(Circulation. 1999;100:1161-1168.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Role of Oxidant Stress in Endothelial Dysfunction Produced by Experimental Hyperhomocyst(e)inemia in Humans
From the Departments of Pediatrics (P.M.K., R.L.B.) and Internal Medicine (C.A.S., M.A., H.R.K., W.G.H.) and General Clinical Research Center (C.A.S., M.A., H.R.K., W.G.H.), University of Iowa College of Medicine, Iowa City, Iowa.
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Abstract |
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Background—Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress.
Methods and Results—Oral administration of
L-methionine (100 mg/kg) was used to induce moderate
hyperhomocyst(e)inemia (
25 µmol/L) in healthy human subjects.
Endothelial function of forearm resistance vessels was
assessed by use of forearm vasodilatation to brachial artery
administration of the endothelium-dependent dilator
acetylcholine. Conduit vessel endothelial function was
assessed with flow-mediated dilatation of the brachial artery. Forearm
resistance vessel dilatation to acetylcholine was significantly
impaired 7 hours after methionine (methionine, 477±82%; placebo,
673±110%; P=0.016). Methionine did not alter
vasodilatation to nitroprusside and verapamil.
Flow-mediated dilatation was significantly impaired 8 hours after
methionine loading (0.3±2.7%) compared with placebo (8.2±1.6%,
P=0.01). Oral administration of the antioxidant ascorbic
acid (2 g) prevented methionine-induced endothelial
dysfunction in both conduit and resistance vessels
(P=0.03).
Conclusions—Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension. Increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.
Key Words: endothelium • nitric oxide • free radicals • acetylcholine • antioxidants
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Homocystinuria markedly increases plasma homocyst(e)ine concentrations (>100 µmol/L) and is associated with premature thrombosis and atherosclerosis.1 Even moderate hyperhomocyst(e)inemia (>10 µmol/L) is associated with increased risk of atherosclerosis and hypertension.2 3
The endothelium modulates platelet adhesion, macrophage migration, lipid transport, and mitogenesis.4 Endothelial vasomotor dysfunction is an important predictor of atherosclerosis and its complications.5 High concentrations of homocysteine have deleterious effects on the vascular endothelium in animals.6 7 8 Thus, homocysteine-induced endothelial dysfunction is a plausible mechanism for predisposition to vascular disease.
Patients with hyperhomocyst(e)inemia exhibit endothelial dysfunction.9 10 In addition, experimental hyperhomocyst(e)inemia induced by oral methionine produces conduit vessel endothelial dysfunction in humans.11 12 However, the effects of hyperhomocyst(e)inemia on resistance vessel endothelial function are unclear. This study was designed to test experimentally the hypothesis that experimental hyperhomocyst(e)inemia induced by oral methionine impairs endothelium-dependent vasodilatation in both resistance and conduit vessels.
The pathophysiological mechanisms underlying endothelial dysfunction to methionine loading are unclear. Homocysteine increases oxidant stress in vitro.6 13 14 Therefore, we also examined whether administration of a potent antioxidant, ascorbic acid, could prevent endothelial dysfunction induced by experimental hyperhomocyst(e)inemia.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Subjects
Forty healthy subjects without risk factors for or clinical evidence of atherosclerosis were recruited by advertisement to participate in 3 separate protocols (Table 1
). The studies were conducted
after written informed consent was obtained from each subject and with
approval of the Institutional Review Board. No subject received
vasoactive drugs in the week before the study, and all abstained from
alcohol for 24 hours and from caffeine for 
12 hours before any
measurements. Studies were performed in a quiet room maintained at a
constant temperature between 22°C and 25°C.
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Measurements
To study resistance vessel endothelial
function, forearm blood flow was measured in both arms with
strain-gauge venous occlusion plethysmography (model EC-4, Hokanson
Inc) during brachial artery infusion of vasoactive
agents.15 To study conduit vessel
endothelial function, flow-mediated dilatation of the
brachial artery was induced with reactive hyperemia as a
stimulus.9 10 11 12 The brachial artery was imaged in a
longitudinal section above the antecubital fossa by use of a 7.5-MHz
linear-array ultrasound Doppler transducer (Toshiba SSA-270). We
used the same ultrasonographer for image acquisition, a standard arm
support, and identical probe distance from the antecubital fossa (2.5
cm proximal). Measurements were obtained for 20 seconds at baseline. An
occluding forearm cuff placed 5 cm below the antecubital fossa was
inflated to 50 mm Hg above systolic pressure for 5
minutes and then released to induce reactive hyperemia.
Recordings were made 5, 60, and 120 seconds after onset of
reactive hyperemia. Brachial artery diameter and flow velocity
were also measured before and for 6 minutes after sublingual
administration of nitroglycerin spray (400 µg). Blood
pressure was recorded with an automated sphygmomanometer (LifeStat
200, Physio Control).
Laboratory Assays
Plasma homocyst(e)ine assays were performed in the
University of Iowa General Clinical Research Center Core Laboratory in
a modification of the assay described by Noguchi and
Higuchi.16 Samples were collected in chilled EDTA tubes,
and plasma was frozen at -70°C. Plasma was spiked with known amounts
of internal standard (mercaptopropionyl glycine) reduced with
tri-n-butyl phosphine and then deproteinized with sulfosalicylic acid.
The thiol-specific fluorogenic labeling reagent ammonium
7-fluorobenzo-2-oxa-1,3-diazole-4-sulfonate was added to the
supernatant; the sample was neutralized with HCl, washed with a 5%
tributyl phosphate solution, filtered, and injected onto a
reversed-phase high-performance liquid
chromatography column. Quantification was by
measurement of the emission signal of the analyte at 515 nm
(excitation, 385 nm). The coefficient of variation was <2%. Results
of this assay are expressed as plasma homocyst(e)ine and
represent the sum of free and bound forms of homocysteine,
homocystine, and homocysteine-cysteine mixed disulfide. Plasma
methionine was measured with an automated amino acid analyzer
(Beckman 7300, Beckman Instruments) by use of a lithium
physiological ion-exchange column system.
Quantification was achieved by postcolumn derivatization with
ninhydrin, monitoring UV absorbance with norleucine as internal
standard. Plasma B6 and B12
and plasma and red cell folate, as well as cholesterol,
triglycerides, LDL cholesterol, and HDL
cholesterol, were measured by use of established
methodologies.
Study Design
Effect of Experimental Hyperhomocyst(e)inemia on Endothelial
Function
This was a randomized, double-blind, crossover study
comparing the effects of oral L-methionine and placebo on
endothelial function with 1 week between the 2 study
days. Subjects were admitted to the University of Iowa General Clinical
Research Center the previous night and studied the next morning after
fasting. An antecubital vein of the noninfused arm was cannulated for
blood sampling. Subjects received oral L-methionine
(Ajinomoto) 100 mg/kg dissolved in cranberry juice or cranberry juice
alone at about 7 AM.
Ten subjects (protocol A) had vascular function assessed within 3 hours of oral methionine or placebo. Flow-mediated dilatation of the brachial artery was assessed 1 and 3 hours after methionine or placebo, with nitroglycerin-induced vasodilatation tested at 3 hours. Resistance vessel endothelial function was assessed 1.5 to 3 hours after methionine or placebo. The left brachial artery was cannulated under local anesthesia with a 27-gauge steel needle attached to an 18-gauge epidural catheter. Baseline forearm blood flows were obtained during infusion of 0.9% saline (1 mL/min) for 30 minutes. Acetylcholine (3 to 30 µg/min, Iolab) and nitroprusside (1 to 10 µg/min, Elkins-Sinn) were then separately administered into the brachial artery, each dose for 6 minutes, separated by saline infusion to allow flow to return to baseline. The order of intra-arterial drugs was randomized, with individual subjects receiving drugs in the same order on the 2 study days. Forearm blood flow was measured in the last 3 minutes of each dose. Arterial pressure was measured twice at baseline and after each dose. Venous blood for assay of plasma homocyst(e)ine and methionine was obtained before and 1, 2, 3, and 4 hours after L-methionine or placebo administration.
Twenty subjects (protocol B) had assessment of vascular function 6 to 8 hours after L-methionine or placebo administration. A standard breakfast containing 58 mg L-methionine and 5 g fat was served 2 hours after methionine or placebo administration. The brachial artery was cannulated at 5.5 hours, and a resistance vessel protocol similar to that of the first group was followed except that verapamil was also infused in 10 subjects (10 to 100 µg/min, SoloPak Labs). Verapamil was always administered last because of its long duration of action. Eleven subjects from this group had conduit vessel endothelial function assessed 8 to 8.5 hours after L-methionine or placebo administration. Venous blood for assay of plasma homocyst(e)ine and methionine was obtained before and 2, 4, 6, and 8 hours after L-methionine or placebo administration.
Effect of Ascorbic Acid on Homocyst(e)ine-Induced Endothelial
Dysfunction
This was a 4-phase, randomized, double-blind, crossover study in
which 10 subjects received (1) placebo at 7 AM, (2)
L-methionine at 7 AM, (3) placebo at 7
AM plus ascorbic acid at 11 AM, and (4)
L-methionine at 7 AM plus ascorbic acid at 11
AM, with 1 week between study phases. Ascorbic acid was
administered in a dose of 2 g orally, which is known to increase
plasma ascorbate concentrations 2.5-fold, with stable concentrations
from 2 to 5 hours after dosing.17 Venous blood for assay
of plasma ascorbate concentrations was obtained before and 4, 6, and 8
hours after L-methionine or placebo administration. The
study day timetable was otherwise identical to that of protocol B, with
endothelial function being assessed 6 to 9 hours after
L-methionine administration (2 to 5 hours after ascorbic
acid administration).
Data and Statistical Analyses
All analyses were performed by observers blinded to
treatment assignment. Basal blood flow and blood pressure were taken as
the average of the 3 baseline recording periods during saline
infusion. In addition to absolute blood flows, we calculated percent
change from baseline in the ratio of blood flow between infused and
noninfused arms, because this halves variability in blood flow
responses to infused agents.15 Forearm vascular resistance
was calculated as mean arterial pressure/forearm blood
flow.
For conduit vessel endothelial function, brachial
artery diameter and blood velocity measurements were analyzed
by use of a Toshiba vascular ultrasound Doppler analysis
package. For each of 3 consecutive cardiac cycles, brachial artery
diameter (millimeters) was calculated as the mean of 3 evenly spaced
measurements of the distance from the trailing edge to the leading edge
of ultrasonic arterial borders at end diastole
with electronic calipers on the ultrasound machine. Mean Doppler
velocity was averaged over 3 consecutive cardiac cycles. Percentage
changes in diameter and velocity were calculated 10 seconds; 1 and 2
minutes after induction of reactive hyperemia; and 2, 4, and 6
minutes after nitroglycerin. In 40 studies performed in
healthy subjects, dilatation to reactive hyperemia was maximal
2 minutes after cuff deflation (1 minute, 5.6±0.7%; 2 minutes,
6.2±0.6%), so the 2-minute time point is shown in graphs and tables.
Maximum dilatation to nitroglycerin occurred 6 minutes
after administration (2 minutes, 6.2±0.7%; 4 minutes, 14.1±1.4%; 6
minutes, 14.5±1.5%), so the 6-minute time point is shown in graphs
and tables. Our methodology for assessment of conduit vessel
flow–mediated dilatation has good within-subject reproducibility, with
a correlation coefficient of 0.75 between 10 paired studies and an
average coefficient of variability of 13.6% in 3 subjects studied on
4 occasions.
Two-way repeated-measures ANOVA was used to compare the effects of methionine and placebo on resistance vessel dilatation to acetylcholine, nitroprusside, and verapamil and conduit vessel dilatation to nitroglycerin and increased flow. All doses of drugs or time points after reactive hyperemia were used in the ANOVA. Tukey's test was used for post hoc analysis if the ANOVA was positive. Multiple regression was used to assess determinants of endothelial function 1, 3, and 8 hours after administration of methionine and placebo in protocols A and B. Data are expressed as mean±SE; P<0.05 was taken as statistically significant. Data were analyzed with StatView software (Brainpower Inc).
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Effect of Experimental Hyperhomocyst(e)inemia on Endothelial Function
Baseline blood pressure, lipids, vitamins, and homocysteine levels were normal at baseline (Table 1
). Methionine loading slowly
increased plasma homocyst(e)ine concentrations by 4-fold to a maximum
of 28±2 µmol/L at 8 hours (P=0.001; Figure 1). Plasma homocyst(e)ine concentrations
did not change after placebo administration. Methionine concentrations
increased more substantially (30-fold) and rapidly, peaking at 2
hours and then decreasing by 50% by 8 hours (P=0.001;
Figure 1). Blood pressure, heart rate, and forearm blood flow
did not differ between study days (Table 2).
|
; placebo, 
) and methionine concentrations
(L-methionine, •; placebo, 
) in 20 subjects.
*P<0.05 vs baseline.
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Brachial artery infusion of vasodilator agents did not alter blood flow
in the noninfused arm, confirming that drug effects were confined to
the infused arm (Table 2). Forearm vasodilatation to
acetylcholine was nonsignificantly decreased 2 hours after methionine
loading (P=0.31; Table 2 and Figure 2A), when plasma methionine
concentrations were maximal. However, acetylcholine-induced dilatation
was significantly impaired 7 hours after methionine loading
(P=0.016; Table 2 and Figure 2A).
Nitroprusside and verapamil responses did not differ
between the methionine and placebo days (Table 2 and Figure
2B). On multiple regression analysis, plasma
homocyst(e)ine was a significant predictor of resistance vessel
endothelial function (R=0.375,
P=0.04; Figure 3A). Plasma
methionine (P=0.59), age (P=0.65), sex
(P=0.14), and arterial pressure
(P=0.54) were not predictive of resistance vessel
endothelial function.
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Baseline brachial artery diameter and flow velocity were no
different between methionine and placebo study days (Table 3). Methionine administration
progressively decreased flow-mediated dilatation, which closely
paralleled plasma homocyst(e)ine but not plasma methionine
concentration (Figures 1 and 4).
Flow-mediated vasodilatation was not impaired 1 hour after methionine
loading (P=0.12) but was significantly reduced at 3 hours
(P<0.0001) and abolished 8 hours after methionine loading
(Figure 4). The increase in flow velocity during reactive
hyperemia and brachial artery dilatation to
nitroglycerin was similar on methionine and placebo
days (Table 3). On multiple regression analysis, plasma
homocyst(e)ine was a significant predictor of conduit vessel
endothelial function (R=0.492,
P=0.001; Figure 3B). Plasma methionine
(P=0.71), age (P=0.55), sex (P=0.19),
and arterial pressure (P=0.66) were not
predictive of conduit vessel endothelial function.
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HC indicates mean
difference in plasma homocyst(e)ine between placebo and methionine
sessions;
Effect of Ascorbic Acid on Homocysteine-Induced Endothelial
Dysfunction
The increase in plasma homocyst(e)ine produced by methionine
administration was not altered by ascorbic acid. Blood pressure, heart
rate, and resting forearm hemodynamics did not change
(Tables 4 and 5). Plasma ascorbate
increased by 3-fold from 2 to 4 hours after administration of
ascorbic acid (ie, 6 to 8 hours after methionine or placebo; Table 5). Ascorbic acid alone did not alter
endothelium-dependent dilatation in resistance and
conduit vessels (Figure 5). Impairment of
resistance vessel dilatation to acetylcholine by methionine
(P=0.045 versus placebo) was prevented by administration of
ascorbic acid (P=0.03 versus methionine alone; Table 4 and Figure 5). Similarly,
methionine-induced impairment of conduit vessel
endothelial function (P=0.035 versus
placebo; Table 5 and Figure 5)
could be completely prevented by coadministration of ascorbic acid
(P=0.03 versus methionine alone; Table 5 and Figure 5).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In our study, experimental elevation of plasma homocysteine concentrations rapidly impaired both conduit and resistance vessel endothelial function in human subjects. Our study confirms recent reports that methionine loading produces conduit vessel endothelial dysfunction.11 12 The effect of experimental hyperhomocyst(e)inemia on resistance vessel endothelial function has been unclear. One preliminary report in a limited number of subjects suggested that methionine loading did not alter forearm vasodilatation to acetylcholine.18 We demonstrated in a substantial number of subjects that methionine loading does impair endothelium-dependent vasodilatation in resistance vessels, albeit partially. Importantly, endothelial dysfunction caused by experimental hyperhomocyst(e)inemia was completely prevented by administration of an antioxidant, ascorbic acid. Given the diverse functions of the endothelium, these results may help to explain how moderate hyperhomocyst(e)inemia predisposes to atherosclerosis and hypertension.
Mechanisms
Impaired resistance vessel dilatation to acetylcholine and conduit
vessel dilatation to hyperemia were not due to impaired
vascular smooth muscle relaxation, because vasodilatation to
verapamil and nitroprusside was not altered. Thus,
methionine loading probably decreased the generation or activity of
vasoactive endothelium-derived mediators. Impaired
endothelium-dependent vasodilatation after methionine
loading could reflect decreased nitric oxide activity,7
increased thromboxane formation,19 or
alteration in other endothelial mediators.
Homocysteine increases generation of free radical oxidant species in vitro, possibly through auto-oxidation, inhibition of glutathione peroxidase, or oxidation of LDL.13 14 20 We have demonstrated that administration of ascorbic acid prevents induction of endothelial dysfunction by homocysteine. Vitamin C is a potent antioxidant scavenger of reactive oxygen species and may prevent direct inactivation of nitric oxide by superoxide or increase intracellular reduced glutathione concentrations.21 22 It appears likely that experimental hyperhomocyst(e)inemia caused by methionine loading produces endothelial dysfunction through increased oxidant stress.
Potential Study Limitations
Brachial artery atherosclerosis correlates with
coronary and carotid
atherosclerosis.23 Forearm
endothelial function is impaired in patients with
established coronary
atherosclerosis.24 Thus, the brachial
circulation appears to be a reasonable surrogate for study of the
coronary circulation.
Our model for inducing experimental hyperhomocyst(e)inemia uses oral
methionine loading. A nonspecific effect of amino acids on
endothelial function appears unlikely, because high
concentrations of amino acids such as L-arginine and
N-acetylcysteine do not impair
endothelium-dependent relaxation in
humans.25 26 Plasma methionine concentrations increased by
almost 30-fold compared with an increase of only 4-fold in plasma
homocysteine (Figure 1). However, endothelial
function was not significantly impaired 1 hour after administration of
oral methionine, when plasma methionine was already markedly elevated
but plasma homocysteine concentrations were only 11 µmol/L.
Endothelial dysfunction was maximal at 8 hours, when
methionine concentrations had fallen by 50% from their peak but
plasma homocyst(e)ine was maximal. Nonetheless, we cannot exclude the
possibility that impaired endothelial function after
methionine loading is due to changes in plasma methionine. Even if this
is the case, our results are still clinically relevant, given that many
foods are rich in methionine (see below).
Implications
We have shown that experimental induction of moderate
hyperhomocyst(e)inemia (20 µmol/L) impairs
endothelium-dependent vasodilatation in human
resistance and conduit vessels. In addition to vascular tone, the
endothelium regulates cell adhesion, platelet
aggregation, coagulation, lipid transport and oxidation, inflammation,
and mitogenesis.4 Changes in
endothelium-dependent dilatation precede structural
changes during experimental induction or regression of
atherosclerosis in monkeys.5 Impaired
resistance vessel endothelial function may predispose
to hypertensive structural remodeling and offer an explanation for the
association between homocysteine and systolic
hypertension.2
The clinical relevance of these data is emphasized by the recent report
that plasma homocysteine concentrations >20 µmol/L are
associated with a 4-fold increase in total mortality in patients with
coronary artery disease.3 The average fasting
homocyst(e)ine concentration in American middle-aged men is 10
µmol/L, with the 95th percentile at 16
µmol/L.27 In our study, the largest decrease in
endothelial function occurred between 1 and 3 hours
after administration of methionine (Figure 3), when plasma
homocyst(e)ine increased from 11 to 20 µmol/L. Thus,
endothelial dysfunction may be induced at plasma
homocyst(e)ine concentrations that are applicable to the general
population.
Most epidemiological studies have measured fasting rather than postprandial homocyst(e)ine. Methionine is an essential amino acid, present in relatively large amounts in foods rich in animal protein (0.5% to 1% methionine).28 Many individuals may consume 2 to 3 g methionine daily compared with the 7 to 8 g administered to our subjects. Such individuals could have postprandial homocyst(e)ine concentrations considerably >20 µmol/L, particularly if fasting plasma homocyst(e)ine was >10 µmol/L. Thus, it is possible that meals high in animal protein may lead to repeated episodes of endothelial dysfunction, which may in turn predispose to atherosclerosis or hypertension. In addition, dietary methionine intake from foods rich in animal protein and fat may have confounded previous assessments of the effect of dietary saturated fat intake on cardiovascular disease.
Our results are consistent with the concept that moderate hyperhomocyst(e)inemia predisposes to atherosclerosis and hypertension by causing endothelial dysfunction. These findings emphasize the need for outcome trials testing whether treatment of moderate hyperhomocyst(e)inemia reduces cardiovascular events. Our studies suggest that increased oxidant stress is an important pathophysiological mechanism underlying the deleterious endothelial effects of homocysteine. Antioxidant therapy warrants investigation as an alternative clinical approach to prevention of the atherothrombotic complications of hyperhomocyst(e)inemia, particularly in patients with hyperhomocyst(e)inemia resistant to B-vitamins.29
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health (NHLBI, HL-55006 and HL-58972; NCRR General Clinical Research Centers program, RR00059), the Iowa Affiliate of the American Heart Association (IA-97-GB-28), and the Department of Veterans Affairs. Dr Kanani received a training grant in pediatric cardiology from the NHLBI (HL-07413). Dr Haynes is supported by a faculty development grant from the Pharmaceutical Research Manufacturers of America Foundation.
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Footnotes |
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Reprint requests to William G. Haynes, MD, Department of Internal Medicine, University of Iowa College of Medicine, 200 Hawkins Dr, Iowa City, IA 52242.
Received April 21, 1999; revision received June 2, 1999; accepted June 14, 1999.
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 A. Silvestro, V. Schiano, R. Bucur, G. Brevetti, F. Scopacasa, and M. Chiariello Effect of Propionylcarnitine on Changes in Endothelial Function and Plasma Levels of Adhesion Molecules Induced by Acute Exercise in Patients with Intermittent Claudication Angiology, March 1, 2006; 57(2): 145 - 154. [Abstract] [PDF]
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J. D. Symons, J. C. Rutledge, U. Simonsen, and R. A. Pattathu Vascular dysfunction produced by hyperhomocysteinemia is more severe in the presence of low folate Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H181 - H191. [Abstract] [Full Text] [PDF]
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S. Dayal and S. R Lentz ADMA and hyperhomocysteinemia Vascular Medicine, May 1, 2005; 10(2_suppl): S27 - S33. [Abstract] [PDF]
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H. Lee, J.-m. Kim, H. J. Kim, I. Lee, and N. Chang Folic Acid Supplementation Can Reduce the Endothelial Damage in Rat Brain Microvasculature Due to Hyperhomocysteinemia J. Nutr., March 1, 2005; 135(3): 544 - 548. [Abstract] [Full Text] [PDF]
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S. J. Moat, S. N. Doshi, D. Lang, I. F. W. McDowell, M. J. Lewis, and J. Goodfellow Treatment of coronary heart disease with folic acid: is there a future? Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H1 - H7. [Full Text] [PDF]
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A. S. De Vriese, H. J. Blom, S. G. Heil, S. Mortier, L. A.J. Kluijtmans, J. Van de Voorde, and N. H. Lameire Endothelium-Derived Hyperpolarizing Factor-Mediated Renal Vasodilatory Response Is Impaired During Acute and Chronic Hyperhomocysteinemia Circulation, May 18, 2004; 109(19): 2331 - 2336. [Abstract] [Full Text] [PDF]
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Z. Bagi, C. Cseko, E. Toth, and A. Koller Oxidative stress-induced dysregulation of arteriolar wall shear stress and blood pressure in hyperhomocysteinemia is prevented by chronic vitamin C treatment Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2277 - H2283. [Abstract] [Full Text] [PDF]
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A. Vychytil, M. Fodinger, J. Pleiner, M. Mullner, P. Konner, S. Skoupy, C. Rohrer, M. Wolzt, and G. Sunder-Plassmann Acute effect of amino acid peritoneal dialysis solution on vascular function Am. J. Clinical Nutrition, November 1, 2003; 78(5): 1039 - 1045. [Abstract] [Full Text] [PDF]
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P. Ganz and J. A. Vita Testing Endothelial Vasomotor Function: Nitric Oxide, a Multipotent Molecule Circulation, October 28, 2003; 108(17): 2049 - 2053. [Full Text] [PDF]
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 W. I. Sivitz, S. M. Wayson, M. L. Bayless, L. F. Larson, C. Sinkey, R. S. Bar, and W. G. Haynes Leptin and Body Fat in Type 2 Diabetes and Monodrug Therapy J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1543 - 1553. [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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S. Dayal, K. L. Brown, C. J. Weydert, L. W. Oberley, E. Arning, T. Bottiglieri, F. M. Faraci, and S. R. Lentz Deficiency of Glutathione Peroxidase-1 Sensitizes Hyperhomocysteinemic Mice to Endothelial Dysfunction Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1996 - 2002. [Abstract] [Full Text] [PDF]
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 O. Stanger, H.-J. Semmelrock, W. Wonisch, U. Bos, E. Pabst, and T. C. Wascher Effects of Folate Treatment and Homocysteine Lowering on Resistance Vessel Reactivity in Atherosclerotic Subjects J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 158 - 162. [Abstract] [Full Text] [PDF]
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Y.-F. Chen, P.-L. Li, and A.-P. Zou Effect of Hyperhomocysteinemia on Plasma or Tissue Adenosine Levels and Renal Function Circulation, September 3, 2002; 106(10): 1275 - 1281. [Abstract] [Full Text] [PDF]
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N. Li, F.-X. Yi, E. Rute, D. X. Zhang, G. R. Slocum, and A.-P. Zou Effects of homocysteine on intracellular nitric oxide and superoxide levels in the renal arterial endothelium Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1237 - H1243. [Abstract] [Full Text] [PDF]
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S. R. Lentz, D. J. Piegors, J. A. Fernandez, R. A. Erger, E. Arning, M. R. Malinow, J. H. Griffin, T. Bottiglieri, W. G. Haynes, and D. D. Heistad Effect of hyperhomocysteinemia on protein C activation and activity Blood, August 28, 2002; 100(6): 2108 - 2112. [Abstract] [Full Text] [PDF]
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N. Weiss, C. Keller, U. Hoffmann, and J. Loscalzo Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia Vascular Medicine, August 1, 2002; 7(3): 227 - 239. [Abstract] [PDF]
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H. Zheng, C. Dimayuga, A. Hudaihed, and S. D. Katz Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): e15 - 18. [Abstract] [Full Text] [PDF]
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E.M. Cottington, C. LaMantia, S. P. Stabler, R. H. Allen, A. Tangerman, C. Wagner, S. H. Zeisel, and S. H. Mudd Adverse Event Associated With Methionine Loading Test: A Case Report Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 1046 - 1050. [Abstract] [Full Text] [PDF]
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P. J. M. Best, R. Lennon, H. H. Ting, M. R. Bell, C. S. Rihal, D. R. Holmes Jr, and P. B. Berger The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions J. Am. Coll. Cardiol., April 3, 2002; 39(7): 1113 - 1119. [Abstract] [Full Text] [PDF]
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K. R Dimitrova, K. DeGroot, A. K Myers, and Y. D Kim Estrogen and homocysteine Cardiovasc Res, February 15, 2002; 53(3): 577 - 588. [Abstract] [Full Text] [PDF]
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K. R. Dimitrova, K. W. DeGroot, A. M. Pacquing, J. P. Suyderhoud, E. A. Pirovic, T. J. Munro, J. A. Wieneke, A. K. Myers, and Y. D. Kim Estradiol prevents homocysteine-induced endothelial injury in male rats Cardiovasc Res, February 15, 2002; 53(3): 589 - 596. [Abstract] [Full Text] [PDF]
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N. Li, Y.-F. Chen, and A.-P. Zou Implications of Hyperhomocysteinemia in Glomerular Sclerosis in Hypertension Hypertension, February 1, 2002; 39(2): 443 - 448. [Abstract] [Full Text] [PDF]
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Z. Bagi, Z. Ungvari, and A. Koller Xanthine Oxidase-Derived Reactive Oxygen Species Convert Flow-Induced Arteriolar Dilation to Constriction in Hyperhomocysteinemia: Possible Role of Peroxynitrite Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 28 - 33. [Abstract] [Full Text] [PDF]
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B. Bayes, M. C. Pastor, J. Bonal, J. Junca, and R. Romero Homocysteine and lipid peroxidation in haemodialysis: role of folinic acid and vitamin E Nephrol. Dial. Transplant., November 1, 2001; 16(11): 2172 - 2175. [Abstract] [Full Text] [PDF]
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A. Virdis, L. Ghiadoni, H. Cardinal, S. Favilla, P. Duranti, R. Birindelli, A. Magagna, G. Bernini, G. Salvetti, S. Taddei, et al. Mechanisms responsible for endothelial dysfunction induced by fasting hyperhomocystinemia in normotensive subjects and patients with essential hypertension J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1106 - 1115. [Abstract] [Full Text] [PDF]
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G. Davi, G. Di Minno, A. Coppola, G. Andria, A. M. Cerbone, P. Madonna, A. Tufano, A. Falco, P. Marchesani, G. Ciabattoni, et al. Oxidative Stress and Platelet Activation in Homozygous Homocystinuria Circulation, September 4, 2001; 104(10): 1124 - 1128. [Abstract] [Full Text] [PDF]
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S. R. Lentz Does Homocysteine Promote Atherosclerosis? Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1385 - 1386. [Full Text] [PDF]
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S. N. Doshi, I. F. W. McDowell, S. J. Moat, D. Lang, R. G. Newcombe, M. B. Kredan, M. J. Lewis, and J. Goodfellow Folate Improves Endothelial Function in Coronary Artery Disease : An Effect Mediated by Reduction of Intracellular Superoxide? Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1196 - 1202. [Abstract] [Full Text] [PDF]
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G. Sesmilo, B. M. K. Biller, J. Llevadot, D. Hayden, G. Hanson, N. Rifai, and A. Klibanski Effects of Growth Hormone (GH) Administration on Homocyst(e)ine Levels in Men with GH Deficiency: A Randomized Controlled Trial J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1518 - 1524. [Abstract] [Full Text]
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C G Hanratty, L T McGrath, D F McAuley, I S Young, and G D Johnston The effects of oral methionine and homocysteine on endothelial function Heart, March 1, 2001; 85(3): 326 - 330. [Abstract] [Full Text]
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A. K. Nightingale, P. P. James, J. Morris-Thurgood, F. Harrold, R. Tong, S. K. Jackson, J. R. Cockcroft, and M. P. Frenneaux Evidence against oxidative stress as mechanism of endothelial dysfunction in methionine loading model Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1334 - H1339. [Abstract] [Full Text] [PDF]
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Z. Bagi, Z. Ungvari, L. Szollar, and A. Koller Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A2 Mediation Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 233 - 237. [Abstract] [Full Text] [PDF]
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G. Block, A. R. Mangels, E. P. Norkus, B. H. Patterson, O. A. Levander, and P. R. Taylor Ascorbic Acid Status and Subsequent Diastolic and Systolic Blood Pressure Hypertension, February 1, 2001; 37(2): 261 - 267. [Abstract] [Full Text] [PDF]
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L. M. Title, P. M. Cummings, K. Giddens, and B. A. Nassar Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2185 - 2191. [Abstract] [Full Text] [PDF]
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L. Ghiadoni, A. E. Donald, M. Cropley, M. J. Mullen, G. Oakley, M. Taylor, G. O'Connor, J. Betteridge, N. Klein, A. Steptoe, et al. Mental Stress Induces Transient Endothelial Dysfunction in Humans Circulation, November 14, 2000; 102(20): 2473 - 2478. [Abstract] [Full Text] [PDF]
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J. C. Chambers, P. M. Ueland, O. A. Obeid, J. Wrigley, H. Refsum, and J. S. Kooner Improved Vascular Endothelial Function After Oral B Vitamins : An Effect Mediated Through Reduced Concentrations of Free Plasma Homocysteine Circulation, November 14, 2000; 102(20): 2479 - 2483. [Abstract] [Full Text] [PDF]
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L. M. Title, P. M. Cummings, K. Giddens, J. J. Genest Jr, and B. A. Nassar Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease J. Am. Coll. Cardiol., September 1, 2000; 36(3): 758 - 765. [Abstract] [Full Text] [PDF]
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S. R. Lentz, R. A. Erger, S. Dayal, N. Maeda, M. R. Malinow, D. D. Heistad, and F. M. Faraci Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine beta -synthase-deficient mice Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H970 - H975. [Abstract] [Full Text] [PDF]
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L. Brattstrom and D. E. Wilcken Homocysteine and cardiovascular disease: cause or effect? Am. J. Clinical Nutrition, August 1, 2000; 72(2): 315 - 323. [Abstract] [Full Text] [PDF]
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P. Stenvinkel, O. Heimburger, B. Lindholm, G. A. Kaysen, and J. Bergstrom Are there two types of malnutrition in chronic renal failure? Evidence for relationships between malnutrition, inflammation and atherosclerosis (MIA syndrome) Nephrol. Dial. Transplant., July 1, 2000; 15(7): 953 - 960. [Full Text] [PDF]
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D. W. Jacobsen Hyperhomocysteinemia and Oxidative Stress : Time for a Reality Check? Arterioscler Thromb Vasc Biol, May 1, 2000; 20(5): 1182 - 1184. [Full Text] [PDF]
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S. Mak, Z. Egri, G. Tanna, R. Colman, and G. E. Newton Vitamin C prevents hyperoxia-mediated vasoconstriction and impairment of endothelium-dependent vasodilation Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2414 - H2421. [Abstract] [Full Text] [PDF]
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J. C. Chambers, P. M. Ueland, M. Wright, C. J. Dore, H. Refsum, and J. S. Kooner Investigation of Relationship Between Reduced, Oxidized, and Protein-Bound Homocysteine and Vascular Endothelial Function in Healthy Human Subjects Circ. Res., July 20, 2001; 89(2): 187 - 192. [Abstract] [Full Text] [PDF]
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K. Bennett-Richards, M. Kattenhorn, A. Donald, G. Oakley, Z. Varghese, L. Rees, and J.E. Deanfield Does Oral Folic Acid Lower Total Homocysteine Levels and Improve Endothelial Function in Children With Chronic Renal Failure? Circulation, April 16, 2002; 105(15): 1810 - 1815. [Abstract] [Full Text] [PDF]
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