxiben was found to be related to an increase in endothelial generation of prostacyclin.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Aspirin; Blood Platelets; Endothelium, Vascular; Epoprostenol; Imidazoles; Indomethacin; Leukotrienes; Lipid Peroxides; Platelet Adhesiveness; Rabbits; Superoxide Dismutase; Thrombosis; Xanthine; Xanthine Oxidase; Xanthines

Based on the findings presented in this study, we propose the hypothesis that calcium could be a mediator for the development of atherosclerosis. Figure 8 shows a schematic illustration of the hypothesis. The presence of risk factors such as hypertension, hyperlipidemia, and smoking may increase the influx of calcium into vascular ECs. We have shown that reactive oxygen species, which are considered to be a risk factor for the development of atherosclerosis, actually increase [Ca++]i in vascular ECs. Increased intracellular calcium may damage the function of ECs, resulting in platelet aggregation at the damaged site. Increased intracellular calcium may also increase uptake of macromolecules in plasma such as fibrinogen and LDL, eventually forming atherosclerotic plaque. We have also shown that the influx of calcium into vascular ECs is associated with LDL transport across vascular ECs. The pretreatment by nifedipine inhibited both the increase in [Ca++]i and the increase in LDL transport, suggesting that intracellular calcium modulates LDL transport across ECs. Growth factors released from platelets may provoke migration and proliferation of medial SMCs in the aterial intima. It has been reported that migration of SMCs from arterial media to intima is enhanced by the presence of calcium, and can be inhibited by the pretreatment of calcium antagonist. As demonstrated in this study, calcium also plays an important role in the proliferation of SMCs provoked by some kinds of growth factors such as EGF. On the other hand, we found that an increased amount of dietary Mg suppressed the development of atherosclerotic lesions in the aorta of cholesterol-fed rabbits without affecting plasma total cholesterol and HDL-cholesterol concentrations. The mechanism of action might also be related to the calcium entry blocking action. The clinical and nutritional implications of these phenomena should be investigated further. The evidences presented in this study, however, would not be sufficient to fully explain the etiological role of calcium in atherogenesis. Further studies are required to elucidate the mechanism of the contribution of calcium to atherogenesis. The efficacy of calcium antagonist for the prevention of atherosclerosis in humans should also be investigated further.

Topics: Animals; Arteriosclerosis; Calcium; Cells, Cultured; DNA; Epidermal Growth Factor; Female; Guinea Pigs; Humans; Lipoproteins, LDL; Magnesium; Male; Middle Aged; Nifedipine; Platelet-Derived Growth Factor; Rabbits; Xanthine Oxidase

Toxic oxygen metabolites can damage endothelial cells and may play an important role in the initiation and progression of atherosclerotic lesions. Since the antithrombotic drug heparin, interacts with endothelium, we wished to determine if heparin would protect endothelial cells from free radical injury. Endothelial cell injury was produced by the addition of xanthine and xanthine oxidase to cultured cells and assessed by changes in cell viability and release of lactate dehydrogenase (LDH) to the media. Pretreatment with heparin 24 h prior to addition of xanthine and xanthine oxidase significantly decreased cell damage. We suggest that heparin (and related compounds) can protect endothelium from free radical damage, and is therefore prophylactic for ischemic and inflammatory injury, and the development and progression of atheroma.

Topics: Animals; Arteriosclerosis; Cells, Cultured; Endothelium, Vascular; Free Radicals; Heparin; Ischemia; Swine; Xanthine Oxidase; Xanthines

Milk consumption is related to arteriosclerosis. Recent landmark studies confirm a previously suspected close correlation between milk intake and arteriosclerotic heart disease. Support is therefore provided for a recently proposed novel hypothesis that arteriosclerosis is a chronic infectious disease caused by blue-green bacteria and that milk is a carrier vehicle for these contaminant organisms. A revisionist view of diet and milk in the causation of arteriosclerosis is developed. Previous hypotheses relating milk consumption to arteriosclerosis and advances in pasteurization techniques are discussed and integrated with this infection theory.

Topics: Animals; Arteriosclerosis; Coronary Disease; Cyanobacteria; Dietary Fats; Feeding Behavior; Female; Hot Temperature; Humans; Lactose; Male; Milk; Sex Factors; Sterilization; Xanthine Oxidase

Topics: Adult; Aged; Allopurinol; Arteriosclerosis; Coronary Disease; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Hypolipidemic Agents; Lipids; Male; Middle Aged; Uric Acid

Topics: Animals; Arteriosclerosis; Cattle; Female; Food Preservation; Humans; Intestinal Absorption; Liposomes; Male; Milk; Rats; Xanthine Oxidase

Topics: Animals; Arteriosclerosis; Cattle; Intestinal Absorption; Milk; Rabbits; Rats; Xanthine Oxidase

Increasing incidence of gout and its importance as a risk factor for arteriosclerosis stimulate the practitioner to improve his knowledge about therapeutic possibilities. Therapy of gout includes (1) treatment of acute attack with colchicine and indometacin, (2) decrease of uric acid blood concentration in tophaceous gout using uricosurica, alkalinization of urin, increased diuresis, and blockade of de-novo synthesis of uric acid, and (3) maintenance therapy with allopurinol or uricosurica to avoid recurrent arthritis as well as tophi. In addition, surgical removal of larger tophi may be of benefit.

Topics: Allopurinol; Arteriosclerosis; Benzbromarone; Colchicine; Gout; Humans; Immobilization; Indomethacin; Uric Acid

The present paper adopts a definite attitude to the differentiated therapy of the disturbances of the uric acid metabolism. This demands an exacter subdivision of the kind of the metabolic disturbance (types Ia, Ib, IIa, IIb, and III). On the basis of this classification in types an individually adapted therapy is possible. It might form the prerequisite of a still more effective meeting of the nephrogenic complications of the gout and of the reduction of the side effects of the necessary permanent therapy.

Topics: Allopurinol; Arteriosclerosis; Citrates; Gout; Humans; Hypertension; Kidney Diseases; Obesity; Phenylbutazone; Uric Acid; Urinary Calculi

Topics: Allopurinol; Animals; Arteriosclerosis; Blood Glucose; Blood Urea Nitrogen; Breeding; Corticosterone; Enzymes; Heart; Kidney; Lipids; Liver; Male; Myocardial Infarction; Pancreas; Rats; Uric Acid

Xanthine oxidase activity was assayed in commercial samples of homogenized milk subjected to pH ranging from 6.7 to 2.0 and held at room temperature for 5 min. Activity decreased sharply between pH 5.5 and 3.2. Below pH 3.2 no activity was detected. Also, rabbit anti-bovine xanthine oxidase failed to crossreact immunologically with xanthine oxidase of mouse milk. These results cast doubt on the hypothesis that dietary xanthine oxidase participates in the formation of atherosclerotic plaques.

Topics: Animals; Arteriosclerosis; Cattle; Cross Reactions; Food Handling; Gastric Juice; Hydrogen-Ion Concentration; Mice; Milk; Species Specificity; Xanthine Oxidase

Topics: Animals; Arteriosclerosis; Dairy Products; Intestinal Absorption; Male; Rats; Xanthine Oxidase

Topics: Aged; Animals; Arteriosclerosis; Cell Membrane; Coronary Disease; Humans; Intestinal Absorption; Middle Aged; Milk; Myocardium; Plasmalogens; Xanthine Oxidase

Topics: Arteriosclerosis; Cell Membrane; Humans; Myocardium; Phospholipids; Plasmalogens; Xanthine Oxidase

Topics: Allopurinol; Analgesics; Arteriosclerosis; Blood Platelets; Colchicine; Diabetes Complications; Gout; Halofenate; Humans; Hyperlipidemias; Hypertension; Hypoxanthines; In Vitro Techniques; Kidney Diseases; Uric Acid; Uricosuric Agents; Vascular Diseases; Xanthines

Topics: Allopurinol; Arteriosclerosis; Blood Protein Disorders; Citrates; Colchicine; Diabetes Mellitus; Diet Therapy; Gout; Humans; Hyperlipidemias; Hypertension; Kidney Calculi; Kidney Diseases; Phenylbutazone; Physical Therapy Modalities; Time Factors; Uremia; Uric Acid

Topics: Adult; Aged; Amines; Aortic Diseases; Arteriosclerosis; Autopsy; Coronary Disease; Humans; Male; Middle Aged; Myocardium; Pteridines; Xanthine Oxidase

Topics: Adult; Aged; Animals; Anticholesteremic Agents; Arteriosclerosis; Cholesterol; Female; Folic Acid; Humans; Male; Middle Aged; Milk; Milk Proteins; Uric Acid; Xanthine Oxidase

Topics: Africa, Eastern; Animals; Arteriosclerosis; Diet; Finland; Heart Diseases; Humans; Hyperlipidemias; Japan; Milk; Myocardial Infarction; Pain; Plasmalogens; Switzerland; United States; Xanthine Oxidase

Topics: Aged; Allopurinol; Aortic Diseases; Arteriosclerosis; Brain; Catheterization; Chlorothiazide; Diagnosis, Differential; Endocarditis, Bacterial; Female; Heart Failure; Humans; Hypertension; Iatrogenic Disease; Intracranial Aneurysm; Kanamycin; Kidney; Liver; Nephrosclerosis; Sepsis; Staphylococcal Infections; Thromboembolism; Uric Acid