allopurinol and Coronary-Artery-Disease

The xanthine oxidase inhibitor allopurinol that is commonly used to treat gout, has been suggested to have pleiotropic effects that are likely to reduce the incidence of myocardial infarction (MI) in at risk individuals. The aim of this meta-analysis was to assess the efficacy of allopurinol treatment in reducing the incidence of MI.. MEDLINE, Scopus, Web of Science, and Cochrane Library databases were searched for randomised controlled trials examining the efficacy of allopurinol in reducing the incidence of MI. The quality of study methodology was assessed by two independent reviewers using the Cochrane Collaboration's tool for assessing risk of bias. This meta-analysis was conducted using a fixed-effects model, and heterogeneity was assessed with the I. One thousand one hundred twenty-three citations were screened and only six studies satisfied the inclusion criterion. Published between 1988 and 1995, all studies examined the cardioprotective efficacy of allopurinol in the setting of coronary artery bypass graft (CABG). From a total pooled sample size of 229, MI was reported in 2 (1.77%) allopurinol and 14 (12.07%) control patients. A fixed-effects meta-analysis (I. Based on the limited evidence available, allopurinol appears to reduce the incidence of perioperative MI following CABG. Further research is required to confirm these findings.

Topics: Allopurinol; Coronary Artery Bypass; Coronary Artery Disease; Enzyme Inhibitors; Female; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome; Xanthine Oxidase

Endothelial dysfunction, characterized by a loss in nitric oxide bioactivity, is an early event in the development of atherosclerosis and determines future vascular complications. Emerging evidence suggests a causal role for oxidative stress in this process. Reactive oxygen species can directly inactivate nitric oxide, modulate protein function and act as cellular signaling molecules. These events contribute to the initiation and progression of endothelial dysfunction. Considerable data also indicates that antioxidant compounds limit oxidative damage and restore endothelial function. The purpose of this review is to discuss these data and suggest novel approaches for lowering the oxidative stress in the vasculature.

Topics: Animals; Antioxidants; Coronary Artery Disease; Endothelium, Vascular; Homeostasis; Humans; Mitochondria; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oxidative Stress; Reactive Oxygen Species; Xanthine Oxidase

Heart failure is a growing public health problem, especially in the elderly, often occurring due to ischemia and coronary artery disease. Allopurinol can protect against myocardial ischemia and improve myocardial energy utilization during ischemia. On the other hand, matrix metalloproteinase (MMP) enzymes play an essential role in causing atherosclerosis, obstruction, and myocardial infarction. Therefore, in the present study, the effect of allopurinol on the function of the left ventricular and the activity of MMP-1, MMP-2, MMP-3, and MMP-9 were evaluated in heart failure patients. In this clinical trial, 82 patients were randomly assigned to allopurinol or placebo in addition to standard treatment. Echocardiographic evaluations were performed before treatment and six months after treatment. Also, after allopurinol treatment, plasma and peripheral blood mononuclear cells were extracted from control and intervention groups. The active form of MMPs was measured by ELISA and mRNA expression by Real-time PCR. The rate of change in left ventricular ejection fraction in the allopurinol group was significantly higher than patients in the control group. There was also found more improvement in NYHA class in patients receiving allopurinol than in the control group. ELISA results showed that all plasma MMP levels in the control group were significantly higher than those in the allopurinol group (P<0.001). Quantitative determination of mRNA expression in MMPs by Real-time RT-PCR revealed that, except for MMP-9, there was no significant difference in the expression of evaluated MMPs between the treatment and control groups. In general, the results showed that long-term administration of allopurinol improves left ventricular function, and it has beneficial effects on the life quality of patients with heart failure.

Topics: Allopurinol; Coronary Artery Disease; Heart Failure; Humans; Leukocytes, Mononuclear; Matrix Metalloproteinases; RNA, Messenger; Stroke Volume; Ventricular Function, Left

Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease.. ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426.. Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89-1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87-1·20], p=0·77).. In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care.. UK National Institute for Health and Care Research.

Topics: Aged; Allopurinol; Coronary Artery Disease; Female; Gout; Humans; Male; Myocardial Infarction; Myocardial Ischemia; Prospective Studies; Stroke; Treatment Outcome; United Kingdom; Uric Acid

The xanthine oxidase (XO) system is a significant source of vascular oxidative stress, which is believed to impair endothelial function, an important contributor to atherosclerotic disease. We tested whether febuxostat, a potent XO inhibitor, improves coronary endothelial function (CEF) in patients with stable coronary artery disease (CAD) in a single-center, randomized, placebo-controlled, double-blind crossover trial.. CEF was measured using noninvasive magnetic resonance imaging (MRI) assessment of changes in 30 patients with stable CAD and baseline impaired CEF. Patients received either febuxostat or placebo for 6 weeks and then were crossed over to the alternative for an additional 6 weeks. MRI-detected changes in coronary flow and in coronary cross-sectional area from rest to isometric handgrip exercise, a known endothelial-dependent stressor, were measured at the end of each 6 week period.. Mean serum urate levels were lower at the end of the 6-week febuxostat period (2.9±0.8mg/dL) than at the end of the 6-week placebo period (5.9±0.04, P<.001). However, there were no significant differences in any of the CEF parameters measured at the end of the febuxostat and placebo periods.. In summary, although XO inhibition with febuxostat was well tolerated and lowered serum urate, it did not improve the primary end point of the study, CEF measured using MRI after 6 weeks of treatment. In conclusion, these findings suggest that short-term inhibition of XO does not significantly improve impaired CEF in patients with stable CAD.

Topics: Coronary Artery Disease; Coronary Vessels; Cross-Over Studies; Double-Blind Method; Drug Monitoring; Endothelium, Vascular; Febuxostat; Female; Gout Suppressants; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Oxidative Stress; Treatment Outcome; Xanthine Oxidase

The aim of this study was to evaluate the effect of high-dose allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD).. Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether allopurinol really does reduce vascular tissue OS in CAD patients.. A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine.. Compared with placebo, allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 ± 67% vs. 145 ± 106%, p = 0.006) and flow-mediated dilation (4.2 ± 1.8% vs. 5.4 ± 1.7%, p < 0.001). Vascular oxidative stress was completely abolished by allopurinol. Central augmentation index improved significantly with allopurinol (2.6 ± 7.0%, p < 0.001) but not with placebo.. Our study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina; ISRCTN15253766).

Topics: Aged; Allopurinol; Angina Pectoris; Antioxidants; Ascorbic Acid; Blood Flow Velocity; Brachial Artery; Coronary Artery Disease; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Endothelium, Vascular; Enzyme Inhibitors; F2-Isoprostanes; Female; Humans; Lipoproteins, LDL; Male; Natriuretic Peptide, Brain; Oxidative Stress; Plethysmography; Regional Blood Flow; Ultrasonography

Coronary endothelial dysfunction is a powerful prognostic marker in patients with coronary artery disease (CAD) that is centrally related to oxidative inhibition of nitric oxide (NO)-dependent vascular cell signaling. Xanthine oxidase (XO), which both binds to and is expressed by endothelial cells, generates superoxide and hydrogen peroxide upon oxidation of purines. Whether inhibition of xanthine oxidase activity results in improved coronary vasomotor function in patients with CAD, however, remains unknown. We assessed coronary and peripheral (brachial artery) endothelial function in 18 patients (pts; 65+/-8 years, 86% male) with angiographically documented CAD, preserved left ventricular function, and non-elevated uric acid levels (233+/-10 microM). Patients received incremental doses of intracoronary acetylcholine (ACh; 10(-7) to 10(-5) microM), and minimal lumen diameter (MLD) and coronary blood flow (CBF) were assessed before and after intravenous administration of oxypurinol (200 mg). Oxypurinol inhibited plasma XO activity 63% (0.051+/- 0.001 vs 0.019+/- 0.005 microU/mg protein; p<0.01). In pts who displayed endothelial dysfunction as evidenced by coronary vasoconstriction in response to ACh (n=13), oxypurinol markedly attenuated ACh-induced vasoconstriction (-23+/- 4 vs -15+/- 4% at ACh 10(-5) microM, p<0.05) and significantly increased CBF (16+/-17 vs 62+/-18% at ACh 10(-5) microM, p<0.05), whereas in patients with preserved coronary endothelial function, oxypurinol had no effect on ACh-dependent changes in MLD (+2.8+/- 4.2 vs 5.2+/- 0.7%, p>0.05) or CBF (135+/-75 vs 154+/-61%, p>0.05). Flow-mediated dilation of the brachial artery, assessed in eight consecutive patients, increased from 5.1+/-1.5 before to 7.6+/-1.5% after oxypurinol administration (p < 0.05). Oxypurinol inhibition of XO improves coronary vascular endothelial dysfunction, a hallmark of patients with CAD. These observations reveal that XO-derived reactive oxygen species significantly contribute to impaired coronary NO bioavailability in CAD and that XO inhibition represents an additional treatment concept for inflammatory vascular diseases that deserves further investigation.

Topics: Aged; Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Endothelial Cells; Endothelium, Vascular; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Oxypurinol; Purines; Vasoconstriction; Xanthine Oxidase

Topics: Allopurinol; Cardiovascular Diseases; Cardiovascular System; Coronary Artery Disease; Heart; Humans; Myocardial Ischemia

We aimed to study the effect of cariporide (CP) on protecting the saphenous vein and the role of acetaldehyde dehydrogenase 2 (ALDH2) in coronary artery bypass grafting (CABG).. The saphenous vein is the main graft material used in CABG. Recent studies suggested that CP is effective in protecting against various cardiovascular diseases.. Segments of a surgically removed saphenous vein were used to examine the vascular response to CP. The ALDH2 genotype and expression of related proteins were assessed by Western blotting and immunohistochemistry.. Among the conditions tested, the University of Wisconsin solution with CP (4°C, 5 min) treatment showed the best protective effect on the saphenous vein. The incidence of major adverse cardiac events was higher in the ALDH2-GA (heterozygous mutant) genotype population after CABG.. CP plays a role in reducing the production of reactive oxygen species and apoptosis by ALDH2-mediated mitochondrial function improvement. The ALDH2 mutant genotype might be one of the risk factors for coronary atherosclerotic heart disease.

Topics: Adenosine; Adult; Aldehyde Dehydrogenase, Mitochondrial; Allopurinol; Apoptosis; Coronary Artery Bypass; Coronary Artery Disease; Female; Genotype; Glutathione; Guanidines; Humans; Insulin; Male; Middle Aged; Organ Preservation Solutions; Raffinose; Reactive Oxygen Species; Saphenous Vein; Sulfones

Increased production of oxygen free radicals and decreased oxidant capacity occur in coronary artery diseases (CAD) This pro-oxidant shift in intracellular redox state may induce cell death by either direct cell membrane damage by lipic peroxidation or apoptosis through activation of transcription factors. These changes occur not only in cardiomyocytes, bu also in cardiac sympathetic nerves, which are very sensitive to oxidative damage. Patients with heart failure encountel reduced peripheralblood flow at rest, during exercise and in response to endothelium-dependentvasodilators. Current treatments of cardiomyopathy, a degenerative condition of the myocardium frequently associated with heart failure have done little to enhance patient survival. Decreased myocardial contractility and altered regulation of peripheral circulation along with oxidative conditions are important contributors to the symptoms and prognosis of the disease process. Nitric oxide formed from L-arginine (2-amino-5 guanidinovaleric acid) metabolism in endothelial cells contributes to regulation of blood flow under these conditions. L-Arginine is the precursor of nitric oxide, an endogenous messenger molecule involved in a variety of endothelium-mediated physiological effects in the vascular system. In the present study, we investigated the effect of oral administration of L-arginine (3 g/day) on the intracellular redox status of the patients of ischemic cardiomyopathy aged 45-60 yrs. The enzymatic and non-enzymatic antioxidant parameters like superoxide dismutase, catalase, total thiols (TSH) and ascorbic acid along with pro-oxidant parameters, such as xanthine oxidase, as well as index of oxidative stress as protein carbonyl content and malondialdehyde (a marker of lipid peroxidation) were investigated in the plasma and RBC lysate. L-Arginine (3 g/day) administration was found to improve the levels of these parameters in the patients and regulate the blood flow, as evident by the improved blood pressure of the patients. Thus, it is inferred that L-arginine attenuates the oxidative stress conditions along with maintaining the blood pressure rate of patients suffering from cardiomyopathy.

Topics: Antioxidants; Arginine; Ascorbic Acid; Cardiomyopathies; Catalase; Coronary Artery Disease; Female; Free Radicals; Humans; Male; Middle Aged; Models, Biological; Myocardial Ischemia; Oxidants; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Superoxide Dismutase; Thyrotropin; Xanthine Oxidase

The long-term success of cardiac transplantation is limited by graft atherosclerosis, also known as graft vascular disease (GVD). GVD is currently the leading cause of late allograft failure in cardiac transplant recipients. The aim of this study was to assess the effects of cold ischemic preservation time (CIPT) and degree of donor-recipient histocompatibility on GVD using a rat heterotopic cardiac transplantation model.. ACI-Lewis (n=9), Lewis-F344 (n=9), and Lewis-Lewis (n=9) donor-recipient rat strain combinations were subjected to variable durations of CIPT (0, 4, and 24 hours in University of Wisconsin solution at 4°C) prior to transplantation (n=81 total). The ACI-Lewis allografts differed in both major histocompatibility complex (MHC) class I and II antigens, the Lewis-F344 allograft combination differed in multiple non-MHC antigens, and the Lewis-Lewis isograft combination was syngeneic. Grafts were harvested at 90 days. Intimal area ratio (IAR), intimal thickness score (ITS), and rejection score (RS) were determined for each specimen.. The Lewis-Lewis transplant group had a significantly higher mean RS (P=.036) with 24 hours than with 0 hours of CIPT in this rat heterotopic transplantation model at 90 days. The Lewis-F344 group had a significantly higher IAR (P=.035), ITS (P=.030), and RS (P=.017) with 24 hours than with 0 hours of CIPT. The ACI-Lewis group had high levels of GVD with all durations of CIPT (0, 4, and 24 hours); as a consequence, there were no significant differences in the ITS, IAR, or RS. With 0 hours of CIPT, the ACI-Lewis transplantation group yielded a significantly higher mean IAR (P=.029), ITS (P=.003), and RS (P=5.02×10(-5)) than the Lewis-Lewis group. The Lewis-F344 group had a significantly higher mean RS (P=.003) than the Lewis-Lewis (syngeneic) group. The ACI-Lewis transplantation group had a significantly higher mean IAR (P=.035), and trended toward a higher ITS (P=.058) than the Lewis-F344 group.. Longer cold ischemic preservation time and less donor-recipient histocompatibility were associated with more advanced GVD in a rat heterotopic transplantation model, especially when there were multiple MHC mismatches as in ACI-Lewis allografts, but also occurred when there were differences in multiple non-MHC antigens as in the Lewis-F344 allografts. There was a lesser effect of longer cold ischemic time on GVD in the Lewis-Lewis syngeneic (isograft) group, suggesting that greater histocompatibility can mitigate the adverse effects of longer ischemic times.

Topics: Adenosine; Allopurinol; Animals; Cold Ischemia; Coronary Artery Disease; Glutathione; Graft Rejection; Heart Transplantation; Histocompatibility; Histocompatibility Antigens; Insulin; Male; Organ Preservation Solutions; Raffinose; Rats; Rats, Inbred ACI; Rats, Inbred F344; Rats, Inbred Lew; Risk Assessment; Risk Factors; Time Factors

Sexual dimorphisms of atherosclerosis and the susceptibility to arrhythmias and antiarrhythmic treatment have been reported. This study investigated acute effects of amiodarone on endothelium-dependent relaxation in the aorta of male and female apoE0 mice with advanced atherosclerosis. Amiodarone tissue uptake was quantified by high-performance liquid chromatography, and xanthine oxidase-dependent superoxide anion formation was investigated in vitro in presence or absence of amiodarone. Incubation with amiodarone for 30 min improved endothelium-dependent relaxation, which was associated with rapid vascular accumulation of amiodarone (P < 0.001) that was sex-dependent. In males, reduced endothelium-dependent relaxation was improved by amiodarone (from 88 +/- 3% to 100 +/- 2%, P < 0.01). Spontaneous phasic contractions, which were greater in females than in males (P < 0.001), were completely abolished by amiodarone (P < 0.0001). Amiodarone also inhibited generation of superoxide anion (P < 0.0001). These data show that amiodarone rapidly accumulates in atherosclerotic vascular tissue, abolishes vascular autorhythmicity, and improves endothelium-dependent function in atherosclerotic arteries. Antioxidant and vasodilator effects following amiodarone administration may contribute to its antiarrhythmic effects.

Topics: Acetylcholine; Amiodarone; Animals; Antioxidants; Aorta; Apolipoproteins E; Coronary Artery Disease; Female; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Muscle, Smooth, Vascular; Nitroprusside; Phenylephrine; Sex Factors; Superoxides; Vasoconstriction; Vasodilation; Vasodilator Agents; Xanthine; Xanthine Oxidase

There is evidence for a relationship between endothelial dysfunction and cardiovascular disease, but a causative role for oxidative stress remains to be determined.. We studied 188 patients with severe coronary artery disease (CAD), of whom 51 were age and sex matched with 51 healthy controls undergoing varicose vein surgery. Relaxation of saphenous vein to calcium ionophore, apocynin, and allopurinol was studied together with the markers of oxidative stress, total antioxidant capacity and reduced/oxidized glutathione ratio. Vascular superoxide levels were measured using lucigenin chemiluminescence and hydroethidine. Relaxation to calcium ionophore was decreased in CAD compared with control patients (maximum relaxation 26+/-2% versus 60+/-1%; P<0.001). Total superoxide production was increased (0.89+/-0.09 versus 0.56+/-0.06 nmol/mg per min; P=0.008), whereas superoxide inhibition with apocynin or allopurinol had a greater effect on vasorelaxation in CAD patients. Low-density lipoprotein (LDL) cholesterol predicted relaxation to calcium ionophore (P<0.001) and oxidative stress markers (P<0.001) in CAD patients.. Endothelial dysfunction is associated with raised levels of superoxide and biomarkers of oxidative stress in saphenous veins from CAD patients. LDL cholesterol is a major determinant of endothelial dysfunction and oxidative stress in these patients. These results support intensive LDL cholesterol-lowering therapy as suggested by recent clinical trials.

Topics: Acetophenones; Adult; Aged; Allopurinol; Antioxidants; Biomarkers; Cholesterol, LDL; Coronary Artery Disease; Endothelium, Vascular; Female; Free Radical Scavengers; Humans; Ionophores; Male; Middle Aged; Nitroprusside; Oxidative Stress; Phenylephrine; Risk Factors; Saphenous Vein; Superoxides; Varicose Veins; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Oxidative stress plays important role in the pathogenesis of atherosclerosis and coronary artery disease (CAD). We aimed to determine the sources and selected molecular mechanisms of oxidative stress in CAD.. We examined basal and NAD(P)H oxidase-mediated superoxide (O2*-) production using lucigenin chemiluminescence, ferricytochrome c and dihydroethidium fluorescence in human coronary arteries from 19 CAD and 17 non-CAD patients undergoing heart transplantation. NAD(P)H oxidase subunits and xanthine oxidase expression were measured. Superoxide production was greater in coronary arteries from patients with CAD, even in vessels without overt atherosclerotic plaques, and was doubled within branching points of coronary arteries. Studies using pharmacological inhibitors and specific substrates showed that NAD(P)H oxidases (60%) and xanthine oxidase (25%) are primary sources of O2*- in CAD. Losartan significantly inhibited superoxide production in coronary arteries. NAD(P)H oxidase activity and protein levels of the NADPH oxidase subunits p22phox, p67phox, and p47phox were significantly increased in CAD, as were mRNA levels for p22phox and nox2, and no NAD(P)H oxidase subunit mRNA levels correlated with NAD(P)H oxidase activity in vessels from individual patients. Activity and protein expression of xanthine oxidase were increased in CAD, whereas xanthine dehydrogenase levels were not changed.. Increased expression and activity of NAD(P)H oxidase subunits and xanthine oxidase, in part mediated through angiotensin II and PKC-dependent pathways, are important mechanisms underlying increased oxidative stress in human coronary artery disease.

Topics: Adult; Angiotensin II; Coronary Artery Disease; Coronary Vessels; Female; Humans; Male; Membrane Transport Proteins; Middle Aged; NADPH Oxidases; Oxidative Stress; Phosphoproteins; Protein Kinase C; Superoxides; Vasoconstrictor Agents; Xanthine Oxidase

Increased inactivation of nitric oxide by superoxide (O2*-) contributes to endothelial dysfunction in patients with coronary disease (CAD). We therefore characterized the vascular activities of xanthine oxidase and NAD(P)H oxidase, 2 major O2*--producing enzyme systems, and their relationship with flow-dependent, endothelium-mediated vasodilation (FDD) in patients with CAD.. Xanthine- and NAD(P)H-mediated O*.- formation was determined in coronary arteries from 10 patients with CAD and 10 controls by using electron spin resonance spectroscopy. Furthermore, activity of endothelium-bound xanthine oxidase in vivo and FDD of the radial artery were determined in 21 patients with CAD and 10 controls. FDD was measured before and after infusion of the antioxidant vitamin C (25 mg/min i.a.) to determine the portion of FDD inhibited by radicals. In coronary arteries from patients with CAD, xanthine- and NAD(P)H-mediated O2*- formation was increased compared with controls (xanthine: 12+/-2 versus 7+/-1 nmol O2*-/ microg protein; NADH: 11+/-1 versus 7+/-1 nmol O2*-/ microg protein; and NADPH: 12+/-2 versus 9+/-1 nmol O2*-/ microg protein; each P<0.05). Endothelium-bound xanthine oxidase activity was increased by >200% in patients with CAD (25+/-4 versus 9+/-1 nmol O2*-/ microL plasma per min; P<0.05) and correlated inversely with FDD (r=-0.55; P<0.05) and positively with the effect of vitamin C on FDD (r=0.54; P<0.05).. The present study represents the first electron spin resonance measurements of xanthine and NAD(P)H oxidase activity in human coronary arteries and supports the concept that increased activities of both enzymes contribute to increased vascular oxidant stress in patients with CAD. Furthermore, the present study suggests that increased xanthine oxidase activity contributes to endothelial dysfunction in patients with CAD and may thereby promote the atherosclerotic process.

Topics: Adult; Coronary Artery Disease; Coronary Vessels; Electron Spin Resonance Spectroscopy; Endothelium, Vascular; Humans; Hypercholesterolemia; Male; Middle Aged; NADPH Oxidases; Oxidative Stress; Superoxides; Vasodilation; Xanthine Oxidase

Total coronary artery occlusion followed by reperfusion leads to neutrophil accumulation in the reperfused myocardium and a reduction in endothelium-dependent coronary artery relaxation. Attenuated coronary artery relaxation in the affected regions is thought to be related to breakdown of endothelium-derived relaxing factor (EDRF) by free oxygen radicals released during reperfusion. To determine if temporary subtotal coronary artery narrowing leads to similar alteration in vascular reactivity, eight open-chest dogs were subjected to 1 h of left anterior descending (LAD) coronary artery narrowing (70% reduction in basal flow) and pacing-induced increase in heart rate (30% above baseline) followed by reperfusion for 1 h. Thereafter reactivity of ischemic-reperfused LAD and nonischemic circumflex (Cx) coronary artery rings to the thromboxane A2 analog U46,619 and EDRF-dependent vasorelaxants acetylcholine (ACh), thrombin, and adenosine diphosphate (ADP), as well as to EDRF-independent vasorelaxant nitroglycerin (NTG), was examined. Unlike in the setting of total coronary artery occlusion, reperfused myocardium or LAD did not reveal neutrophil infiltration. However, contraction in response to U46,619 was markedly (P < .001) increased in the LAD rings compared to that in the Cx rings. ACh-induced relaxation was only modestly decreased (P < .05) in the LAD coronary artery rings, but the relaxation in response to both thrombin and ADP was markedly diminished (P < .01) as compared to that in the Cx rings. Coronary artery ring relaxation in response to NTG was preserved in the LAD rings. Pretreatment of coronary artery rings with indomethacin did not alter the enhanced contraction or diminished endothelium-dependent relaxation of LAD coronary artery rings.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcholine; Animals; Coronary Artery Disease; Dogs; Endothelium, Vascular; Female; Free Radicals; In Vitro Techniques; Male; Myocardial Reperfusion Injury; Neutrophils; Nitric Oxide; Prostaglandin Endoperoxides, Synthetic; Vasodilation; Xanthine; Xanthine Oxidase; Xanthines