From Abteilung Kardiologie, Medizinische Hochschule Hannover, Hannover,
Germany.
Correspondence to Helmut Drexler, MD, Abteilung Kardiologie, Medizinische Hochschule Hannover, Carl-Neubergstr 1, 30625 Hannover, FRG.
Methods and Results—High-resolution ultrasound and Doppler
was used to measure radial artery diameter and blood flow in 15
patients with CHF and 8 healthy volunteers. Vascular effects of vitamin
C (25 mg/min IA) and placebo were determined at rest and during
reactive hyperemia (causing
endothelium-mediated dilation) before and after
intra-arterial infusion of
N-monomethyl-L-arginine (L-NMMA) to
inhibit endothelial synthesis of nitric oxide. Vitamin
C restored FDD in patients with heart failure after acute
intra-arterial administration (13.2±1.7% versus
8.2±1.0%; P<.01) and after 4 weeks of oral therapy
(11.9±0.9% versus 8.2±1.0%; P<.05). In particular,
the portion of FDD mediated by nitric oxide (ie, inhibited by L-NMMA)
was increased after acute as well as after chronic treatment (CHF
baseline: 4.2±0.7%; acute: 9.1±1.3%; chronic: 7.3±1.2%; normal
subjects: 8.9±0.8%; P<.01).
Conclusions—Vitamin C improves FDD in patients with CHF as the
result of increased availability of nitric oxide. This observation
supports the concept that endothelial dysfunction in
patients with CHF is, at least in part, due to accelerated degradation
of nitric oxide by radicals.
The portion of FDD that is mediated by NO is reduced in patients with
CHF compared with that of normal subjects.6
Therefore it has been hypothesized that endothelial
dysfunction in CHF is caused by a reduced synthesis of NO possibly due
to a reduced NO-synthase gene expression.7
However, other mechanisms may be involved as well, such as a reduced
availability of L-arginine or enhanced inactivation of NO
by radicals. In this respect, there is evidence that radical formation
is increased in patients with CHF,8 raising the
possibility that endothelial dysfunction in CHF is, at
least in part, due to increased inactivation of NO by oxygen free
radicals. Antioxidants such as vitamin C9 10 have
recently been shown to prevent the inactivation of NO-mediated
vasodilation.11 Accordingly, the present
study was designed to determine the effect of vitamin C on NO-mediated
FDD in patients with CHF, both after acute intra-arterial
administration and chronic oral treatment with vitamin C.
Radial artery diameters were measured by a recently developed
high-resolution A-mode ultrasonic echo-tracking device (ASULAB) that
allows measurements of arterial diameter with a precision
of ±2.5 µm, with the use of a novel oversampling
technique.12 This method is well established in
our laboratory, as reported recently.3 4 6
Recordings of arterial diameters (15 cm proximal to
the wrist) were obtained with a 10-MHz transducer positioned
perpendicular to the vessel without direct skin contact, with
ultrasonic gel as the transmitting medium. Stereo Doppler guidance
was used to ensure a correct vertical position of the probe over the
artery. Each diameter measurement represents data digitized
over a 4-second period (three to five beats).
Forearm blood flow was measured continuously by an 8-MHz Doppler
probe (Vasoscope III) 5 cm proximal to the 10-MHz probe.
Arterial blood flow (mL/min) at the mid-forearm level was
calculated as the product of blood flow velocity and
cross-sectional area. For each velocity value, at least 15 beats were
averaged. Wrist arterial occlusion was performed by
inflating an occlusion cuff to 40 mm Hg above systolic
blood pressure for 8 minutes. After release of the arterial
occlusion, arterial diameter was determined at 20-second
intervals for 2 minutes, then every 30 seconds until the diameter
returned to baseline. Arterial blood pressure and heart
rate were measured on the contralateral arm with a commercially
available automatic blood pressure cuff.
In previous experiments, using this technology, we have yielded an
excellent reproducibility and variability. To this end, 48 patients
with heart failure were studied by the same investigator at two
occasions separated by 7 days. The two measurements of radial artery
diameter and blood flow were compared by linear regression
analysis (Pearson's formula). Reproducibility and variability
of radial artery diameter were as follows: baseline diameter:
reproducibility, 3.128±0.06 versus 3.129±0.06 mm
(r=.99; P<.001); variability, 0.04±0.005
mm (ie, 1.3±0.2%); maximal diameter during flow-dependent dilation:
reproducibility, 3.394±0.06 versus 3.381±0.06 mm
(r=.99; P<.001); variability, 0.06±0.0007
mm (ie, 1.7±0.2%); percent change of radial artery diameter during
flow-dependent dilation: reproducibility, 8.5±0.6 versus 8.2±0.6%
(r=.85; P<.001); variability, 1.9±0.3%.
Reproducibility of radial artery blood flow was: baseline, 27.6±2.9
versus 28.2±3.4 mL/min (r=.93; P<.001);
variability, 5.3±0.9 mL/min; maximal blood flow during reactive
hyperemia: reproducibility, 87.3±8.3 versus 85.4±7.4 mL/min
(r=.9; P<.001); variability, 17.3±2.6 mL/min.
Furthermore, we have recently shown that reproducibility of radial
artery diameter and blood flow is also very good when measurements are
repeated after 4 weeks.6 These findings compare
favorably with previously published data from other groups using
high-resolution echo-wall tracking systems to measure radial artery
diameter and blood flow.13
After insertion of a polyethylene catheter into the left brachial
artery (nondominant arm), saline was infused. Blood flow velocity was
recorded continuously and radial artery diameter was determined
every 30 seconds until stable baseline conditions were obtained
(approximately 30 minutes). A wrist arterial occlusion then
was performed and flow-dependent dilation in response to the reactive
hyperemic blood flow response was assessed at baseline and
after intra-arterial infusion of L-NMMA (Calbiochem; 7
µmol/min over 5 minutes). This dose was based on our earlier
observations demonstrating that this dose of L-NMMA attenuated FDD by
64±6%.6 When radial artery diameter and blood
flow had returned to baseline values, patients were randomized (ratio
2:1) to receive intra-arterial infusion of vitamin C (25
mg/min over 10 minutes) or placebo (saline) followed by determination
of FDD with and without coinfusion of L-NMMA. The dose for
intra-arterial vitamin C was based on a recent publication
demonstrating that this dose of vitamin C improved
endothelium-dependent dilation in patients with
diabetes mellitus.14 Finally, all subjects
received an intra-arterial infusion of SNP (10 µg/min
over 5 minutes) to assess endothelium-independent
vasodilatory capacity. In 10 patients with heart failure, the protocol
was repeated after 4 weeks of oral therapy with vitamin C (n=5, 1
g twice daily) or placebo (n=5). These patients were studied 24 hours
after the last oral dose of vitamin C or placebo. This interval was
chosen, since a recent investigation has shown that 24 hours after
2 g of oral vitamin C ascorbic acid plasma levels had returned to
baseline.15 Since we were interested in
evaluating the long-term effect of vitamin C rather than the acute
effect of oral dose after long-term therapy, we elected to study these
patients 24 hours after the last dose.
Blood flow and diameter data, reported for L-NMMA, vitamin C, placebo,
and SNP represent measurements during the last minute of each
infusion. All measurements were recorded and subsequently, vessel
diameter and blood flow velocity were analyzed by two
investigators who were unaware of the sequence of interventions and
treatment assignment.
All data are expressed as mean±SEM. To compare the data at baseline,
after L-NMMA, vitamin C or placebo respectively, and SNP within one
group of patients, a one-way ANOVA for repeated measures was performed
followed by Student-Newman Keuls test. To compare data and in
particular NO-mediated FDD between the three groups, we also used a
one-way ANOVA followed by Student-Newman-Keuls test. A value of
P<.05 was considered to be statistically significant.
The portion of FDD that was inhibited by L-NMMA
(representing the portion of FDD mediated by NO) was
reduced in patients with CHF compared with normal subjects (4.2±0.7%
versus 8.9±0.8%; P<.01; Fig 2
Intra-arterial SNP significantly increased radial artery
diameter to a similar extent in normal individuals and in patients with
CHF; there was a similar response to SNP in patients with CHF
treated with vitamin C or with placebo (normal individuals: 2.76±0.1
to 3.24±0.1 mm; CHF placebo: 2.80±0.1 to 3.33±0.1 mm;
CHF vitamin C: 2.81±0.09 to 3.31±0.14 mm; P<.05
versus before SNP).
Forearm blood flow at rest was reduced significantly by infusion of
L-NMMA but not affected by vitamin C or placebo (Table 3
Infusion of SNP increased forearm blood flow to a similar extent in
normal individuals and patients with CHF (normal subjects: 22±5 to
39±6 mL/min; CHF placebo: 27±5 to 44±5 mL/min; CHF vitamin C: 24±4
to 43±5 mL/min; P<.05 versus before SNP for each).
Systemic blood pressure and heart rate did not change during the
experimental protocol (data not shown).
Effect of Chronic Treatment With Vitamin C
Five patients with CHF were studied again after 4 weeks placebo instead
of vitamin C. Radial artery diameter at rest (2.86±0.2 versus
2.84±0.3 mm) and FDD (8.0±1.1 versus 8.3±1.2%) were similar as
compared with baseline and not affected by intra-arterial
placebo (saline) (diameter at rest: 2.85±0.2 mm; FDD:
8.2±1.1%). Effect of SNP on radial artery diameter was similar before
and after 4 weeks of placebo in patients with CHF (n=5): before
placebo: control, 2.81±0.1 mm to 3.30±0.1 mm after SNP
(P<.05 versus before SNP); after 4 weeks of placebo:
control, 2.78±0.1 mm to 3.28±0.1 mm after SNP
(P<.05 versus before SNP).
Peak blood flow during reactive hyperemia was similar before
and after oral therapy with vitamin C or placebo (Table 4
Effect of intra-arterial SNP on radial artery blood flow
was similar before and after 4 weeks of placebo (patients with CHF;
n=5): before placebo, 27±0.1 to 44±5 mL/min (P<.05 versus
before SNP); after 4 weeks of placebo, 25±6 to 45±5 mL/min
(P<.05 versus before SNP).
Renal function tests in patients with CHF were unchanged after 4 weeks
of oral vitamin C or placebo (each group n=5; before oral vitamin C:
creatinine, 0.9±0.2 mg/dL; BUN, 55±14 mg/dL; after 4
weeks of vitamin C: creatinine, 0.9±0.3 mg/dL; BUN, 51±17
mg/dL; placebo-treated group: before: creatinine, 0.8±0.4
mg/dL; BUN, 60±17 mg/dL; after 4 weeks: creatinine,
0.9±0.3 mg/dL; BUN, 55±16 mg/dL).
We and others have demonstrated endothelial dysfunction
of peripheral conduit and resistance arteries in patients
with CHF.3 4 16 The blunted
endothelium-mediated vasodilation in this setting could
be attributed to impaired intracellular availability of L-arginine (the
precursor of NO), decreased expression of NO synthase (the enzyme that
generates NO from L-arginine), impaired receptor-mediated
release of NO in response to pharmacological or mechanical stimuli
(such as shear stress), or an increased degradation of NO as result of
increased endothelial and/or vascular smooth muscle
production of oxygen free radicals.
The latter possibility is supported by previous studies indicating
increased radical formation in heart failure both in the
circulation8 and the
heart.17 Belch and
coworkers8 measured plasma lipid peroxides as a
marker of free radical production in the circulation and
demonstrated that in patients with CHF, plasma lipid peroxides are
increased compared with normal control subjects. Furthermore, they have
shown that there is an inverse correlation between left
ventricular ejection fraction and plasma lipid peroxide
levels.8 One possible source of increased radical
formation in heart failure might be the cardiac myocyte. In this
respect, Mohazzab and coworkers17 have recently
shown that the basal release of superoxide anion
(O2-) is increased in failing human cardiac
myocytes, apparently due to increased
O2--production by mitochondria and
NADH-oxidoreductases. In addition, myocardial antioxidant reserve may
be reduced in heart failure, as suggested by increased protein
oxidation in cardiac myocytes in heart failure and its prevention by
concomitant therapy with the antioxidant vitamin
E.18 Leukocytes may represent another
potential source of increased radical formation in heart
failure.19 The results of these previous studies
support the notion that free radical formation is increased in CHF.
Since enhanced generation of free radicals inactivate NO,
the availability of NO and its release during FDD would be impaired in
CHF. Thus it is conceivable that increased radical formation is
involved in the pathogenensis of endothelial
dysfunction in patients with CHF. In the present study,
intra-arterial infusion of vitamin C completely restored
FDD in patients with CHF. In particular, the portion of FDD mediated by
NO (ie, the part of FDD that was blocked by L-NMMA) was normalized
immediately after intra-arterial infusion of vitamin C.
Vitamin C has been shown to act as a strong water-soluble antioxidant
in vitro and in vivo,9 10 and its
intra-arterial application has been shown to improve
endothelial dysfunction in patients with
diabetes,14 another clinical entity in which
enhanced radical formation has been reported. Therefore our observation
would support the notion that an increased inactivation of NO was
involved in the impaired NO-mediated FDD in our patients with heart
failure. Interestingly, the beneficial effect of vitamin C was
maintained after a 4-week treatment with 2 g per day given orally.
These first preliminary observations during long-term supplementation
need to be confirmed in a larger group of patients; however, if
confirmed, they may have important clinical implications.
We cannot exclude the possibility that vitamin C might directly improve
heart failure (thereby secondarily improving vascular function) and not
specifically endothelium-mediated vasodilation.
However, the acute effect of vitamin C on
endothelium-mediated vasodilation cannot be explained
by changes in the severity of heart failure. It is highly unlikely that
vitamin C given acutely into the brachial artery results in a major
improvement in central hemodynamics in patients with
NYHA class III heart failure. Notably, neither the acute
intra-arterial infusion of vitamin C nor the chronic oral
treatment with vitamin C had any effect on systemic blood pressure,
heart rate, radial artery blood flow, or radial artery resting
diameter. In addition, there was no change of
echocardiographic characteristics of left
ventricular function after 4 weeks of vitamin C in any of
these patients. Taken together, we think that the hypothesis that
vitamin C improves heart failure per se is unlikely and cannot explain
our results. However, a final answer to this question awaits further
studies involving a large patient population.
It is important to note that the maximal reactive hyperemic
blood flow response after wrist occlusion was not different at control,
vitamin C, placebo, or L-NMMA. Therefore the stimulus that caused
endothelium-mediated dilation was similar during the
different interventions. Furthermore, an unspecific attenuation of
vasodilator capacity during heart failure appears to be unlikely
because the vasodilator response to SNP was preserved in our patients
compared with the normal volunteers. In addition, an effect of vitamin
C on vascular smooth muscle function rather than the
endothelium appears to be unlikely, because vitamin C
per se did not affect radial artery diameter and blood flow and the
vasodilator response to SNP was similar in patients treated with
vitamin C and placebo. These results are consistent with the
notion that in patients with CHF, inactivation of NO by oxygen free
radicals occurs within the vascular wall, that is, between the
endothelium, where NO is synthesized, and the vascular
smooth muscle, the target organ. The enhanced inactivation of NO leads
to a reduced availability of NO for the vascular smooth muscle, which
per se has a preserved vasodilatory capacity as indicated by a
preserved vasodilation in response to excessive doses of exogenously
administered NO. Our observations are consistent with recent
reports using SNP and vitamin C in patients with coronary
artery disease or diabetes.14 15 Our observations
as well as reports by others therefore suggest that using excessive
doses of exogenous NO donors appears to overcome an increased vascular
stress. We therefore think that during
physiological conditions in humans,
endothelium-mediated vasodilation is a question of
balance between NO availability and NO inactivation by oxygen free
radicals within the vascular wall as discussed
recently.20 This balance, however, may be lost in
pathophysiological conditions; that is, our results
indicate a pathophysiological role of increased
oxidative stress in CHF.
It is also unlikely that a correction of an absolute vitamin C
deficiency may explain our findings, because it has recently been shown
that there is no correlation between baseline vitamin C plasma levels,
endothelial dysfunction, or improvement with
treatment.15 Therefore, our results support the
concept that the impaired NO-mediated FDD in CHF is, at least in part,
due to increased inactivation of endothelium-derived NO
by radicals and that vitamin C exerts its antioxidant properties within
the vasculature by directly scavenging oxygen derived free
radicals10 such as superoxide anion or hydroxyl
radicals.
The present study was not designed to elucidate the underlying
mechanism(s) leading to increased oxidative stress in CHF. However,
there is evidence that angiotensin II, whose plasma and
tissue levels are typically elevated in CHF, activates
NADH/NADPH-driven oxidases located within the vascular
wall21 that appear to be the main enzymes
responsible for vascular synthesis of radicals within the vessel wall.
However, other factors may be involved as well, such as increased
levels of cytokines such as tumor necrosis factor-
The functional significance of the beneficial effect of vitamin C on
large-artery function in patients with CHF remains to be fully
determined. It is important to note, however, that large arteries are
more than passive conduits22 and that NO appears
to be involved in the regulation of the passive elastic properties of
the arterial wall, thereby controlling the mechanical
properties of the arterial wall and contributing to the
dynamic control of cardiac performance. Previous studies have
shown that the compliance of peripheral conduit arteries is
reduced in patients with CHF.23 Furthermore,
there is evidence that endothelial control of conduit
artery distensibility is impaired in patients with
CHF.24 Despite the fact that our observations are
limited to the radial artery, it is conceivable that if similar changes
were found to be present throughout the large arterial
tree, they would increase the impedance to the failing left ventricle.
Moreover, there is evidence that an intact endothelium
appears to protect large vessels against constrictor effects of
catecholamines during exercise.25
In conclusion, the present study demonstrates that
endothelial dysfunction in patients with congestive
heart failure can be improved and normalized by acute
intra-arterial as well as by chronic oral treatment
with the antioxidant vitamin C. Our observations support the notion
that CHF is associated with increased radical formation which, in turn,
affects endothelium-mediated vasomotor tone. Our
results extend previous findings reporting beneficial effects of acute
administration of vitamin C on endothelium-mediated
vascular relaxation in patients with coronary artery disease,
diabetes, or chronic smoking. Importantly, the present study
indicates that the beneficial effect is related to increased
availability of NO. While our initial observations suggest that this
beneficial effect may be sustained during long-term supplementation,
this finding needs to be confirmed in large-scale clinical trials.
Received July 22, 1997;
revision received September 15, 1997;
accepted September 30, 1997.
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© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Vitamin C Improves Endothelial Function of Conduit Arteries in Patients With Chronic Heart Failure
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Chronic heart failure
(CHF) is associated with endothelial dysfunction
including impaired endothelium-mediated, flow-dependent
dilation (FDD). There is evidence for increased radical formation in
CHF, raising the possibility that nitric oxide is
inactivated by radicals, thereby impairing
endothelial function. To test this hypothesis, we
determined the effect of the antioxidant vitamin C on FDD in patients
with CHF.
Key Words: endothelium • antioxidants • vasoconstriction • vasodilation
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patients with CHF are
characterized by systemic vasoconstriction and a reduced
peripheral perfusion. While an increased sympathetic tone
and an activated renin- angiotensin system have
been proposed to be involved in the reduced vasodilator capacity in
heart failure,1 the important role of the
endothelium in coordinating tissue perfusion has now
been recognized.2 Recent clinical studies have
documented endothelial dysfunction of
peripheral resistance arteries3 and
an impaired flow-dependent, endothelium-mediated
dilation of conduit arteries (FDD) in patients with
CHF.4 An important functional consequence of
endothelial dysfunction is the inability of a vessel to
dilate in response to endothelium-derived NO after
physiological stimuli, such as increases of blood
flow,5 reflecting impaired FDD.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Fifteen patients with congestive heart failure in New York Heart
Association functional class III with radiological and
echocardiographic signs of cardiomegaly and eight
healthy volunteers (8 men; age, 27.5±0.5 years) were studied.
Characteristics of heart failure patients are shown in Table 1
. All patients were treated with
digitalis, angiotensin-converting enzyme
inhibitors, and diuretics but no further vasoactive
drugs. Digoxin and captopril were stopped 24 hours, diuretics
12 hours, and enalapril 48 hours before measurements. Alcohol and
caffeine were prohibited within 12 hours of the study. Patients with
diabetes mellitus, hypercholesterolemia (LDL
cholesterol >140 mg/dL), arterial
hypertension, or significant hematologic, renal, or hepatic dysfunction
were excluded by a careful history, physical examination, ECG, and
laboratory analysis. Vitamin C is to a large extent excreted by
the kidney. An impaired renal function in patients with heart failure
might therefore be associated with elevated plasma levels of ascorbic
acid leading to a potentiation of the effect of vitamin C. To rule out
an impaired renal function as underlying mechanism for the effect of
vitamin C on endothelium-mediated vasodilation in all
patients with CHF, plasma creatinine and blood urea
nitrogen (BUN) were determined before and after 4 weeks of oral vitamin
C administration. All subjects were nonsmokers. Written informed
consent was obtained for all subjects, and the protocol was approved by
the local ethics committee.
View this table:
[in a new window]
Table 1. Characteristics of Patients With CHF
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Acute Effects of Vitamin C
After wrist occlusion, a significant increase in radial
arterial diameter was noted (Table 2), representing FDD (Fig 1), defined as percent increase in vessel
diameter. FDD was impaired in patients with CHF compared with normal
individuals (Fig 1 and Table 2). Infusion of L-NMMA did not change
radial artery diameter under resting conditions (Table 2). However, FDD
was significantly reduced by L-NMMA as compared with baseline values
(Fig 1 and Table 2). Infusion of vitamin C or placebo did not change
radial artery diameter at rest. However, after administration of
vitamin C but not after placebo, FDD was significantly increased in
patients with CHF (Table 2 and Fig 1).
View this table:
[in a new window]
Table 2. Effect of L-NMMA, Vitamin C, and Placebo on Radial
Artery Diameter at Baseline and During Flow-Dependent,
Endothelium-Mediated Dilation
View larger version (19K):
[in a new window]
Figure 1. Change in radial artery diameter (%) during
reactive hyperemia (flow-dependent dilation) after wrist
occlusion in normal individuals (n=8) and patients with CHF (n=10)
before (black bars) and after L-NMMA (open bars); effect of
intra-arterial infusion of vitamin C. ). After administration of vitamin C,
the portion of FDD mediated by NO was significantly increased and
normalized in patients with CHF (9.1±1.3%; P<.01 versus
baseline; Fig 2).
View larger version (11K):
[in a new window]
Figure 2. Change in radial artery diameter (%) during
reactive hyperemia that can be blocked by L-NMMA
(representing the part of flow-dependent dilation that is
mediated by NO) in normal individuals (Normals; n=8), patients with
congestive heart failure at baseline (CHF; subgroup, n=5), after
intra-arterial infusion of placebo (CHF Placebo; n=5),
vitamin C (CHF acute vitamin C; subgroup, n=5) and after 4 weeks of
oral therapy with vitamin C (CHF chronic vitamin C; subgroup, n=5).
*P<.01 vs CHF; #P<.01 vs CHF
placebo. ). Maximal forearm blood flow during
reactive hyperemia was similar in normal subjects and patients
with CHF and was not affected by L-NMMA, vitamin C, placebo, or
combination of both (Table 3).
View this table:
[in a new window]
Table 3. Radial Artery Blood Flow at Baseline and During
Reactive Hyperemia: Effect of L-NMMA, Vitamin C, and Placebo
Five patients with CHF were studied again after 4 weeks of oral
therapy with vitamin C. There was no change in the severity of left
ventricular dysfunction as assessed by
echocardiography (left ventricular ejection
fraction: 21±3% versus 22±2% after 4 weeks of vitamin C; left
ventricular end-diastolic diameter: 67±4
versus 68±5 mm after 4 weeks of vitamin C; n=5). Radial artery
diameter at rest was similar as compared with baseline (2.87±0.3
versus 2.85±0.2 mm). However, FDD was significantly increased
compared with baseline values (11.9±0.9% versus 8.2±1.0%;
P<.05). The portion of FDD mediated by NO was increased as
compared with baseline values (7.3±1.2% versus 2.7±0.6%;
P<.01) and similar to values obtained in normal individuals
(8.9±0.8%) (Fig 2
). After rechallenge with intra-arterial
vitamin C, FDD and the portion of FDD mediated by NO were not
significantly affected (Fig 2). Effect of SNP on radial artery diameter
was similar before and after 4 weeks of oral vitamin C in patients with
CHF (n=5): before vitamin C: control, 2.79±0.1 mm to
3.28±0.1 mm after SNP; (P<.05 versus before SNP);
after 4 weeks of vitamin C: control, 2.81±0.1 mm to
3.27±0.1 mm (P<.05 versus before SNP). ). Effects of intra-arterial
L-NMMA and vitamin C on forearm blood flow at rest and during reactive
hyperemia were similar as before oral vitamin C (Table 4).
Effect of intra- arterial SNP on radial artery blood
flow was similar before and after 4 weeks of vitamin C (patients with
CHF; n=5) before vitamin C: 24±4 to 43±5 mL/min (P<.05
versus before SNP); after 4 weeks of vitamin C: 22±4 to 41±4 mL/min
(P<.05 versus before SNP).
View this table:
[in a new window]
Table 4. Effect of 4 Weeks of Oral Vitamin C and Placebo on
Radial Artery Blood Flow at Baseline and During Reactive
Hyperemia: Effect of Intra-arterial L-NMMA, Vitamin
C, and Placebo
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The salient finding of the present study is that the impaired
FDD in patients with CHF is improved by the antioxidant vitamin C both
after intra-arterial administration and 4 weeks of oral
therapy, whereas FDD was not affected by vitamin C in healthy
volunteers. Furthermore, this study indicates that the beneficial
effect of vitamin C on FDD in humans is mediated by an increased
availability of NO, since the portion of FDD mediated by NO was
increased by vitamin C. 
, which in
turn may enhance oxidative stress.
Selected Abbreviations and Acronyms
CHF
=
chronic heart failure
FDD
=
flow-dependent dilation
L-NMMA
=
N-monomethyl-L-arginine
NO
=
nitric oxide
SNP
=
sodium nitroprusside
Acknowledgments
This study was supported in part by the Deutsche
Forschungsgemeinschaft (Dr 148/7–2). Dr Arakawa was supported by a
grant of the Japan-Europe Scientist Exchange Program from the
Ciba- Geigy Foundation.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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Y. Ishibashi, T. Shimada, T. Sakane, N. Takahashi, T. Sugamori, S. Ohhata, S.-i. Inoue, H. Katoh, K. Sano, Y. Murakami, et al. Contribution of endogenous nitric oxide to basal vasomotor tone of peripheral vessels and plasma B-Type natriuretic peptide levels in patients with congestive heart failure J. Am. Coll. Cardiol., November 1, 2000; 36(5): 1605 - 1611. [Abstract] [Full Text] [PDF]
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S. D. Katz, K. Balidemaj, S. Homma, H. Wu, J. Wang, and S. Maybaum Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure J. Am. Coll. Cardiol., September 1, 2000; 36(3): 845 - 851. [Abstract] [Full Text] [PDF]
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D. Tomasian, J. F. Keaney Jr., and J. A. Vita Antioxidants and the bioactivity of endothelium-derived nitric oxide Cardiovasc Res, August 18, 2000; 47(3): 426 - 435. [Full Text] [PDF]
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R. Varin, P. Mulder, F. Tamion, V. Richard, J.-P. Henry, F. Lallemand, G. Lerebours, and C. Thuillez Improvement of Endothelial Function by Chronic Angiotensin-Converting Enzyme Inhibition in Heart Failure : Role of Nitric Oxide, Prostanoids, Oxidant Stress, and Bradykinin Circulation, July 18, 2000; 102(3): 351 - 356. [Abstract] [Full Text] [PDF]
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U. Landmesser, R. Merten, S. Spiekermann, K. Buttner, H. Drexler, and B. Hornig Vascular Extracellular Superoxide Dismutase Activity in Patients With Coronary Artery Disease : Relation to Endothelium-Dependent Vasodilation Circulation, May 16, 2000; 101(19): 2264 - 2270. [Abstract] [Full Text] [PDF]
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O. T. Raitakari, M. R. Adams, R. J. McCredie, K. A. Griffiths, R. Stocker, and D. S. Celermajer Oral vitamin C and endothelial function in smokers: short-term improvement, but no sustained beneficial effect J. Am. Coll. Cardiol., May 1, 2000; 35(6): 1616 - 1621. [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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T. Munzel and D. G. Harrison Increased Superoxide in Heart Failure : A Biochemical Baroreflex Gone Awry Circulation, July 20, 1999; 100(3): 216 - 218. [Full Text] [PDF]
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J. Bauersachs, A. Bouloumie, D. Fraccarollo, K. Hu, R. Busse, and G. Ertl Endothelial Dysfunction in Chronic Myocardial Infarction Despite Increased Vascular Endothelial Nitric Oxide Synthase and Soluble Guanylate Cyclase Expression : Role of Enhanced Vascular Superoxide Production Circulation, July 20, 1999; 100(3): 292 - 298. [Abstract] [Full Text] [PDF]
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N. Gokce, J. F. Keaney Jr, B. Frei, M. Holbrook, M. Olesiak, B. J. Zachariah, C. Leeuwenburgh, J. W. Heinecke, and J. A. Vita Long-Term Ascorbic Acid Administration Reverses Endothelial Vasomotor Dysfunction in Patients With Coronary Artery Disease Circulation, June 29, 1999; 99(25): 3234 - 3240. [Abstract] [Full Text] [PDF]
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R. Varin, P. Mulder, V. Richard, F. Tamion, C. Devaux, J.-P. Henry, F. Lallemand, G. Lerebours, and C. Thuillez Exercise Improves Flow-Mediated Vasodilatation of Skeletal Muscle Arteries in Rats With Chronic Heart Failure : Role of Nitric Oxide, Prostanoids, and Oxidant Stress Circulation, June 8, 1999; 99(22): 2951 - 2957. [Abstract] [Full Text] [PDF]
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A. C Carr and B. Frei Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans Am. J. Clinical Nutrition, June 1, 1999; 69(6): 1086 - 1107. [Abstract] [Full Text] [PDF]
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W. G. Mayhan and G. M. Sharpe Chronic exposure to nicotine alters endothelium-dependent arteriolar dilatation: effect of superoxide dismutase J Appl Physiol, April 1, 1999; 86(4): 1126 - 1134. [Abstract] [Full Text] [PDF]
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 R. Heller, F. Munscher-Paulig, R. Grabner, and U. Till L-Ascorbic Acid Potentiates Nitric Oxide Synthesis in Endothelial Cells J. Biol. Chem., March 19, 1999; 274(12): 8254 - 8260. [Abstract] [Full Text] [PDF]
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B. Hornig, N. Arakawa, D. Haussmann, and H. Drexler Differential Effects of Quinaprilat and Enalaprilat on Endothelial Function of Conduit Arteries in Patients With Chronic Heart Failure Circulation, December 22, 1998; 98(25): 2842 - 2848. [Abstract] [Full Text]
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H. Drexler Endothelium as a Therapeutic Target in Heart Failure Circulation, December 15, 1998; 98(24): 2652 - 2655. [Full Text] [PDF]
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 T. S. Jackson, A. Xu, J. A. Vita, and J. F. Keaney Jr Ascorbate Prevents the Interaction of Superoxide and Nitric Oxide Only at Very High Physiological Concentrations Circ. Res., November 2, 1998; 83(9): 916 - 922. [Abstract] [Full Text] [PDF]
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A. Huang, J. A. Vita, R. C. Venema, and J. F. Keaney Jr. Ascorbic Acid Enhances Endothelial Nitric-oxide Synthase Activity by Increasing Intracellular Tetrahydrobiopterin J. Biol. Chem., June 2, 2000; 275(23): 17399 - 17406. [Abstract] [Full Text] [PDF]
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R. Heller, A. Unbehaun, B. Schellenberg, B. Mayer, G. Werner-Felmayer, and E. R. Werner L-Ascorbic Acid Potentiates Endothelial Nitric Oxide Synthesis via a Chemical Stabilization of Tetrahydrobiopterin J. Biol. Chem., January 5, 2001; 276(1): 40 - 47. [Abstract] [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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V. A. Tyurin, S.-X. Liu, Y. Y. Tyurina, N. B. Sussman, C. A. Hubel, J. M. Roberts, R. N. Taylor, and V. E. Kagan Elevated Levels of S-Nitrosoalbumin in Preeclampsia Plasma Circ. Res., June 8, 2001; 88(11): 1210 - 1215. [Abstract] [Full Text] [PDF]
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