Xanthine Oxidase Inhibition With Oxypurinol Improves Endothelial Vasodilator Function in Hypercholesterolemic but Not in Hypertensive Patients

Cardillo, Carmine; Kilcoyne, Crescence M.; Cannon, Richard O.; Quyyumi, Arshed A.; Panza, Julio A.

doi:10.1161/01.hyp.30.1.57

Cited by 225 publications

(150 citation statements)

References 35 publications

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“…In these subjects, eXO activity was increased by Ͼ200% compared with age-matched controls. This finding is in line with the observations of Cardillo et al, 22 who demonstrated that inhibition of XO improved endotheliumdependent vasodilation in subjects with hypercholesterolemia.…”

Section: Discussionsupporting

confidence: 93%

Electron Spin Resonance Characterization of Vascular Xanthine and NAD(P)H Oxidase Activity in Patients With Coronary Artery Disease

et al. 2003

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Background-Increased inactivation of nitric oxide by superoxide (O 2 ·Ϫ ) 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 O 2 ·Ϫ -producing enzyme systems, and their relationship with flow-dependent, endothelium-mediated vasodilation (FDD) in patients with CAD. Methods and Results-Xanthine-and NAD(P)H-mediated O 2 ·Ϫ 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) 05).Conclusions-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.

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Section: Discussionsupporting

confidence: 93%

Electron Spin Resonance Characterization of Vascular Xanthine and NAD(P)H Oxidase Activity in Patients With Coronary Artery Disease

et al. 2003

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“…2 This is underscored by the observation that administration of scavengers of reactive oxygen species can improve NO bioavailability in hypercholesterolemia. [41][42][43] Our data support the notion that in the early phase of atherosclerosis, ie, in the presence of hypercholesterolemia, decreased NO bioavailability is probably indeed a multifactorial phenomenon, which cannot only be explained by impaired NO production.…”

Section: Discussionsupporting

confidence: 84%

“…36 -38 One major source of superoxide production in hypercholesterolemia appears to be xanthine oxidase; inhibitors of this enzyme reduced endothelial superoxide production in vitro 38 and restored endothelial dysfunction in vivo. 41 Another source is NOS itself, which may exhibit uncoupling of L-arginine oxidation. 2 This is underscored by the observation that administration of scavengers of reactive oxygen species can improve NO bioavailability in hypercholesterolemia.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure

Wever

Boer

Hijmering

et al. 1999

ATVB

198

117

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Abstract-In patients with chronic renal failure (CRF), atherosclerosis is a major cause of cardiovascular morbidity and mortality. Generally, atherosclerosis has been associated with a reduced bioavailability of nitric oxide (NO). Experimental studies have indicated the presence of enhanced NO degradation by reactive oxygen species as well as decreased NO production as possible causes for this reduced NO bioavailability. So far, the question whether or not NO production is impaired in patients with CRF has never been investigated. Therefore, we measured whole body NO production in 7 patients with CRF, and in 7 matched healthy subjects. To assess the relative importance of a dysfunction of NO synthase (NOS), we compared the NO production of these patients to that of 2 other groups known to have endothelial dysfunction, ie, 7 patients with familial hypercholesterolemia (FH) who did not yet have signs of clinical cardiovascular disease (all nonsmokers), and 5 cigarette smokers. These groups were also compared with 7 nonsmoking, age-matched healthy subjects. Whole body NO production, determined as in vivo arginine-to-citrulline conversion, was assessed by giving an intravenous infusion of [ 15 N 2 ]-arginine as a substrate for NOS and measuring isotopic plasma enrichment of [15 N]-citrulline by LC-MS. NO production in the CRF patients (0.13Ϯ0.02 mol ⅐ kg -1 ⅐ h -1 ) was significantly lower (PϽ0.05) than in the corresponding control group (0.23Ϯ0.09 mol ⅐ kg -1 ⅐ h -1 ). NO production also tended to be lower in the FH patients (0.16Ϯ0.04 mol ⅐ kg -1 ⅐ h -1 ), but the difference with the corresponding control group did not reach significance (0.22Ϯ0.06 mol ⅐ kg -1 ⅐ h -1 ). In the group of smokers, NO production was similar to that in nonsmokers (0.22Ϯ0.09 mol ⅐ kg -1 ⅐ h -1 ).In conclusion, it is demonstrated for the first time that basal whole body NO production is reduced in patients with CRF. This finding implies that therapeutic interventions to endothelial dysfunction in these patients should be primarily directed toward improvement of NO production. The finding of only a tendency toward reduction of NO production in patients with FH and the absence of a reduction in cigarette smokers suggests that other mechanisms such as enhanced NO degradation may be involved in the decrease of NO bioavailability in these groups. (Arterioscler Thromb Vasc Biol. 1999;19:1168-1172.) Key Words: nitric oxide Ⅲ chronic renal failure Ⅲ atherosclerosis Ⅲ endothelium Ⅲ hypercholesterolemia P remature atherosclerosis is one of the primary causes of morbidity and mortality in patients with chronic renal insufficiency. 1 Over the last decade endothelial dysfunction has been identified as an early mediator in this process. Nitric oxide (NO) is one of the main factors involved in the antiatherosclerotic effects of the endothelium, 2 and chronic renal failure (CRF) has been associated with impaired NO bioavailability in the absence of concomitant risk factors, [3][4][5] even in children. 6,7 However, the finding of a reduced NO bioavailabi...

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“…Recent experimental data directly implicate UA in endothelial dysfunction (18,19), but few studies were conducted in humans and available data are controversial. In patients with heart failure (20), with type 2 diabetes (21), at increased cardiovascular risk (10), and with hypercholesterolemia but not in patients with essential hypertension (22), allopurinol, a xanthine oxidase inhibitor that lowers UA and interacts with anion superoxide generation (23), improves endothelial dysfunction. In the study of Mercuro et al (10), the beneficial effect of allopurinol could have been a direct consequence of the reduced UA levels rather than of superoxide anions mediated by xanthine oxidase inhibition because of the close correlation found between the amount of that decrease and the improvement of endothelial function.…”

Section: Discussionmentioning

confidence: 99%

Uric Acid and Endothelial Dysfunction in Essential Hypertension

Zoccali

Maio²,

Mallamaci³

et al. 2006

Journal of the American Society of Nephrology

208

137

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Recent epidemiologic and experimental evidence suggests that serum uric acid (UA) is an independent risk factor for cardiovascular and renal diseases. However, endothelial dysfunction is an early predictor of cardiovascular events, particularly in hypertensive patients. For assessment of the association between UA and endothelial function, 217 (108 men, 109 women; aged 48.0 ؎ 10.6 yr) white never-treated hypertensive patients were studied. All patients underwent the following procedures: BP measurements, laboratory tests (C-reactive protein [CRP], insulin resistance by homeostasis model assessment, serum creatinine, and UA), and endothelial function evaluated by intra-arterial infusion of acetylcholine (ACh). Serum creatinine, CRP, and maximal vasodilatory response to ACh were related to the UA (all P < 0.0001). In the multiple regression analysis, serum UA ranked as the third correlate of peak of forearm blood flow predictor, after homeostasis model assessment and CRP. The data show an independent link between UA and endothelial function, also in a statistical model that included CRP. In conclusion, the data demonstrate an inverse and significant relationship between UA and ACh-stimulated vasodilation in patients with uncomplicated, untreated essential hypertension, independent of traditional cardiovascular risk factors. Probably, the chronic inflammation that was documented in these patients may be considered the mechanistic link between serum UA and vascular damage.

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Xanthine Oxidase Inhibition With Oxypurinol Improves Endothelial Vasodilator Function in Hypercholesterolemic but Not in Hypertensive Patients

Cited by 225 publications

References 35 publications

Electron Spin Resonance Characterization of Vascular Xanthine and NAD(P)H Oxidase Activity in Patients With Coronary Artery Disease

Electron Spin Resonance Characterization of Vascular Xanthine and NAD(P)H Oxidase Activity in Patients With Coronary Artery Disease

Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure

Uric Acid and Endothelial Dysfunction in Essential Hypertension

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