Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1168-1172
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1168-1172.)
© 1999 American Heart Association, Inc.
Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure
Robert Wever;
Peter Boer;
Michel Hijmering;
Erik Stroes;
Marianne Verhaar;
John Kastelein;
Kees Versluis;
Fija Lagerwerf;
Herman van Rijn;
Hein Koomans;
Ton Rabelink
From the Department of Clinical Chemistry (R.W., H.v.R.), and the
Department of Nephrology and Hypertension (P.B., M.H., E.S., M.V., H.K.,
T.R.), University Hospital Utrecht, The Netherlands; the U-Gene Clinical
Pharmacology Unit, Utrecht, The Netherlands (M.H.); the Department of Vascular
Medicine, University Medical Center, Amsterdam, The Netherlands (J.K.); and
the Bijvoet Center for Biomolecular Research, Department of Mass Spectrometry,
Utrecht University, The Netherlands (K.V., F.L.).
Correspondence to Peter Boer, University Hospital Utrecht, Deptartment of Nephrology and Hypertension, Room F03.226, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail p.boer{at}digd.azu.nl
 |
Abstract
|
|---|
AbstractIn patients with
chronic renal failure (CRF),
atherosclerosis is a major
cause of cardiovascular morbidity
and mortality.
Generally, atherosclerosis has been associated
with a
reduced bioavailability of nitric oxide (NO). Experimental
studies have
indicated the presence of enhanced NO degradation
by reactive oxygen
species as well as decreased NO production
as possible causes
for this reduced NO bioavailability. So far,
the question whether or
not NO production is impaired in patients
with CRF has never
been investigated. Therefore, we measured
whole body NO
production in 7 patients with CRF, and in 7 matched
healthy
subjects. To assess the relative importance of a dysfunction
of NO
synthase (NOS), we compared the NO production of these
patients
to that of 2 other groups known to have endothelial
dysfunction,
ie, 7 patients with familial
hypercholesterolemia (FH) who did
not yet have
signs of clinical cardiovascular disease (all
nonsmokers),
and 5 cigarette smokers. These groups were also compared
with
7 nonsmoking, age-matched healthy subjects. Whole body NO
production,
determined as in vivo arginine-to-citrulline
conversion, was
assessed by giving an intravenous infusion
of [
15N
2]-arginine
as a substrate for NOS and
measuring isotopic plasma enrichment
of [
15N]-citrulline
by LC-MS. NO production in the CRF patients
(0.13±0.02
µmol · kg
1 · h
1)
was
significantly lower (
P<0.05) than in the corresponding
control
group (0.23±0.09 µmol · kg
1
·
h
1). NO production also tended to be lower in
the FH patients
(0.16±0.04 µmol · kg
1
· h
1),
but the difference with the corresponding
control group did
not reach significance (0.22±0.06 µmol
·
kg
1 · h
1). In the group of
smokers, NO production
was similar to that in nonsmokers
(0.22±0.09 µmol
· kg
1 ·
h
1). In conclusion, it is
demonstrated for the first time
that basal whole body NO production
is reduced in patients with
CRF. This finding implies that therapeutic
interventions to
endothelial dysfunction in these patients should
be
primarily directed toward improvement of NO production. The
finding
of only a tendency toward reduction of NO production in
patients
with FH and the absence of a reduction in cigarette smokers
suggests
that other mechanisms such as enhanced NO degradation may be
involved
in the decrease of NO bioavailability in these groups.
Key Words: nitric oxide chronic renal failure atherosclerosis endothelium hypercholesterolemia
 |
Introduction
|
|---|
Premature atherosclerosis is one of the
primary causes of morbidity
and mortality in patients with chronic
renal insufficiency.
1 Over the last decade
endothelial dysfunction has been identified
as an early
mediator in this process. Nitric oxide (NO) is one
of the main factors
involved in the antiatherosclerotic effects
of the
endothelium,
2 and chronic renal failure
(CRF) has been
associated with impaired NO bioavailability in the
absence of
concomitant risk factors,
3 4 5 even in
children.
6 7 However,
the finding of a reduced NO
bioavailability as demonstrated
by functional studies does not provide
insight into the mechanisms
causing endothelial
dysfunction, because reduced bioavailability
can be the result of
decreased NO production, increased NO degradation,
or both. In
patients with CRF, NO production can be reduced
by a diminished
NO synthase (NOS) activity, which in turn can
be the result of a
decreased clearance of the endogenous NOS
inhibitor
asymmetric dimethylarginine
(ADMA),
7 8 9 or a decreased bioavailability
of the NOS
substrate
L-arginine.
10 11 12 On the other hand,
CRF
has also been associated with enhanced concentrations of oxygen
radical
species that can inactivate
NO.
13 14 15
NOS incorporates molecular oxygen into the guanidino group of
L-arginine, yielding NO and
L-citrulline.16 By utilizing this reaction, NO
production by NOS can be monitored by measuring the isotopic
enrichment of [15N]-citrulline in plasma during
intravenous infusion of
[15N2]-arginine.17
This reaction is specific for NOS and discriminates from alternative
L-citrulline formation via the urea cycle
pathway.17 Unlike NOS-derived citrulline, the
[15N]-label is not retained in urea
cycle-derived citrulline because the complete guanidino group of
arginine is removed yielding ornithine, which then condenses with
carbamoyl phosphate to give citrulline. Unlike measurements with an NO
electrode, which measures net NO release, this method gives direct
information on the enzymatic activity of NOS in vivo. To investigate NO
production in patients with CRF, we used a recently developed
LC-MS technique to quantitate whole body NO production. We
studied a matched group of healthy subjects as controls. In addition,
to judge the severity of a possible dysfunction of NOS in patients with
CRF, we determined NO production in 2 other groups known to
have impaired NO bioavailability, ie, patients with familial
hypercholesterolemia (FH), at a stage at which
clinical cardiovascular disease was not yet
present,3 4 5 and in cigarette
smokers.18 19 The latter groups were also compared with a
corresponding age-matched control group.
 |
Methods
|
|---|
Subjects
In total, in vivo NO production was assessed in 33
subjects
(Table 1

). Seven patients with
CRF participated in the study.
Causes of renal failure were
nephrosclerosis (3), chronic interstitial
nephritis
(2), and polycystic kidney disease (2). None of the patients
were
on hemodialysis; 3 were cigarette smokers; 4 had manifest
cardiovascular
disease, as indicated by angina pectoris
(2), claudicatio intermittens
(2), and abdominal aortic aneurism (1).
Four patients received
concomitant antihypertensive therapy, ie,
angiotensin converting
enzyme inhibition (3), calcium
channel entry blockers (2), and
diuretics (3). The CRF patients
were compared with a control
group of 7 age-matched healthy subjects
(Control 1). The group
of FH patients also consisted of 7 subjects, all
of them nonsmokers.
None of them had signs of
cardiovascular disease on clinical
examination and ECG.
Any medication had been discontinued for
a period of 2 weeks. They were
compared with an age-matched
control group of 7 healthy subjects, also
nonsmokers (Control
2). The FH patients and the corresponding control
group were
also compared with a group of 5 cigarette smokers. All
smokers
had refrained from smoking for at least 24 hours. The study
protocol
was approved by the institutional committee on ethics for
studies
in humans. The subjects had given written informed consent
after
the aim of the study had been explained to them.
Study Protocol
The subjects were fasting at the time of study. After blood
sampling for determination of the background isotope ratios of plasma
arginine and citrulline, a priming dose of 12 µmol
L-[guanidino-15N2]-arginine
(purity >98%; Mass Trace) per kg body weight was given, followed by a
constant infusion for 120 minutes of 11.2 µmol ·
h1 · kg1 body
weight. Under these conditions, plasma enrichments of
[15N2]-arginine and
[15N]-citrulline reached steady state levels in
30 to 60 minutes. Blood samples for measurement of
[15N2]-arginine and
[15N]-citrulline enrichments were collected
every 30 minutes and immediately centrifuged at 4°C. Plasma
samples were stored at 20°C.
HPLC-MS
Arginine-to-citrulline conversion rates were measured by
HPLC-MS.20 Briefly, plasma samples were deproteinized,
chromatographed on Dowex AG-50W-X4 cation exchange columns, and
eluted with 4 mol/L ammonia. The eluates were dried under nitrogen,
derivatized to benzylesters by heating with benzyl alcohol:
acetylchloride 4:1 (vol/vol) at 45°C for 2 hours, extracted with
1 mmol/L acetic acid, dried, and redissolved in 0.06%
trifluoroacetic acid. HPLC separations were performed on a Pharmacia
Smart System with a 4x250 mm Sephasil C18 column. Peaks were
monitored with UV-detection at 214 nm. Aliquots were injected and
eluted isocratically with acetonitrile: water: trifluoroacetic acid
15:85:0.06 (vol/vol/vol) at a flow rate of 0.4 mL/min. The
benzylarginine and benzylcitrulline fractions were collected, dried,
and redissolved. A VG Platform single quadrupole mass spectrometer was
used for positive ion electrospray ionization mass spectrometry.
Aliquots of the redissolved fractions were injected at a solvent flow
of 30 µL/min, and the m/z range from 260 to 270 was
scanned. The isotope ratios m/z 267/265 and m/z
267/266 were calculated for arginine and citrulline, respectively. The
detection limit of plasma citrulline enrichment was 0.09 atom percent
excess (APE). Analysis of plasma samples spiked with
[15N]-citrulline (range 0.12 to 2.40 APE)
showed good agreement between observed and calculated enrichments
(Y=1.049X+0.045, r=0.9985).
Calculations
Plasma isotope enrichments were expressed as:
where r
sa is
the isotope ratio of the
enriched sample, and r
bg is the background
ratio
of the preinfusion sample. Plasma arginine fluxes were
calculated from
plasma arginine enrichment during steady state
infusion, using the
single pool model for flux
17 :
where
Q
arg is the arginine flux
(µmol · kg
1 ·
h
1),
I
arg is the infusion rate of
[
15N
2]-arginine
(µmol
· kg
1 · h
1),
APE
inf is the enrichment
of infused arginine, and
APE
arg is the plasma arginine enrichment
at
steady state conditions. Arginine-to-citrulline conversion
rates were
calculated as:
where Q
arg
cit is the
arginine-to-citrulline
conversion rate
(µmol · kg
1 · h
1),
Q
cit is the citrulline flux, for which we used a
value of 9.5
µmol
· kg
1 · h
1,
17
APE
cit is the plasma
citrulline enrichment at
steady state conditions, and the term
[Q
arg/(Q
arg+I
arg)]
is
a correction factor for the contribution of the infused arginine
to
Q
arg
cit.
Statistics
Data are presented as mean±SD. Differences between
groups were evaluated by Kruskal-Wallis 1-way analysis of
variance on ranks and Dunn's test for multiple comparisons. A value of
P<0.05 was considered significant.
 |
Results
|
|---|
Basal preinfusion plasma arginine levels are given in Table
1

. There were no significant differences between the 5 groups,
albeit
that the CRF group tended to be lower than the other groups.
The
results of the
[
15N
2]-arginine infusion
studies are shown
in Table 2

. Steady
state plasma
[
15N
2]-arginine
enrichments
as well as arginine plasma fluxes were similar in the 5
groups.
Steady state plasma [
15N]-citrulline
enrichments were lower
in the CRF and FH groups as compared with the
control groups
and smokers, but this was not statistically significant.
Mean
NOS activities (measured as arginine-to-citrulline conversion
rates)
are also shown in Table 2

. In the patients with CRF, mean
NOS
activity was significantly lower (
P<0.05) than in the
corresponding
control group. In the patients with FH, mean NOS activity
tended
to be lower than in the corresponding control group, but this
difference
did not reach statistical significance. There were no
significant
differences between control groups 1 and 2, nor between
smokers
and nonsmokers. In the Figure

,
the NOS activities of all groups
are presented in a Box-Whisker
plot.
View this table:
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Table 2. Steady State Plasma Enrichments of
[15N2]-Arginine and
[15N]-Citrulline During Infusion of
[15N2]-Arginine, Calculated Arginine Flux,
and NOS Activity Determined as Arginine-to-Citrulline Conversion Rate
|
|

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Figure 1. NOS activities in elderly patients with renal
insufficiency (CRF-pat) with a corresponding control group of
healthy subjects (Ctr-1); and young patients with familial
hypercholesterolemia (FH-pat) with
corresponding control groups of healthy nonsmoking (Ctr-2) and
cigarette smoking (Ctr-sm) subjects.
|
|
 |
Discussion
|
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Using a novel method to measure NO production, we
demonstrate
for the first time that whole body NO production is
reduced
in patients with CRF. Endothelial dysfunction
is an early event
in the development of atherosclerosis
in CRF
6 7 and is known
to precede formation of
atherosclerotic plaques.
21 Our data
indicate that the
resulting reduction in NO bioavailability
in CRF is caused by decreased
NO production. In our patients
with FH, NO production
only showed a tendency to decrease, indicating
that increased NO
degradation is at least partially responsible
for the decreased NO
bioavailability that has been reported
in
hypercholesterolemia.
3 4 5 In
cigarette smokers NO production
was normal, which suggests that
increased NO degradation is
the major determinant of the decreased NO
bioavailability that
has been reported in this
group.
18 19
Notably, some of the CRF patients had manifest
atherosclerosis, which is almost invariably present
in adults with CRF.22 Atherosclerosis
itself may be one of the causes of the impaired NO production,
because a reduced expression of e-NOS enzyme has recently been reported
to occur in conditions of
atherosclerosis.23 Alternatively, impaired
NO production may also have resulted from accumulation of the
endogenous NOS-inhibitor ADMA in patients with
end-stage renal disease, which is well documented.7 8 9
Furthermore, the bioavailability of the NOS substrate
L-arginine has been found to be decreased in subtotally
nephrectomized rats10 11 as well as in dialysis patients,
possibly as a result of malnutrition or arginine loss caused by
hemodialysis.12 In the present study, plasma
L-arginine levels of the CRF patients also tended to be
lower than that of the other groups, although the differences were not
significant. Conceivably, decreased L-arginine levels may
become a rate-limiting factor for NOS in conditions of increased
ADMA/L-arginine ratios. In patients with end-stage renal
disease on chronic hemodialysis treatment, other factors may also
contribute to endothelial dysfunction, including
dyslipidemia,1
hyperhomocysteinemia,24 25 26 and increased oxidative stress
as a result of decreased antioxidant levels12 13 14 27 28
and increased lipid peroxidation.14 29 However, from the
findings of the present study, enhanced inactivation of NO by
reactive oxygen species does not seem to be the most obvious
explanation for a reduced NO bioavailability in patients with CRF.
Contrary to our findings in patients with CRF, we found NO
production to be less disturbed in patients with FH. A reduced
basal as well as receptor-dependent NO bioavailability has been
consistently reported in patients with FH by many groups,
including our own.3 4 5 NO bioavailability may be decreased
secondary to Gi protein uncoupling30
or reduced NOS expression by oxidized LDL.31 In addition,
increased ADMA levels32 33 as well as reduced
bioavailability of L-arginine have been found in
hypercholesterolemia.34 35 On the
other hand, many studies have suggested that
hypercholesterolemia is accompanied by
increased oxygen radical stress, which is an important determinant of
NO bioavailability.36 37 38 39 In this respect, the reaction of
NO with superoxide and the subsequent formation of peroxynitrite
appears to be crucial in determining NO bioavailability.40
In various experimental studies increased endothelial
superoxide generation associated with
hypercholesterolemia has now been
demonstrated.36 37 38 One major source of superoxide
production in hypercholesterolemia
appears to be xanthine oxidase; inhibitors of this enzyme
reduced endothelial superoxide production in
vitro38 and restored endothelial
dysfunction in vivo.41 Another source is NOS itself, which
may exhibit uncoupling of L-arginine
oxidation.2 This is underscored by the observation that
administration of scavengers of reactive oxygen species can improve NO
bioavailability in
hypercholesterolemia.41 42 43 Our
data support the notion that in the early phase of
atherosclerosis, ie, in the presence of
hypercholesterolemia, decreased NO
bioavailability is probably indeed a multifactorial phenomenon, which
cannot only be explained by impaired NO production.
Smoking is considered to be a typical model of increased oxygen radical
stress.44 This has been demonstrated by the finding of a
compromised endothelial function18 19 45
as well as observations that administration of the radical scavenger
vitamin C can restore endothelial
dysfunction.44 46 Our data support the concept that NO
bioavailability is decreased in smokers mostly as a result of enhanced
NO degradation, because we found no difference in NO production
between smoking and nonsmoking healthy subjects (Table 2
) nor
between smoking and nonsmoking patients with CRF (data not shown). This
also implies that smoking did not contribute to the impaired NO
bioavailability in those patients with CRF who were smokers.
The LC-MS technique employed by us is capable of detecting relevant
decreases in NO production, as demonstrated by the finding of a
decrease in NO production from 0.30±0.14 to 0.10±0.06
µmol · kg1 ·
h1 in subjects receiving an
intravenous infusion of the synthetic NOS
inhibitor L-NMMA in a previous
study.20 In addition, arginine fluxes and
arginine-to-citrulline conversion rates, as measured in the healthy
control groups, are of the same order of magnitude as values reported
in the literature obtained by GC-MS and GC-IRMS
techniques.17 47
A limitation inherent to all techniques used to measure NO
production17 20 47 is that they do not
discriminate between the various isoforms of NOS
(endothelial, neuronal, and inducible). In animal
studies, both renal failure and atherosclerosis have
been associated with increased, as well as decreased, expression of
iNOS, depending on the stage of disease.48 49 50 51 This makes
it difficult to assess to what extent changes in iNOS expression
contributes to our observation of reduced NO production in
these humans. If iNOS is present in the renal patients, this would
mean that eNOS activity in patients with CRF must be suppressed even to
a larger degree than becomes apparent from overall NO
production. On the other hand, even if the reduction in NO
production in these patients was entirely caused by a reduction
in iNOS, this may be relevant to atherosclerosis.
Recent studies indicated that iNOS expression is important in
prevention of neointima proliferation and
endothelial regeneration,52 53 54 whereas
iNOS blockade could accelerate atherogenesis, and vascular transfection
of iNOS could inhibit atherogenesis.54 55 Another, more
practical limitation is that the technique, being expensive and
technically complicated, could not be applied to large groups of
patients. Nevertheless, despite these limitations, the degree of
impairment of NO production in our patients with CRF was found
to be statistically significant and very consistent, which
underscores the severity of the observed impairment in NOS function as
a mechanism for endothelial dysfunction in these
patients.
 |
Acknowledgments
|
|---|
This study was supported by grants C95.1437 of the Dutch Kidney
Foundation
and 96.169 of the Dutch Heart Foundation. Ton Rabelink is
sponsored
by a fellowship of the Royal Dutch Academy of Sciences
(KNAW).
Received April 23, 1998;
accepted September 2, 1998.
 |
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