allopurinol and Vascular-Diseases

Endothelium-derived nitric oxide (NO) is a paracrine factor that controls vascular tone, inhibits platelet function, prevents adhesion of leukocytes, and reduces proliferation of the intima. An enhanced inactivation and/or reduced synthesis of NO is seen in conjunction with risk factors for cardiovascular disease. This condition, referred to as endothelial dysfunction, can promote vasospasm, thrombosis, vascular inflammation, and proliferation of vascular smooth muscle cells. Vascular oxidative stress with an increased production of reactive oxygen species (ROS) contributes to mechanisms of vascular dysfunction. Oxidative stress is mainly caused by an imbalance between the activity of endogenous pro-oxidative enzymes (such as NADPH oxidase, xanthine oxidase, or the mitochondrial respiratory chain) and anti-oxidative enzymes (such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase, and paraoxonase) in favor of the former. Also, small molecular weight antioxidants may play a role in the defense against oxidative stress. Increased ROS concentrations reduce the amount of bioactive NO by chemical inactivation to form toxic peroxynitrite. Peroxynitrite-in turn-can "uncouple" endothelial NO synthase to become a dysfunctional superoxide-generating enzyme that contributes to vascular oxidative stress. Oxidative stress and endothelial dysfunction can promote atherogenesis. Therapeutically, drugs in clinical use such as ACE inhibitors, AT(1) receptor blockers, and statins have pleiotropic actions that can improve endothelial function. Also, dietary polyphenolic antioxidants can reduce oxidative stress, whereas clinical trials with antioxidant vitamins C and E failed to show an improved cardiovascular outcome.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Arginine; Aryldialkylphosphatase; Biopterins; Calcium; Cardiovascular Diseases; Catalase; Electron Transport; Glutathione Peroxidase; Heme Oxygenase (Decyclizing); Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mitochondria; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphorylation; Protein Multimerization; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors; Superoxide Dismutase; Superoxides; Thioredoxins; Vascular Diseases; Xanthine Oxidase

Oxidative stress plays an important role in the progression of vascular endothelial dysfunction. The two major systems generating vascular oxidative stress are the NADPH oxidase and the xanthine oxidase pathways. Allopurinol, a xanthine oxidase inhibitor, has been in clinical use for over 40 years in the treatment of chronic gout. Allopurinol has also been shown to improve endothelial dysfunction, reduce oxidative stress burden and improve myocardial efficiency by reducing oxygen consumption in smaller mechanistic studies involving various cohorts at risk of cardiovascular events. This article aims to explain the role of xanthine oxidase in vascular oxidative stress and to explore the mechanisms by which allopurinol is thought to improve vascular and myocardial indices.

Topics: Allopurinol; Animals; Antioxidants; Endothelium, Vascular; Enzyme Inhibitors; Humans; Myocardium; Oxidative Stress; Oxygen Consumption; Uric Acid; Vascular Diseases; Xanthine Oxidase

We aimed examining apple polyphenols' effect on uricemia and endothelial function in a sample of overweight subjects.. This was a two-phased study. In vitro experiment aimed to evaluate apple polyphenols' ability to lower uric acid in comparison with allopurinol. In vivo study consisted in a randomized, double-blind, parallel placebo-controlled clinical trial involving 62 overweight volunteers with suboptimal values of fasting plasma glucose (100 mg/dL≤FPG≤125 mg/dL), randomized to 300 mg apple polyphenols or placebo for 8 weeks. Apple polyphenols extract inhibited xanthine oxidase activity, with an IC50 = 130 ± 30 ng/mL; reducing uric acid production with an IC50 = 154 ± 28 ng/mL. During the trial, after the first 4 weeks of treatment, FPG decreased in the active treated group (-6.1%, p < 0.05), while no significant changes were observed regarding the other hematochemistry parameters. After 4 more weeks of treatment, active-treated patients had an improvement in FPG compared to baseline (-10.3%, p < 0,001) and the placebo group (p < 0,001). Uric acid (-14.0%, p < 0.05 versus baseline; p < 0.05 versus placebo) and endothelial reactivity (0.24±0.09, p = 0.009 versus baseline; p < 0.05 versus placebo) significantly improved too.. In vivo, apple polyphenols extract has a positive effect on vascular oxidative stress and endothelium function and reduce FPG and uric acid by inhibiting xanthine oxidase, as our In vitro experiment attests.

Topics: Antioxidants; Blood Glucose; Body Mass Index; Cells, Cultured; Dietary Supplements; Double-Blind Method; Endothelium, Vascular; Enzyme Inhibitors; Female; Human Umbilical Vein Endothelial Cells; Humans; Hyperuricemia; Male; Malus; Overweight; Oxidative Stress; Plant Extracts; Polyphenols; Prediabetic State; Uric Acid; Vascular Diseases; Vascular Resistance; Xanthine Oxidase

Use of upper-arm arterial occlusion to induce reactive hyperemia, and endothelium-dependent flow-mediated dilation (FMD) of the brachial artery, induces greater conduit vessel dilatation than lower-arm occlusion. However, brachial artery ischemia after upper arm arterial occlusion may make this approach unreliable. We studied whether upper or lower arm occlusions differ in their ability to detect endothelial dysfunction in cigarette smokers, and its improvement with an antioxidant strategy.. Ten cigarette smokers with a >20 pack year history and 10 age- and gender-matched healthy controls participated in a 2-phase randomized controlled study of xanthine oxidase inhibition, using a 600-mg oral dose of allopurinol administered beforehand. Endothelium-dependent dilatation was assessed using ultrasound-Doppler after lower and upper arm occlusion. After lower arm occlusion, FMD was significantly impaired in smokers compared with controls (3.8+/-1.1% versus 8.7+/-2.2%; P=0.001). However, after upper arm occlusion, brachial artery dilatation in smokers was higher (11.8+/-2.7%; P<0.0001 versus lower arm) and did not differ from controls (9.4+/-2.9%; P=0.3). There was no difference in endothelium-independent dilatation to sublingual nitroglycerin between smokers and controls. Inhibition of xanthine oxidase with allopurinol improved lower arm FMD (3.8+/-1.1 to 10.1+/-1.9%; P<0.0001), but did not improve upper arm FMD (11.8+/-2.7 to 14.1+/-3.7%; P=0.4).. Although upper arm occlusion induces robust brachial vasodilatation, it cannot detect endothelial dysfunction induced by smoking or its improvement by inhibition of xanthine oxidase. The increase in brachial artery diameter with upper arm occlusion may be confounded by ischemia of the artery. Conduit artery FMD after release of lower arm occlusion appears to be a more valid method for assessment of endothelial function in humans.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Brachial Artery; Cross-Over Studies; Endothelium, Vascular; Enzyme Inhibitors; Follow-Up Studies; Humans; Middle Aged; Nitroglycerin; Prognosis; Prospective Studies; Reference Values; Single-Blind Method; Smoking; Ultrasonography, Doppler; Vascular Diseases; Vasodilation; Vasodilator Agents; Xanthine Oxidase

We studied the evolution of the liver graft with preservation in Celsior (CS) compared with University of Wisconsin solution (UW).. A randomized prospective clinical study in 80 liver transplants (OLTs) from May 2001 to October 2003, compared CS (group I; n = 40) and UW (group II; n = 40). The characteristics of the donors were homogeneous, with no significant differences in 15 variables. CS was perfused with 4 L through the aorta, 2 L through the portal vein, and 1 L, through the portal vein on the back table; and the UW, as 3 L, 2 L, and 1 L, respectively. All OLTs were performed using the piggyback technique.. Group I experienced reperfusion syndrome (n = 2; 5.9%), primary graft nonfunction (n = 0); vascular complications (n = 0); biliary anastomosis stenosis (n = 8; 22.9%), intensive care unit (ICU) days (n = 4.1 +/- 1), death within 30 days (n = 1; 3.1%). The patient and graft survivals at 1, 3, 6, 12, and 24 months were 93.7%, 93.7%, 90.2%, 85.7%, 85.7%, and 94.3%, 88.5%, 85.2%, 78%, 78%, respectively. For group II; the reperfusion syndrome occured in 6 patients (17.6%); primary graft nonfunction (n = 0); vascular complications (n = 0), biliary anastomosis stenosis (n = 3; 8.6%), ICU days (n = 4.9 +/- 2.4) and death within 30 days (n = 1; 3.1%); The patient and graft survival at 1, 3, 6, 12, and 24 months were 96.9%, 93.5%, 89.8%, 79.8%, 79.8% and 94.3%, 88.3%, 84.9%, 75.5%, 66.1%, respectively.. CS offers the similar safety to UW for preservation of liver grafts within these ischemia times.

Topics: Adenosine; Adult; Aged; Allopurinol; Disaccharides; Electrolytes; Female; Glutamates; Glutathione; Histidine; Humans; Insulin; Liver; Liver Transplantation; Male; Mannitol; Middle Aged; Organ Preservation; Organ Preservation Solutions; Portal Vein; Postoperative Complications; Prospective Studies; Raffinose; Reperfusion; Reperfusion Injury; Treatment Outcome; Vascular Diseases

Topics: Allopurinol; Humans; Peripheral Vascular Diseases; Vascular Diseases

Elevated serum urate may be associated with an increase in cardiovascular (CV) disease. Treating asymptomatic hyperuricemia with urate-lowering drugs such as allopurinol may reduce CV events. We designed a model to simulate the effect of allopurinol treatment on reducing frequency of CV events in individuals with elevated serum urate.. A Markov state-transition model was constructed to assess occurrence of vascular events (VE) for 2 treatment strategies: treat all asymptomatic individuals with allopurinol (Treat All) and treat only if symptomatic (Treat Symptomatic). The model simulated a hypothetical cohort of 50-year-old men with different serum urate concentrations (6-6.9 and 7-7.9 mg/dl) followed over 20 years. Age and sex subgroups were analyzed. Model inputs were derived from current literature. The main outcome measures were mean number of VE and mean number of deaths from VE.. For 50-year-old men with serum urate 6.0-6.9 mg/dl, individuals in the Treat All strategy have a 30% reduction in the mean number of VE compared to those in the Treat Symptomatic strategy (mean VE: 0.078 vs 0.11), and a 39% reduction in mean number of deaths from VE. At higher serum urate concentrations, treatment is more effective in reducing the mean number of VE and mean number of deaths from VE (38% event, 54% death). Results for women show similar trends. As the cohort ages, treatment has less effect on reducing VE. The number needed to treat to prevent 1 event is 20 (men, 7.0-7.9 mg/dl).. The model predicts that treating asymptomatic hyperuricemia with allopurinol is most effective in preventing VE at a serum urate above 7.0 mg/dl in men and 5.0 mg/dl in women.

Topics: Aged; Allopurinol; Decision Support Techniques; Female; Follow-Up Studies; Gout Suppressants; Humans; Hyperuricemia; Male; Markov Chains; Middle Aged; Risk Assessment; Severity of Illness Index; Sex Factors; Treatment Outcome; Uric Acid; Vascular Diseases

Radiation exposure is associated with the development of various cardiovascular diseases. Although irradiation is known to cause elevated oxidant stress and chronic inflammation, both of which are detrimental to vascular function, the molecular mechanisms remain incompletely understood. We previously demonstrated that radiation causes endothelial dysfunction and increased vascular stiffness by xanthine oxidase (XO) activation. In this study, we investigated whether dietary inhibition of XO protects against radiation-induced vascular injury. We exposed 4-mo-old rats to a single dose of 0 or 5 Gy gamma radiation. These rats received normal drinking water or water containing 1 mM oxypurinol, an XO inhibitor. We measured XO activity and superoxide production in rat aorta and demonstrated that both were significantly elevated 2 wk after radiation exposure. However, oxypurinol treatment in irradiated rats prevented aortic XO activation and superoxide elevation. We next investigated endothelial function through fluorescent measurement of nitric oxide (NO) and vascular tension dose responses. Radiation reduced endothelium-dependent NO production in rat aorta. Similarly, endothelium-dependent vasorelaxation in the aorta of irradiated rats was significantly attenuated compared with the control group. Dietary XO inhibition maintained NO production at control levels and prevented the development of endothelial dysfunction. Furthermore, pulse wave velocity, a measure of vascular stiffness, increased by 1 day postirradiation and remained elevated 2 wk after irradiation, despite unchanged blood pressures. In oxypurinol-treated rats, pulse wave velocities remained unchanged from baseline throughout the experiment, signifying preserved vascular health. These findings demonstrate that XO inhibition can offer protection from radiation-induced endothelial dysfunction and cardiovascular complications.

Topics: Animals; Aorta; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Elasticity; Endothelium, Vascular; Enzyme Inhibitors; Gamma Rays; Male; Nitric Oxide; Oxypurinol; Pulsatile Flow; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Superoxides; Time Factors; Ultrasonography, Doppler; Vascular Diseases; Vasodilation; Vasodilator Agents; Whole-Body Irradiation; Xanthine Oxidase

University of Wisconsin solution (UWS) is the gold standard for graft preservation. Celsior solution (CS) is a new solution not as yet widely used in liver grafts. The aim of this study was to compare the liver function of transplanted grafts stored in these 2 preservation solutions. The primary endpoints were the rates of primary nonfunction (PNF) and primary dysfunction (PDF). We performed a prospective and pseudorandomized study that included 196 patients (representing 104 and 92 livers preserved in UWS and CS, respectively) at La Fe University Hospital (Valencia, Spain) between March 2003 and May 2005. PNF and PDF rates, liver function laboratory parameters, postoperative bleeding, vascular and biliary complications, and patient and graft survival at 3 years were compared for the 2 groups. The 2 groups were similar in terms of donor variables, recipient variables, and surgical techniques. The PNF rates were 2.2% and 1.9% in the CS and UWS groups, respectively (P = not significant), and the PDF rates were 15.2% and 15.5% in the CS and UWS groups, respectively (P = not significant). There were no significant differences in the laboratory parameters for the 2 groups, except for alanine aminotransferase levels in month 3, which were lower in the CS group (P = 0.01). No significant differences were observed in terms of complications. Three-year patient and graft survival rates were as follows for years 1, 2, and 3: 83%, 80%, and 76% (patient) and 80%, 77%, and 73% (graft) for the UWS group and 83%, 77%, and 70% (patient) and 81%, 73%, and 67% (graft) for the CS group (P = not significant). In conclusion, this study shows that CS is as effective as UWS in liver preservation.

Topics: Adenosine; Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Biliary Tract Diseases; Disaccharides; Electrolytes; Female; Glutamates; Glutathione; Graft Survival; Histidine; Humans; Insulin; Liver; Liver Function Tests; Liver Transplantation; Male; Mannitol; Middle Aged; Organ Preservation; Organ Preservation Solutions; Pilot Projects; Postoperative Hemorrhage; Primary Graft Dysfunction; Prospective Studies; Raffinose; Time Factors; Transplantation, Homologous; Vascular Diseases; Young Adult

Elevated levels of tumor necrosis factor-alpha (TNF), a proinflammatory cytokine, are associated with coronary artery disease. However, it is unclear whether vasodilator function of coronary resistance arterioles is susceptible to TNF. Herein, we examined whether TNF can affect endothelium-dependent nitric oxide (NO)-mediated dilation of coronary arterioles to adenosine and whether inflammatory signaling pathways such as mitogen-activated protein kinases, ceramide sphingolipids, and oxidative stress are involved in the TNF-mediated effect. To eliminate confounding influences associated with in vivo preparations, coronary arterioles from porcine heart were isolated and pressurized without flow for in vitro study. Intraluminal treatment with TNF (1 ng/ml, 90 min) significantly attenuated the NO release and vasodilation to adenosine. This inhibitory effect was not observed in denuded vessels or in the presence of NO synthase inhibitor l-NMMA. Histochemical data showed that superoxide production and JNK phosphorylation in arteriolar endothelial cells was enhanced by TNF. Administration of superoxide scavenger or inhibitors of ceramide-activated protein kinase (dimethylaminopurine), JNK (SP600125 and dicumarol), and xanthine oxidase (allopurinol) reduced superoxide production as well as restored NO release and vasodilation to adenosine. Conversely, the effects of TNF were insensitive to inhibitors of p38 (SB203580), ERK (PD98059), NAD(P)H oxidase (apocynin), or mitochondrial respiratory chain (rotenone). These data indicate that TNF inhibits endothelium-dependent NO-mediated dilation of coronary arterioles by ceramide-induced activation of JNK and subsequent production of superoxide via xanthine oxidase. Because myocardial ischemia augments adenosine production and elevates TNF level, inhibiting adenosine-stimulated endothelial release of NO by TNF could contribute to inadequate regulation of coronary blood flow during the development of ischemic heart disease.

Topics: Adenosine; Animals; Arterioles; Ceramides; Coronary Vessels; Electron Transport; JNK Mitogen-Activated Protein Kinases; Mitochondria; Mitogen-Activated Protein Kinases; NADPH Oxidases; Nitric Oxide; Signal Transduction; Sphingomyelin Phosphodiesterase; Superoxides; Swine; Tumor Necrosis Factor-alpha; Vascular Diseases; Vasodilation; Xanthine Oxidase

Hyperuricemia is associated with hypertension and vascular disease, but whether this represents a causal relationship or an epiphenomenon remains unknown. We recently reported a model of mild hyperuricemia in rats that results in increased blood pressure and mild renal fibrosis. In this study, we examined the effect of hyperuricemia on the renal vasculature. Rats fed 2% oxonic acid and a low-salt diet for 7 wk developed mild hyperuricemia (1.8 vs. 1.4 mg/dl, P < 0.05), hypertension [147 vs. 127 mmHg systolic blood pressure (SBP), P < 0.05], and afferent arteriolar thickening, with a 35% increase in medial area (P < 0.05). Allopurinol or benziodarone prevented the hyperuricemia, hypertension, and arteriolopathy. Hydrochlorothiazide treatment did not prevent the hyperuricemia or arteriolopathy despite controlling blood pressure. In contrast, the arteriolopathy and hypertension were prevented by both enalapril and losartan. Uric acid also directly stimulated vascular smooth muscle cell proliferation in vitro, and this was partially inhibited by losartan. Thus hyperuricemia induces a renal arteriolopathy in rats that is blood pressure independent and involves the renin-angiotensin system.

Topics: Administration, Oral; Allopurinol; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Arterioles; Benzofurans; Blood Pressure; Diuretics; Enalapril; Hydrochlorothiazide; Hypertension; Kidney; Losartan; Male; Muscle, Smooth, Vascular; Oxonic Acid; Rats; Rats, Sprague-Dawley; Sodium Chloride Symporter Inhibitors; Sodium Chloride, Dietary; Uric Acid; Uricosuric Agents; Vascular Diseases

Topics: Adult; Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Eruptions; Drug Hypersensitivity; Humans; Inflammation; Kidney Diseases; Male; Middle Aged; Vascular Diseases

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; Diabetes Mellitus; Diet Therapy; Gout; Humans; Kidney Diseases; Metabolic Diseases; Uric Acid; Uricosuric Agents; Vascular Diseases

Topics: Aged; Allopurinol; Drug Hypersensitivity; Gout; Humans; Inflammation; Male; Pulmonary Artery; Renal Artery; Spleen; Vascular Diseases