(Hypertension. 1997;30:57-63.)
© 1997 American Heart Association, Inc.
Articles |
Xanthine Oxidase Inhibition With Oxypurinol Improves Endothelial Vasodilator Function in Hypercholesterolemic but Not in Hypertensive Patients
From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Correspondence to Julio A. Panza, MD, Cardiology Branch, National Institutes of Health, Building 10, Room 7B-15, Bethesda, MD 20892-1650. E-mail panzaj{at}gwgate.nhlbi.nih.gov
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Abstract |
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Abstract Hypercholesterolemic and hypertensive patients have impaired endothelium-dependent vasorelaxation because of decreased nitric oxide activity, but the mechanism underlying this abnormality is unknown. This study sought to determine whether an increased breakdown of nitric oxide by xanthine oxidase–generated superoxide anions could participate in these forms of endothelial dysfunction. We studied vascular responses to intrabrachial infusion of acetylcholine (an endothelium-dependent vasodilator, 7.5 to 30 µg/min) and sodium nitroprusside (a direct smooth muscle dilator, 0.8 to 3.2 µg/min) by strain-gauge plethysmography before and during the combined administration of oxypurinol (300 µg/min), a xanthine oxidase inhibitor, in 20 hypercholesterolemic patients, 20 essential hypertensive patients, and 20 normal subjects. The vasodilator response to acetylcholine was blunted in hypercholesterolemic (highest flow, 8.2±8 mL·min-1·dL-1) and hypertensive (8.5±4 mL·min-1·dL-1) patients compared with control subjects (13.8±6.6 mL·min-1·dL-1) (both P<.001); however, no differences were observed in the response to sodium nitroprusside. Oxypurinol did not change the response to acetylcholine in control subjects (P=.26) and improved, but did not normalize, its vasodilator effect in hypercholesterolemic patients (P<.01). Oxypurinol did not affect the response to acetylcholine in hypertensive patients (P=.34) and did not modify the response to sodium nitroprusside in any group. These results suggest that xanthine oxidase–generated superoxide anions are partly responsible for the impaired endothelial vasodilator function of hypercholesterolemic patients. In contrast, this mechanism does not appear to play a significant role in essential hypertension.
Key Words: xanthine oxidase • nitric oxide • free radicals • cholesterol • hypertension, arterial
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Introduction |
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The synthesis of nitric oxide (NO) by the vascular endothelium importantly contributes to the maintenance of vasodilator tone. Moreover, endothelium-derived NO inhibits the proliferation of smooth muscle cells, reduces platelet aggregability, and prevents leukocyte adhesion to the vascular surface.1 These relevant physiological actions in the regulation of cardiovascular homeostasis suggest that an impaired bioavailability of endothelium-derived NO may contribute to the development of the atherosclerotic process. Endothelial dysfunction related to decreased NO activity has previously been described in patients with known risk factors for atherosclerosis, such as hypercholesterolemia2 3 4 and arterial hypertension.5 6 7 However, the pathophysiological mechanisms underlying the NO abnormalities in these conditions remain unclear.
Recent studies in animal models of hypercholesterolemia and hypertension have linked the pathogenesis of endothelial dysfunction with an increased degradation of NO. Principal among the substances involved in this breakdown process is superoxide anion, an avid scavenger of endothelium-derived NO.8 9 An increased production of superoxide radical has been directly assessed by chemiluminescence in the aortic wall of cholesterol-fed rabbits,10 11 and chronic treatment with superoxide dismutase has been shown to be effective in restoring endothelium-dependent vasodilator function in this model of hypercholesterolemia.12 Previous studies have also shown that the administration of superoxide dismutase, a scavenger of superoxide anion,13 decreases blood pressure in hypertensive but not in normotensive rats,14 supporting the concept that superoxide anion might be increased in the arterial wall of spontaneously hypertensive rats and might trigger the development of hypertension, probably by inactivating the vasodilator effect of NO.
Superoxide anions may be generated by different enzymatic and nonenzymatic sources. In the vascular endothelium, the xanthine oxidase system is one of the main sources of superoxide anion within and around endothelial cells, both directly and through the activation of circulating neutrophils.15 16 Inhibition of xanthine oxidase can be achieved by oxypurinol, which has a molecular structure similar to that of xanthine and binds to xanthine oxidase, preventing the formation of uric acid and superoxide radicals.17
In the present study, we tested the hypothesis that an increased activity of superoxide anions formed by the xanthine oxidase system could be involved in the decreased bioavailability of NO in patients with hypercholesterolemia and patients with essential hypertension. To this purpose, we assessed endothelium-dependent vascular relaxation to acetylcholine before and during the infusion of oxypurinol in control subjects and in hypercholesterolemic and hypertensive patients.
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Methods |
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Study Population
The clinical characteristics and lipid profiles of the 60 subjects who took part in the study are reported in Table 1
.
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The hypercholesterolemic group included 20
patients selected for the study because their plasma
cholesterol levels after a 12-hour fasting period were
greater than 250 mg/dL. Eighteen of the 20 patients had low-density
lipoprotein (LDL) plasma levels greater than 160 mg/dL. Their plasma
high-density lipoprotein and triglyceride levels (Table 1
)
were not significantly different from those of the control group
(P=.32 and P=.10, respectively). Patients had not
taken any cholesterol-lowering agent within the previous 2
months or any antioxidant vitamin supplement in the preceding 6 months.
No effort was made to change the patients' diet before studies were
performed. All hypercholesterolemic patients had normal
blood pressure values.
The hypertensive group included 20 patients with a history of
chronically elevated blood pressure (
145/95 mm Hg) without any
apparent underlying cause who were followed at the outpatient clinic of
the National Heart, Lung, and Blood Institute. Each patient had been
previously treated with one or more antihypertensive agents for more
than 3 years. Patients were asked to discontinue their current
antihypertensive therapy 2 weeks before the study day; during that
period, they were closely monitored for any evidence of accelerated or
malignant hypertension. Patients in whom withdrawal of antihypertensive
therapy was considered hazardous, mostly because of severely elevated
blood pressure despite medications, were excluded from the study. All
hypertensive patients had normal plasma cholesterol levels
(<200 mg/dL).
A population of 20 normal volunteers with no evidence of present or
past hypertension and hypercholesterolemia
(plasma cholesterol 
200 mg/dL) was selected as a control
group. They were matched with the patients of both experimental groups
for approximate age and sex.
Before admission, participants were screened by clinical history, physical examination, routine chemical analyses, electrocardiography, and chest radiography. Exclusion criteria were history or evidence of present or past diabetes mellitus, cardiac disease, peripheral vascular disease, coagulopathy, or any other disease predisposing them to vasculitis or Raynaud's phenomenon. One normal volunteer, 1 hypercholesterolemic patient, and 3 hypertensive patients were smokers. Six normal volunteers, 4 hypercholesterolemic patients, and 5 hypertensive patients were postmenopausal women; none of them were on estrogen replacement therapy at the time of the study.
All participants gave written informed consent for all procedures; the study protocol was approved by the National Heart, Lung, and Blood Institute Investigational Review Board.
Protocol
All studies were performed in the morning in a quiet room with a
temperature of approximately 22°C. Participants were asked to refrain
from drinking alcohol or beverages containing caffeine and from smoking
for at least 24 hours before studies.
Each study consisted of infusion of drugs into the brachial artery and measurement of the response of the forearm vasculature by means of strain-gauge venous-occlusion plethysmography. All drugs used in this study were approved for human use by the Food and Drug Administration in the form of Investigational New Drug (IND) and were prepared by the Pharmaceutical Development Service of the National Institutes of Health following specific procedures to ensure accurate bioavailability and sterility of the solutions.
While the participants were supine, a 20-gauge polytetrafluoroethylene catheter (Arrow Inc) was inserted into the brachial artery of the nondominant arm (left in most cases). This arm was slightly elevated above the level of the right atrium, and a mercury-filled silicone elastomer strain gauge was placed on the widest part of the forearm.18 The strain gauge was connected to a plethysmograph (model EC-4, DE Hokanson) calibrated to measure the percent change in volume and connected in turn to a chart recorder to record flow measurements. For each measurement, a cuff placed around the upper arm was inflated to 40 mm Hg with a rapid cuff inflator (model E-10, Hokanson) to occlude venous outflow from the extremity. A wrist cuff was inflated to suprasystolic pressures 1 minute before each measurement to exclude hand circulation.19 Flow measurements were recorded for approximately 7 seconds every 15 seconds; seven readings were obtained for each mean value.
Basal measurements were obtained after a 3-minute infusion of 5% dextrose solution at 1 mL/min. Forearm blood flow was measured after infusion of sodium nitroprusside and acetylcholine. Sodium nitroprusside was used as an endothelium-independent vasodilator because its vasodilator effect is largely due to its direct action on smooth muscle cells.20 Acetylcholine, in contrast, induces vasodilation by stimulating the release of relaxing factors from the vascular endothelium.21
Sodium nitroprusside was infused at 0.8, 1.6, and 3.2 µg/min and acetylcholine chloride (Sigma Chemical Co) at 7.5, 15, and 30 µg/min (the infusion rates were 0.25, 0.5, and 1 mL/min, respectively, for each drug). Each dose was infused for 5 minutes, and forearm blood flow was measured during the last 2 minutes. A 30-minute rest period was allowed and another basal measurement obtained between infusions of the two drugs.
Oxypurinol (Sigma), dissolved in 5% dextrose solution, was infused at 300 µg/min (infusion rate, 1 mL/min) for 30 minutes, and baseline flow measurements were obtained. The oxypurinol dose was chosen to achieve, at baseline flow conditions, an intravascular concentration of 10 µg/mL, which has been shown to achieve more than 90% inhibition of xanthine oxidase activity in the forearm blood vessels.22
Subsequently, cumulative dose-response curves for acetylcholine and sodium nitroprusside were repeated during the concomitant infusion of oxypurinol using the same doses, infusion rates, and resting interval reported above. Oxypurinol infusion was continued during the resting period.
The sequence of acetylcholine and sodium nitroprusside infusions, both before and after oxypurinol infusion, was randomized to avoid any bias related to the order of drug infusion.
During the studies, participants were unaware of the drug being infused. All blood pressures were recorded directly from the intra-arterial catheter after each flow measurement. Forearm vascular resistance was calculated as the mean arterial pressure divided by the forearm blood flow.
Statistical Analysis
Differences among means of the three groups were
analyzed by ANOVA followed by Dunnett's test for post hoc
comparisons between patients and control subjects when the global test
showed statistical significance. Absolute values of
hemodynamic variables were used for these
comparisons when basal values were similar in patients and control
subjects; however, because basal forearm vascular resistance was higher
in the hypertensive group, changes in vascular resistance were
expressed as percentage of baseline values. Oxypurinol effects on
baseline hemodynamic variables were
analyzed by paired Student's t test. The responses
to acetylcholine and sodium nitroprusside before and after oxypurinol
were compared by ANOVA for repeated measures. All calculated
probability values are two-tailed, and a value of P<.05 was
considered statistically significant. All group data are reported as
mean±SD, except in the figures, where values represent
mean±SEM.
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Results |
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Basal Blood Flow and Vascular Resistance
Basal forearm blood flow, measured at the beginning of the study, was similar in control subjects and hypercholesterolemic and hypertensive patients (P=.43) (Table 2
). As expected, basal forearm
vascular resistance was significantly higher in hypertensive patients
than control subjects (P<.01); basal vascular resistance
did not differ significantly between control subjects and
hypercholesterolemic patients (P=NS).
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Blood Pressure and Heart Rate
Group differences in baseline mean arterial pressure
and heart rate values are reported in Table 1. Throughout the study,
during the infusion of the different substances, no significant change
from baseline in mean arterial pressure and heart rate was
observed in each of the three groups.
Vascular Response to Acetylcholine and Sodium
Nitroprusside
As shown in Fig 1, the increase in blood flow and
decrease in vascular resistance induced by acetylcholine infusion were
significantly reduced in hypercholesterolemic and
hypertensive patients compared with control subjects. Forearm blood
flow measured at the highest dose of acetylcholine was 13.8±6.6
mL·min-1·dL-1
in control subjects compared with 8.2±8 in
hypercholesterolemic patients and 8.5±4 in
hypertensive patients (both P<.001). In contrast, no
significant difference was observed among the three groups in the
forearm blood flow and vascular resistance responses to sodium
nitroprusside (P=NS) (Table 3).
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), 20
hypercholesterolemic patients (
), and 20
hypertensive patients (
). Values represent mean and SEM.
P values refer to comparison of the curves obtained in
hypercholesterolemic and hypertensive patients vs that
of control subjects by ANOVA.
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Effects of Oxypurinol on Basal Blood Flow
As reported in Table 2, oxypurinol infusion did not produce any
significant change in blood flow or vascular resistance in either
control subjects (P=.77 and P=.80, respectively,
compared with baseline values) or hypercholesterolemic
(P=.93 and P=.65, respectively, compared with
baseline values) and hypertensive (P=.96 and
P=.89, respectively, compared with baseline values)
patients.
Effect of Oxypurinol on Vascular Responses to Acetylcholine and
Sodium Nitroprusside
In control subjects, the vasodilator response to acetylcholine was
not significantly modified after oxypurinol infusion (forearm blood
flow at the highest dose of acetylcholine was 15.2±7.6
mL·min-1·dL-1;
P=.26 compared with values obtained without oxypurinol) (Fig 2). Although a trend was observed toward higher blood
flow during oxypurinol, no such trend was found in vascular resistance,
indicating that the slight changes in forearm blood flow were not
related to changes in vascular tone induced by oxypurinol.
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) and
after (
In contrast, in hypercholesterolemic patients,
both the increase in forearm blood flow and the decrease in vascular
resistance were significantly greater after oxypurinol infusion
(highest forearm blood flow, 9.8±7.3
mL·min-1·dL-1;
lowest vascular resistance, 14±10.1
mm Hg·mL-1·min-1 · dL-1)
(P<.01 and P<.05, respectively, compared with
values obtained without oxypurinol) (Fig 3).
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In hypertensive patients, the response to acetylcholine was not
significantly modified during concomitant oxypurinol infusion (Fig 4). Forearm blood flow responses to acetylcholine before
and during oxypurinol administration were not significantly different
(P=.34), although similar to findings in control subjects,
there was a trend toward greater forearm blood flow during oxypurinol
infusion (highest forearm blood flow, 9.9±5.2
mL·min-1·dL-1).
However, no such trend was observed in the response to acetylcholine in
terms of vascular resistance (P=.64); in fact, at the
highest acetylcholine dose, vascular resistance without oxypurinol was
16.2±7.2
mm Hg·mL-1·min-1·dL-1
compared with 18.5±18.5 with oxypurinol.
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Oxypurinol infusion did not modify the vasodilator response to
sodium nitroprusside in normal subjects or in
hypercholesterolemic or hypertensive patients (Table 3).
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Discussion |
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We designed the present study to investigate the possibility that an enhanced breakdown of NO by xanthine oxidase–generated superoxide anions may contribute to the impaired endothelium-dependent vasodilation in patients with hypercholesterolemia and in those with essential hypertension. We hypothesized that if the activity of superoxide anions produced by xanthine oxidase were increased in these conditions, then oxypurinol, by virtue of its antagonistic effect on xanthine oxidase, would allow a greater delivery of endothelium-derived NO to the underlying smooth muscle. This, in turn, would improve the abnormal response to acetylcholine previously reported in these patients.
The main finding of our study was that oxypurinol infusion improved acetylcholine-induced vasodilation in hypercholesterolemic patients, an effect not observed in control subjects. This beneficial effect of oxypurinol was observed at all doses of acetylcholine infused, whereas no difference in basal vascular tone was found with oxypurinol administration. Because many regulatory mechanisms independent of endothelial release of NO contribute to the determination of basal vascular tone, these findings may indicate that increased NO breakdown by xanthine oxidase–generated superoxide anions affects vascular tone only in situations of stimulated NO release. The results of this study are in keeping with those of studies in animal models of hypercholesterolemia which have shown that exposure to oxypurinol for 30 minutes normalizes the increased production of superoxide anions and improves acetylcholine-induced relaxation only in aortic preparations from hypercholesterolemic rabbits, without any effect in control animals.10 These results have recently been confirmed in the same animal model after dietary correction of hypercholesterolemia for 1 month.23 The overproduction of superoxide anions in hypercholesterolemic animals appears to occur predominantly in endothelial cells, since endothelium removal normalizes superoxide anion generation.10 12 Thus, the inactivation of NO within endothelial cells, or shortly after its release from the endothelium, is one possible mechanism by which superoxide anion excess leads to endothelial dysfunction. Moreover, endothelium-derived superoxide anions also participate in the oxidation of LDL.24 Oxidized LDL, in turn, inhibits endothelium-dependent relaxation by affecting either membrane receptors25 or intracellular signal transduction pathways26 and by degrading NO directly,27 further promoting endothelial dysfunction and atherosclerosis. It has recently been reported that lipoprotein(a), another atherogenic plasma lipoprotein, could also influence vascular tone in a fashion similar to that of oxidized LDL. In fact, exposure to oxidized lipoprotein(a) increased superoxide anion production and suppressed acetylcholine-induced dilator response in rabbit renal artery,28 suggesting that enhanced NO inactivation by reactive oxygen species could be the underlying mechanism for the impaired endothelium-dependent relaxation. Evidence that abnormal vascular oxidative stress plays an important role in the endothelial dysfunction of hypercholesterolemic animals stems from studies demonstrating that dietary antioxidants such as probucol increase LDL resistance to oxidative modification, prevent the increase in vascular superoxide generation, and normalize relaxation to acetylcholine even without lowering plasma cholesterol levels.29 Human studies seem to be in agreement with these findings, since combined LDL-lowering and antioxidant therapy has been shown to provide a greater improvement in the vasoconstrictor response to acetylcholine in patients with hypercholesterolemia and atherosclerosis than other LDL-lowering treatments.30
When taken together, these observations emphasize the role of free radicals (especially superoxide anions) and oxidative metabolism in the endothelial dysfunction characteristic of dyslipidemia. We have previously investigated the possible involvement of extracellular superoxide anion generation in the pathogenesis of endothelial dysfunction in patients with hypercholesterolemia using copper-zinc superoxide dismutase (CuZn SOD) as a scavenger of superoxide anions.31 The infusion of CuZn SOD did not have any demonstrable effect on acetylcholine-induced vasorelaxation. Because CuZn SOD has poor intracellular penetrance because of its negative charge,32 those findings suggested that extracellular breakdown of NO is not responsible for the impaired endothelial responses. In contrast, the findings of the present investigation demonstrate that inhibition of xanthine oxidase–mediated formation of superoxide anions by oxypurinol improves endothelium-dependent vasodilator response in hypercholesterolemic humans. Thus, the present findings support the concept that excess vascular oxidative stress derived from the xanthine oxidase system is present within the endothelial cells in the microcirculation of these patients.
It must be noted, however, that oxypurinol infusion improved but did not completely restore the abnormal endothelial vasodilator response to acetylcholine in hypercholesterolemic patients. In fact, oxypurinol restored only about 30% of the difference in the mean forearm blood flow response to the three acetylcholine doses between normal subjects and hypercholesterolemic patients. This suggests that the pathophysiology of endothelial dysfunction in hypercholesterolemic patients is probably multifactorial and only partly related to the generation of superoxide anions via the xanthine–xanthine oxidase pathway. Other sources of free radicals, such as the NADPH oxidase system33 or even a decreased bioavailability of L-arginine,34 35 may also contribute to this abnormality. It is also possible that a greater potentiation of the response to acetylcholine could be observed with higher doses of oxypurinol. However, this is unlikely given the results of previous studies demonstrating that inhibition of xanthine oxidase is maximal with intravascular concentrations of oxypurinol similar to those achieved with the doses used in the present study participants.22
In contrast to the findings in hypercholesterolemic patients, oxypurinol did not significantly modify the endothelium-dependent response to acetylcholine in patients with essential hypertension. Previous studies in animal models of hypertension have demonstrated that oxygen free radicals generated by xanthine oxidase cause greater vasoconstriction in arteries from spontaneously hypertensive rats than in those from normotensive animals36 and that xanthine oxidase inhibition by oxypurinol is effective in reducing blood pressure in spontaneously hypertensive rats but not in normotensive controls.14 These results are consistent with the possibility of xanthine oxidase–mediated increased production of oxygen free radicals that destroy endothelium-derived NO and contribute to the pathogenesis of high blood pressure in hypertensive animals. However, whether reactive oxygen species scavengers effectively improve the abnormal endothelial vasodilator function observed in different hypertensive rat models has not been reported. An alternative possibility is that the enhanced pressor effect of oxygen free radicals in hypertensive animals could be independent of endothelial production of NO. This explanation is supported by the observation that the vasoconstrictor effect of free radicals in hypertensive arteries is enhanced in both the presence and absence of endothelium.36
Using CuZn SOD, we have previously tested the possibility that an increased extracellular oxidative stress in the arterial wall could be involved in the impairment of endothelial vasodilator function in hypertensive humans.37 Similar to the results of the current study, we observed that CuZn SOD administration did not result in improvement of the abnormal endothelium-mediated vasodilator function of these patients. The use of scavengers of superoxide anions that reach intracellular space may be helpful to further characterize the role of these oxygen free radicals in this condition. It must also be pointed out that the present observations are consistent with the concept that the endothelial dysfunction of hypertension is due to either reduced NO synthesis or to a non–NO-related mechanism, such as an increased production of vasoconstrictor prostanoids.38 39
In the present study, the vascular responses to sodium nitroprusside were similar in hypercholesterolemic and hypertensive patients compared with control subjects, confirming that the abnormality in endothelial vasodilator function of hypercholesterolemic and hypertensive patients is not related to an abnormal responsiveness of arterial smooth muscle cells to vasodilator stimuli. Oxypurinol infusion did not modify the response to sodium nitroprusside in any of the three subject groups. This observation further emphasizes the specificity of the beneficial effect of oxypurinol on the response to acetylcholine in hypercholesterolemic patients.
In conclusion, the results of the present study demonstrate that oxypurinol improves the impaired endothelial vasodilator function of patients with hypercholesterolemia. This suggests that increased NO breakdown by superoxide anion generated via xanthine oxidase participates in the pathophysiology of this abnormality. In contrast, this mechanism does not appear to be involved in the abnormal endothelial function of patients with essential hypertension.
Received September 24, 1996; first decision November 7, 1996; accepted December 24, 1996.
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  A. J. Luk, G. P. Levin, E. E. Moore, X.-H. Zhou, B. R. Kestenbaum, and H. K. Choi Allopurinol and mortality in hyperuricaemic patients Rheumatology, July 1, 2009; 48(7): 804 - 806. [Abstract] [Full Text] [PDF]
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 E. C. Viel, K. Benkirane, D. Javeshghani, R. M. Touyz, and E. L. Schiffrin Xanthine oxidase and mitochondria contribute to vascular superoxide anion generation in DOCA-salt hypertensive rats Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H281 - H288. [Abstract] [Full Text] [PDF]
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R. M. Wolfort, K. Y. Stokes, and D. N. Granger CD4+ T lymphocytes mediate hypercholesterolemia-induced endothelial dysfunction via a NAD(P)H oxidase-dependent mechanism Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2619 - H2626. [Abstract] [Full Text] [PDF]
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 S. Guthikonda, C. A. Sinkey, and W. G. Haynes What Is the Most Appropriate Methodology for Detection of Conduit Artery Endothelial Dysfunction? Arterioscler Thromb Vasc Biol, May 1, 2007; 27(5): 1172 - 1176. [Abstract] [Full Text] [PDF]
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L. O. Lerman and A. Lerman All Oxidase Roads Lead to Angiotensin, Too Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 703 - 704. [Full Text] [PDF]
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U. Landmesser, S. Spiekermann, C. Preuss, S. Sorrentino, D. Fischer, C. Manes, M. Mueller, and H. Drexler Angiotensin II Induces Endothelial Xanthine Oxidase Activation: Role for Endothelial Dysfunction in Patients With Coronary Disease Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 943 - 948. [Abstract] [Full Text] [PDF]
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 L. G. Sanchez-Lozada, E. Tapia, R. Lopez-Molina, T. Nepomuceno, V. Soto, C. Avila-Casado, T. Nakagawa, R. J. Johnson, J. Herrera-Acosta, and M. Franco Effects of acute and chronic L-arginine treatment in experimental hyperuricemia Am J Physiol Renal Physiol, April 1, 2007; 292(4): F1238 - F1244. [Abstract] [Full Text] [PDF]
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 A. A. Ejaz, W. Mu, D.-H. Kang, C. Roncal, Y. Y. Sautin, G. Henderson, I. Tabah-Fisch, B. Keller, T. M. Beaver, T. Nakagawa, et al. Could Uric Acid Have a Role in Acute Renal Failure? Clin. J. Am. Soc. Nephrol., January 1, 2007; 2(1): 16 - 21. [Abstract] [Full Text] [PDF]
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N. Erdei, A. Toth, E. T. Pasztor, Z. Papp, I. Edes, A. Koller, and Z. Bagi High-fat diet-induced reduction in nitric oxide-dependent arteriolar dilation in rats: role of xanthine oxidase-derived superoxide anion Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2107 - H2115. [Abstract] [Full Text] [PDF]
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 A. A. El Solh, R. Saliba, T. Bosinski, B. J. B. Grant, E. Berbary, and N. Miller Allopurinol improves endothelial function in sleep apnoea: a randomised controlled study. Eur. Respir. J., May 1, 2006; 27(5): 997 - 1002. [Abstract] [Full Text] [PDF]
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 C. Zoccali, R. Maio, F. Mallamaci, G. Sesti, and F. Perticone Uric Acid and Endothelial Dysfunction in Essential Hypertension J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1466 - 1471. [Abstract] [Full Text] [PDF]
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 U. Forstermann and T. Munzel Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace Circulation, April 4, 2006; 113(13): 1708 - 1714. [Abstract] [Full Text] [PDF]
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 I. Eskurza, Z. D. Kahn, and D. R. Seals Xanthine oxidase does not contribute to impaired peripheral conduit artery endothelium-dependent dilatation with ageing J. Physiol., March 15, 2006; 571(3): 661 - 668. [Abstract] [Full Text] [PDF]
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 E. Daghini, A. R. Chade, J. D. Krier, D. Versari, A. Lerman, and L. O. Lerman Acute inhibition of the endogenous xanthine oxidase improves renal hemodynamics in hypercholesterolemic pigs Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R609 - R615. [Abstract] [Full Text] [PDF]
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T. Munzel, A. Daiber, V. Ullrich, and A. Mulsch Vascular Consequences of Endothelial Nitric Oxide Synthase Uncoupling for the Activity and Expression of the Soluble Guanylyl Cyclase and the cGMP-Dependent Protein Kinase Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1551 - 1557. [Abstract] [Full Text] [PDF]
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 A D Gavin and A D Struthers Allopurinol reduces B-type natriuretic peptide concentrations and haemoglobin but does not alter exercise capacity in chronic heart failure Heart, June 1, 2005; 91(6): 749 - 753. [Abstract] [Full Text] [PDF]
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C. F.H. Mueller, K. Laude, J. S. McNally, and D. G. Harrison Redox Mechanisms in Blood Vessels Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 274 - 278. [Abstract] [Full Text] [PDF]
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A. Tailor and D. N. Granger Hypercholesterolemia Promotes P-Selectin-Dependent Platelet-Endothelial Cell Adhesion in Postcapillary Venules Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 675 - 680. [Abstract] [Full Text] [PDF]
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 Z S Nedeljkovic, N Gokce, and J Loscalzo Mechanisms of oxidative stress and vascular dysfunction Postgrad. Med. J., April 1, 2003; 79(930): 195 - 200. [Abstract] [Full Text] [PDF]
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S. Spiekermann, U. Landmesser, S. Dikalov, M. Bredt, G. Gamez, H. Tatge, N. Reepschlager, B. Hornig, H. Drexler, and D. G. Harrison Electron Spin Resonance Characterization of Vascular Xanthine and NAD(P)H Oxidase Activity in Patients With Coronary Artery Disease: Relation to Endothelium-Dependent Vasodilation Circulation, March 18, 2003; 107(10): 1383 - 1389. [Abstract] [Full Text] [PDF]
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S. Guthikonda, C. Sinkey, T. Barenz, and W. G. Haynes Xanthine Oxidase Inhibition Reverses Endothelial Dysfunction in Heavy Smokers Circulation, January 28, 2003; 107(3): 416 - 421. [Abstract] [Full Text] [PDF]
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 T. Iuchi, M. Akaike, T. Mitsui, Y. Ohshima, Y. Shintani, H. Azuma, and T. Matsumoto Glucocorticoid Excess Induces Superoxide Production in Vascular Endothelial Cells and Elicits Vascular Endothelial Dysfunction Circ. Res., January 10, 2003; 92(1): 81 - 87. [Abstract] [Full Text] [PDF]
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C. A.J. Farquharson, R. Butler, A. Hill, J. J.F. Belch, and A. D. Struthers Allopurinol Improves Endothelial Dysfunction in Chronic Heart Failure Circulation, July 9, 2002; 106(2): 221 - 226. [Abstract] [Full Text] [PDF]
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W. Doehner, N. Schoene, M. Rauchhaus, F. Leyva-Leon, D. V. Pavitt, D. A. Reaveley, G. Schuler, A. J.S. Coats, S. D. Anker, and R. Hambrecht Effects of Xanthine Oxidase Inhibition With Allopurinol on Endothelial Function and Peripheral Blood Flow in Hyperuricemic Patients With Chronic Heart Failure: Results From 2 Placebo-Controlled Studies Circulation, June 4, 2002; 105(22): 2619 - 2624. [Abstract] [Full Text] [PDF]
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 K.Y.K. Wong, R.S. Macwalter, H.W. Fraser, I. Crombie, S.A. Ogston, and A.D. Struthers Urate predicts subsequent cardiac death in stroke survivors Eur. Heart J., May 2, 2002; 23(10): 788 - 793. [Abstract] [Full Text] [PDF]
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M.-C. Desco, M. Asensi, R. Marquez, J. Martinez-Valls, M. Vento, F. V. Pallardo, J. Sastre, and J. Vina Xanthine Oxidase Is Involved in Free Radical Production in Type 1 Diabetes: Protection by Allopurinol Diabetes, April 1, 2002; 51(4): 1118 - 1124. [Abstract] [Full Text] [PDF]
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A D Struthers, P T Donnan, P Lindsay, D McNaughton, J Broomhall, and T M MacDonald Effect of allopurinol on mortality and hospitalisations in chronic heart failure: a retrospective cohort study Heart, March 1, 2002; 87(3): 229 - 234. [Abstract] [Full Text] [PDF]
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D. M. Lenda and M. A. Boegehold Effect of a high-salt diet on oxidant enzyme activity in skeletal muscle microcirculation Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H395 - H402. [Abstract] [Full Text] [PDF]
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T. P. Cappola, D. A. Kass, G. S. Nelson, R. D. Berger, G. O. Rosas, Z. A. Kobeissi, E. Marban, and J. M. Hare Allopurinol Improves Myocardial Efficiency in Patients With Idiopathic Dilated Cardiomyopathy Circulation, November 13, 2001; 104(20): 2407 - 2411. [Abstract] [Full Text] [PDF]
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K. Y. Stokes, E. C. Clanton, J. M. Russell, C. R. Ross, and D. N. Granger NAD(P)H Oxidase-Derived Superoxide Mediates Hypercholesterolemia-Induced Leukocyte-Endothelial Cell Adhesion Circ. Res., March 16, 2001; 88(5): 499 - 505. [Abstract] [Full Text] [PDF]
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 M. Rodriguez-Porcel, A. Lerman, P. J. M. Best, J. D. Krier, C. Napoli, and L. O. Lerman Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity J. Am. Coll. Cardiol., February 1, 2001; 37(2): 608 - 615. [Abstract] [Full Text] [PDF]
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H. Cai and D. G. Harrison Endothelial Dysfunction in Cardiovascular Diseases: The Role of Oxidant Stress Circ. Res., November 10, 2000; 87(10): 840 - 844. [Abstract] [Full Text] [PDF]
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C. A. Gunnett, D. D. Heistad, D. J. Berg, and F. M. Faraci IL-10 deficiency increases superoxide and endothelial dysfunction during inflammation Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1555 - H1562. [Abstract] [Full Text] [PDF]
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C. Berry, C. A. Hamilton, M. J. Brosnan, F. G. Magill, G. A. Berg, J. J. V. McMurray, and A. F. Dominiczak Investigation Into the Sources of Superoxide in Human Blood Vessels : Angiotensin II Increases Superoxide Production in Human Internal Mammary Arteries Circulation, May 9, 2000; 101(18): 2206 - 2212. [Abstract] [Full Text] [PDF]
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 D. L. Sherman, J. F. Keaney Jr, E. S. Biegelsen, S. J. Duffy, J. D. Coffman, and J. A. Vita Pharmacological Concentrations of Ascorbic Acid Are Required for the Beneficial Effect on Endothelial Vasomotor Function in Hypertension Hypertension, April 1, 2000; 35(4): 936 - 941. [Abstract] [Full Text] [PDF]
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R. Butler, A. D. Morris, J. J. F. Belch, A. Hill, and A. D. Struthers Allopurinol Normalizes Endothelial Dysfunction in Type 2 Diabetics With Mild Hypertension Hypertension, March 1, 2000; 35(3): 746 - 751. [Abstract] [Full Text] [PDF]
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U. E. G. Ekelund, R. W. Harrison, O. Shokek, R. N. Thakkar, R. S. Tunin, H. Senzaki, D. A. Kass, E. Marban, and J. M. Hare Intravenous Allopurinol Decreases Myocardial Oxygen Consumption and Increases Mechanical Efficiency in Dogs With Pacing-Induced Heart Failure Circ. Res., September 3, 1999; 85(5): 437 - 445. [Abstract] [Full Text] [PDF]
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R. Wever, P. Boer, M. Hijmering, E. Stroes, M. Verhaar, J. Kastelein, K. Versluis, F. Lagerwerf, H. van Rijn, H. Koomans, et al. Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure Arterioscler Thromb Vasc Biol, May 1, 1999; 19(5): 1168 - 1172. [Abstract] [Full Text] [PDF]
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C. Cardillo, C. M. Kilcoyne, R. O. Cannon III, and J. A. Panza Impairment of the nitric oxide-mediated vasodilator response to mental stress in hypertensive but not in hypercholesterolemic patients J. Am. Coll. Cardiol., November 1, 1998; 32(5): 1207 - 1213. [Abstract] [Full Text] [PDF]
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I. Kurose, R. E. Wolf, M. B. Grisham, and D. N. Granger Hypercholesterolemia Enhances Oxidant Production in Mesenteric Venules Exposed to Ischemia/Reperfusion Arterioscler Thromb Vasc Biol, October 1, 1998; 18(10): 1583 - 1588. [Abstract] [Full Text] [PDF]
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M. C. Verhaar, R. M. F. Wever, J. J. P. Kastelein, T. van Dam, H. A. Koomans, and T. J. Rabelink 5-Methyltetrahydrofolate, the Active Form of Folic Acid, Restores Endothelial Function in Familial Hypercholesterolemia Circulation, January 27, 1998; 97(3): 237 - 241. [Abstract] [Full Text] [PDF]
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