From the Department of Clinical Pharmacology, St Bartholomew's and
The Royal School of Medicine and Dentistry, London (P.F., A.J., N.B.); the
Department of Clinical Pharmacology, UMDS, St Thomas' Hospital, London
(B.J.K., P.J.C., J.M.R.); and the Rowett Research Institute, Aberdeen (E.M.),
UK.
Correspondence to Professor Nigel Benjamin, Department of Clinical Pharmacology, St Bartholomew's and The Royal School of Medicine and Dentistry, Charterhouse Square, London, EC1 M 6BQ, UK. E-mail n.benjamin{at}mds.qmw.ac.uk
Materials
Tracer Infusion Study
Analytical Methods
Measurement of 15N Nitrate
Calculations and Statistical Analysis
Direct measurement of NO production is extremely difficult
because of NO'ss short half-life in vivo.2 NO is
rapidly oxidized to nitrate by oxygenated hemoglobin,
molecular oxygen, and superoxide anions and is excreted as such into
the urine.15 In mammalian cells, NO is
synthesized from the guanidino nitrogen atoms of
L-arginine, and this is the only known route by which these
nitrogen atoms may be incorporated into
nitrate.16 Therefore, determination of the
urinary excretion of 15N nitrate after
intravenous administration of
L-[15N]2-guanidino-arginine
is a more specific measure of whole-body NO synthesis than measurement
of total nitrate, cyclic GMP, and L-citrulline.
In this study, we found that the total urinary nitrate excretion did
not differ between men and women; however, the mean 36-hour urinary
15N nitrate excretion was significantly higher in
women compared with men after systemic administration of
L-[15N]2-arginine.
The main problem with the use of total urinary nitrate excretion as a
measure of NO synthesis is, however, that nitrate may arise from
sources other than that generated from the metabolism of
NO, and dietary intake of nitrate may exceed endogenous
production.7 The subjects received a
limited rather than a free nitrate diet before and after the
administration of the stable isotope; the purpose of using a limited
nitrate diet in this study was to reduce the body nitrate pool
background to achieve urinary nitrate enrichments in the range of 0.5
to 0.8 atom %, during the first 12 hours after the tracer
infusion. The measurement of urinary 15N nitrate
generated from
L-[15N]2-arginine
is independent of nitrate excretion from dietary sources and other
unknown sources. The possibility that the renal clearance of nitrate
may be lower in men than in women could explain this finding. However,
the analysis of the rate of urinary 15N
nitrate excretion was assessed over 36 hours (>90% of generated
nitrate was excreted), and the mean elimination constants of nitrate
were very similar in both groups, as was the creatinine
clearance. Therefore, differences in renal epithelial handling of
nitrate are unlikely to explain the difference in
15N nitrate excretion. It would also be of
interest to measure the concentration of 15N
nitrate in plasma to corroborate that the increased urinary
15N nitrate excretion in the female group was due
to higher production rather than altered renal excretion.
Although the isotope ratio mass spectrometer used in this study for the
determination of 15N nitrate enrichment has a
very high precision (eg, ±0.0004), it suffers from the disadvantage
that relatively large amounts of sample (55 µg nitrogen) are
required. Because the plasma nitrate concentration is
We also contemplated the possibility that a different body handling of
L-[15N]2-arginine
between genders could explain the sex difference in the urinary
excretion of 15N nitrate. For instance, a
difference in the size of L-arginine pools within the
peripheral circulation and tissues could alter the
enrichment of
L-[15N]2-arginine
where NO is synthesized and therefore account for the differences
observed. However, Beaumier et al19 and Castillo
and colleagues20 explored the effect of a high
L-arginine intake on the conversion of
L-[15N]2-arginine
to NO in humans by measuring 15N nitrate
and total nitrate excretion in urine. Although the plasma
L-arginine flux increased approximately 3-fold with
arginine supplementation, the arginine-supplemented diet did not alter
the total daily rate of conversion of plasma
L-[15N]2-arginine
to urinary 15N nitrate in the normal and
supplemented diets. Furthermore, at the dose of tracer used in our
study (1.13 µmol), it is unlikely that different
pharmacokinetics of the infused
L-[15N]2-arginine
in each group could be responsible for the observed findings. Indeed,
Van Haeften and colleagues21 have reported that
constant intravenous infusions of L-arginine at
a rate of 3, 9, and 15 mg/kg per minute during 30 minutes did not
modify the half-life and volume of distribution of
L-arginine in humans. Moreover, as the volume of
distribution of L-arginine is very similar to the
extracellular volume (290 mL/kg),21 we explored
the association between extracellular body water and urinary
15N nitrate excretion. Stepwise multiple
regression analysis showed no association between these
variables. However, whether the increased urinary
15N nitrate excretion observed in healthy women,
which these data suggest, is due primarily to a change in the level and
regulation of NO synthase and/or to changes in the
metabolism and tissue availability of
L-arginine cannot be determined from this study.
We also found in the present study an inverse relationship between
MAP and urinary 15N nitrate excretion throughout
the blood pressure range, a result consistent with
ours9 and other previous
findings22 23 that NO synthesis is reduced in
patients with essential hypertension. Because gender and blood pressure
were significantly correlated with urinary 15N
nitrate excretion, we examined the possibility that blood pressure
acted as a confounding variable. Furthermore, as the LDL
cholesterol concentration was slightly lower in women
compared with men, this may also have affected the results obtained.
However, multiple regression analysis showed that the
regression coefficient associated with gender was still significant
even when blood pressure and LDL concentration were taken into
account.
We detected a positive correlation between serum 17ß-estradiol and
the levels of urinary 15N nitrate excretion
during the follicular development in women, which agrees with previous
findings of an association between serum total nitrate and
17ß-estradiol levels.24 However, the
contribution of other sex hormones such as estrone,
follicle-stimulating hormone, luteinizing hormone, or other
endogenous substances involved in follicular development
may also modulate the conversion of
L-[15N]2-arginine
to 15N nitrate. Further studies are needed before
a direct cause-and-effect relationship between serum 17ß-estradiol
concentration and urinary 15N nitrate excretion
can be established.
Taken together, since subjects were of similar age, body mass index,
and levels of blood pressure, serum cholesterol, and
glucose, the most likely explanation of our findings is that the
production of 15N nitrate after the
intravenous administration
L-[15N]2-arginine
is higher in healthy women than in men. In line with this conclusion,
these results are in agreement with our previous findings in which the
total urinary 15N nitrate excretion was also
higher in hypertensive women than in men.9 In
addition, these findings are compatible with those of Chowienczyk et
al3 and Kharatinov and
colleagues.4 However, our results differ from
those of Jilma et al5 and Takahashi and
colleagues,6 who reported that the plasma levels
of nitrate were greater in men than in women. A confounding factor in
the interpretation of their findings could be the contribution of
nitrite and nitrate to the plasma pool from the diet. In another
report, Giovannoni and colleagues25 did not find
any significant difference in the mean serum nitrate and nitrite
between healthy men and women. However, it is worth highlighting that
plasma nitrate levels do not aid in elucidating the finer differences
in NO production, since the rate of nitrate synthesis and
elimination and its volume of distribution are all factors that modify
the plasma concentration. Moreover, because of its large volume of
distribution (extracellular fluid volume)17 and a
background plasma level of 30 µmol/L, it is possible that the
sample studied was of inadequate power to detect differences in the
activity of the constitutive NO synthase, which produces NO in the
nanomolar range.
In summary, the present data suggest that the most likely
explanation of this gender difference in urinary
15N nitrate excretion is that under ambulatory
conditions, whole-body NO biosynthesis is higher in healthy
premenopausal women than in men. However, in view of the limitations in
the interpretation of whole-body metabolic tracer studies,
further investigations aimed to assess the in vivo significance and
relationship between NO production and vascular function are
essential. It is possible that a difference in
endothelial NO production contributes to
differences in vascular function and predisposition to
arterial disease in men compared with women.
Received April 27, 1998;
first decision May 12, 1998;
accepted June 18, 1998.
© 1998 American Heart Association, Inc.
Scientific Contributions
Evidence for a Difference in Nitric Oxide Biosynthesis Between Healthy Women and Men
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—There is indirect
evidence for a gender difference in nitric oxide (NO) synthesis from
vascular endothelium. The aim of the present study
was to determine NO production more directly in healthy women
and men by the measurement of 15N nitrate excreted in urine
after the intravenous administration of
L-[15N]2-guanidino arginine.
Twenty-four healthy volunteers (13 men aged 22 to 40 years and 11 women
aged 23 to 42 years) participated in this study. No subjects were
receiving any medication. Women were studied between the 7th and 14th
days of their menstrual cycles. Arterial blood pressure was
measured oscillometrically, and 1.13 µmol
L-[15N]2 arginine was
administered intravenously after an overnight fast. Urine
was collected for the next 36 hours in separate 12-hour periods.
Urinary 15N/14N nitrate ratio was assessed by
dry combustion in an isotope ratio mass spectrometer. Mean 36-hour
urinary 15N nitrate excretion was greater in women than in
men (2111±139 versus 1682±87 
mol; P<0.05).
Furthermore, total urinary 15N nitrate excretion was
associated inversely with the mean arterial blood pressure
in the whole group of subjects (coefficient of correlation, 0.47;
P=0.022). The present data show that whole-body
production of NO is greater in healthy premenopausal women than
in men under ambulatory conditions. The cellular origin of NO measured
in this study is unknown, but differences in
endothelial production could underlie
differences in vascular function between men and women.
Key Words: endothelium-derived relaxing factor • arginine • nitrates • gender • adults
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Premenopausal women have less
atheromatous arterial disease, including
stroke or coronary artery disease, than men of similar
age.1 Synthesis of nitric oxide (NO) by the
endothelium regulates vascular tone in the
arterial bed and modulates interactions between the
endothelium and circulating blood cells, including
platelets and leukocytes.2 Previous studies
have suggested that a gender difference in the production of NO
due to ovarian hormones (ie, estrogens) could contribute to
this low risk of cardiovascular events in women of
reproductive age. However, the role of NO is controversial because
increased3 4 or
diminished5 6 production in women
compared with men has been reported. It is possible that the indirect
nature and relative specificity of the methods used for the measurement
of NO in those studies might account for these discrepancies.
Measurement of urinary or serum nitrate is highly affected by
diet.7 Cyclic GMP is also the second messenger of
atrial natriuretic peptide,8 and
exhaled NO reflects local biosynthesis in the lung and/or upper airways
rather than in the whole body. We have developed a sensitive and
specific method to measure more directly the conversion of
L-arginine to NO.9 The method is
based on the measurement of 15N nitrate (stable
oxidation product of NO) excretion in urine after
intravenous single administration of the stable isotope
L-[15N]2-guanidino
arginine. Using this methodology, we recently reported that the basal
production of NO, was significantly higher in women than in men
with essential hypertension. However, this difference was not
statistically significant in the normotensive group, perhaps because of
inadequate power.9 Therefore, the aim of this
study was to use this method to compare the activity of the
L-arginine–NO system in a larger population of healthy
women and men.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Study Protocol
The protocol was approved by the local ethics committee, and all
subjects gave their written informed consent. The study sample
consisted of 13 men (aged 22 to 40 years) and 11 premenopausal women
(aged 23 to 42 years) recruited from our staff. All participants were
healthy, normotensive, normocholesterolemic,
nondiabetic, receiving no medication, and nonsmoking. The women
reported regular menstrual cycles (26 to 32 days) for >6 months before
the study, and none of them was taking oral contraceptives. Women were
studied between the 7th and 14th days of their menstrual cycles. The
subjects' characteristics are summarized in Table 1
.
View this table:
[in a new window]
Table 1. Subjects' Baseline
Characteristics
L-[15N]2-guanidino
arginine (99 mol% 15N) and sodium
15N nitrate (99.3 mol%
15N) were obtained from Tracer Technologies Inc
and C/D/N Isotopes, respectively. IMAC HP555 was purchased from
Merck Laboratories. Sulfanilamide, glycine, sodium chloride, phosphoric
acid, Devarda's alloy, sodium hydroxide, and
N-(1-naphthyl)ethylenediamine were of analytical reagent
grade and were obtained from Sigma Chemical Co. Milli-Q+ water (mili
pore; >18 mol/L S purity) was used for the preparation of
aqueous solutions. Urine samples were stored at -80°C until
analyzed. Nitrogen isotope ratio enrichments were
analyzed using a continuous-flow gas isotope ratio mass
spectrometry (20-20, Europa Scientific).
Subjects received a limited nitrate diet (the diet excluded food
items that contain a high concentration of nitrate, ie, cured meat,
fruit, and particularly green leafy vegetables7 )
for 24 hours before and for 36 hours after the administration of
L-[15N]2-arginine.
The studies were conducted at 9 AM in a quiet,
air-conditioned room maintained at a constant temperature (22°C to
24°C), with subjects in a recumbent position and after an
overnight fast. Blood pressure was then measured 5 times using a
Dinamap (Critikon) automatic recorder, with 3-minute intervals of
rest between measurements. The values used in the study were the
averages of the last 3 readings. Thereafter, an 18-gauge catheter was
inserted into a left antecubital vein and 1.13 µmol sterile
pyrogen-free
L-[15N]2-arginine
dissolved in 20 mL of 0.153 mol/L sodium chloride was administered over
10 minutes by means of a constant-rate infusion pump (Braun Perfusor ED
2). Baseline urine samples (before administration of the isotope) were
collected to determine the natural enrichment of
15N nitrate. Complete urine collections were made
in prewashed (distilled water) 2-L polypropylene bottles containing 5
mL of 5 mol/L sodium hydroxide to prevent reduction of nitrate for the
periods 0 to 12, 12 to 24, and 24 to 36 hours after dosing. The
subjects did not exercise during the study period, but usual ambulatory
activity was permitted. The urine volume was measured, and samples from
each collection were frozen at -80°C until analysis.
Measurement of Total Nitrate
Total urinary nitrate was measured as previously
described.10 Briefly, nitrate was reduced to
nitrite with a copper/cadmium reduction column and subsequent Griess
reaction, modified by replacing carrier fluid with 0.2 mol/L glycine,
pH 9.4. The detection limit of this method is 1 µmol/L, and the
interday coefficient of variation over the measured concentration range
(20 to 1000 µmol/L) was <3%.
To determine 15N enrichment of nitrate in
urine, a modification of that procedure described by Brooks and
colleagues11 was followed.9
Briefly, urinary nitrate was extracted using a selective ion exchange
resin (IMAC HP555) and converted to ammonia using Devarda's alloy with
subsequent conversion to nitrogen gas by combustion at 1000°C and
analysis by continuous-flow gas isotope ratio mass
spectrometry. The precision of the ratio
15N/14N measurement of this
mass spectrometer is ±0.0004%. The linearity of the measurements was
demonstrated across the range of the expected enrichments (0.368 to 1
atom %) with a correlation coefficient of 0.999 by linear
regression analysis. The interday coefficient of variation
ranged from 0.40% to 0.75%.
Urinary nitrate excretion was calculated from the volume of
urine excreted and duplicate measurement of nitrate concentration. The
15N isotope enrichment of nitrate was calculated
according to Hauck and colleagues12 : atom %
15N=100/(2R+1), where R is the ratio of ions with
m/z 28 and 29. Urinary excretion of 15N nitrate
was determined by measuring the urinary nitrate excretion multiplied by
the measured atom percent excess of urinary 15N
nitrate. A 1-compartment pharmacokinetic model was used to
analyze the urine data obtained in this study. The
15N nitrate elimination rate was determined by a
single-pool kinetic equation.13 Extracellular
body water was estimated using the following formulas: 0.135xW+7.35
(males) and 0.135xW+5.27 (females), where W is body weight
(kilograms).14 All values are summarized as
mean±SE. Stepwise regression analysis was performed to
determine the relationship between the 36-hour urinary
15N nitrate excretion and gender, body mass
index, mean arterial blood pressure (MAP), total
cholesterol, HDL and LDL cholesterol, serum
glucose, triglyceride, and 17ß-estradiol levels.
Differences were sought using repeated-measures ANOVA of urinary
15N nitrate excretion for each 12-hour period. A
value of P<0.05 was considered significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Thirty-six-hour total urinary nitrate excretion was similar in the
female and male groups (2481±285 versus 2537±288 µmol,
respectively; P=NS). However, the mean 36-hour urinary
15N nitrate excretion was greater in women than
in men (2111±139 versus 1682±87 mol; P<0.05). These
values represent 0.172±0.012% and 0.140±0.008% of
15N nitrogen administered (P<0.05),
respectively, assuming that 1 labeled guanidino nitrogen per arginine
molecule is converted to nitrate. The difference in urinary
15N nitrate excretion was statistically
significant during the first 12 hours but not for the second and third
12-hour periods. The urinary excretion of 15N
nitrate in each 12-hour period after the administration of
L-[15N]2-arginine
is shown in Table 2. The
cumulative recovery of 15N nitrate in urine is
shown graphically in the Figure. LDL
cholesterol concentration was lower in women compared with
men, albeit not statistically significant. In addition, stepwise
regression analysis showed an inverse correlation between MAP
and 36-hour urinary 15N nitrate excretion
(coefficient of correlation, 0.47; P=0.022) in all subjects
studied. Multiple regression analysis showed that the
regression coefficient associated with gender was still significant
even when blood pressure and LDL cholesterol concentration
analyzed separately were taken into account (r=0.61,
P<0.001 and r=0.81, P<0.001,
respectively). In addition, stepwise multiple regression
analysis showed no association between extracellular body water
and 36-hour urinary 15N nitrate excretion
(r=0.08, P=NS). There was a positive correlation
between serum 17ß-estradiol levels and 36-hour total urinary
15N nitrate excretion (coefficient of
correlation, 0.66; P=0.038) in the female group. The mean
elimination rates of 15N nitrate in men and women
were similar (-0.084 hour-1 and -0.083
hour-1, respectively).
View this table:
[in a new window]
Table 2. Urinary Excretion of Total Nitrate and
15N Nitrate at Each 12-Hour Period After Intravenous Dose
of L-[15N]2-Arginine, Tabulated
by Gender
View larger version (18K):
[in a new window]
Figure 1. Cumulative urinary excretion of 15N nitrate after
the intravenous administration of
L-[15N]2-guanidino arginine in
men (solid symbols) and women (open symbols). Values are mean±SE for
13 men and 11 women.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The results of this study provide evidence that the whole-body
conversion of
L-[15N]2-arginine
to 15N nitrate is greater in healthy women than
in men, although the total urinary nitrate excretion does not differ
between groups. Furthermore, 36-hour urinary 15N
nitrate excretion is associated inversely with the MAP over the whole
group of subjects studied and positively with serum 17ß-estradiol
levels in the female group. 15N nitrate is
derived from oxidation of 15N NO produced from
L-[15N]2-arginine
by NO synthase. However, the enzyme isoform(s) and tissue(s) in which
this is occurring are unknown and cannot be addressed by measurement of
urinary nitrate excretion. 
30
µmol/L,17 the required plasma volume containing
this amount of nitrogen-nitrate would be approximately 130 mL, which
represents a limitation for ethical reasons and because of the
difficulty of handling such a large volume of sample. In such
instances, other spectrometric techniques such as gas
chromatography–mass spectrometry on selected ion
monitoring may be suitable. However, the precision of measurements with
this procedure is rarely better than 1%,18 and
this limitation precludes reliable measurements on plasma nitrate
enrichment in the range of 0.5 to 0.8 atom %.
Acknowledgments
This study was supported by the Joint Research Board at St
Bartholomew's Hospital (Project XMLH) and the British Heart
Foundation.
Footnotes
Presented as an oral presentation at the 5th International Meeting on Biology of Nitric Oxide, Kyoto, Japan, September 15–19, 1997; published in abstract form (Jpn J Pharmacol. 1997;75:16P).
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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