European Journal of Obstetrics & Gynecology

and Reproductive Biology 82 (1999) 201–207

Original article

Maternal serum nitric oxide levels associated with biochemical and clinical
parameters in hypertension in pregnancy
a, a b a
Jose L. Bartha *, Rafael Comino-Delgado , Francisco J. Bedoya , Manel Barahona ,
a a
Daniel Lubian , Fatima Garcia-Benasach
a
Department of Obstetrics and Gynecology, University Hospital of Puerto Real, Puerto Real, Carretera Nacional IV. KM 665.11510 Cadiz, Spain
b
Department of Biochemistry and Molecular Biology, University of Seville, Seville, Spain

Received 13 March 1998; accepted 22 September 1998

Abstract

Objectives: To measure maternal serum concentrations of total nitrites, as an index of nitric oxide synthesis, in normal and hypertensive
pregnant women, and to examine the correlation between these concentrations and several variables of clinical interest. Study design: A
total of 60 women in four different groups were studied: 10 normotensive pregnant women, 17 pregnant women with preeclampsia, 18
pregnant women with gestational hypertension and 15 pregnant women with chronic hypertension. Serum nitrite levels were determined
using the Griess reaction after reduction with nitrate reductase. Results: Serum nitrite levels were higher in preeclamptic women
(34.11614 mmol / l, P50.04), lower in chronic hypertensive women (19.5666.46 mmol / l, P50.04) and similar in women with
gestational hypertension (26.9769.44 mmol / l) in comparison to the control group (25.3767.24 mmol / l). Serum nitrite levels in
preeclamptic women had significant positive correlations with hematocrit, fasting insulinemia, and apolipoprotein B and negative
correlations with platelet count, serum phosphorus and glucose:insulin ratio. In pregnant women with chronic hypertension a negative
correlation was found between serum nitrite levels and active partial thromboplastin time. In pregnant women with gestational
hypertension, serum nitrite levels had negative correlations with birthweight and 24-h urine calcium, and positive correlations with mean
corspuscular hemoglobin, 24-h urine sodium and maternal age. Conclusions: We suggest that in women with preclampsia, a higher
maternal nitric oxide level may act as a compensatory mechanism against hemoconcentration and platelet aggregation and that nitric oxide
production may be related to some metabolic events. In women with gestational hypertension, higher serum nitrite levels may be related
to clinical and biochemical findings common in preeclampsia. In chronic hypertension, a lower maternal nitric oxide level is related to the
status of coagulation.  1999 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Nitric oxide; Preeclampsia; Hypertension; Pregnancy complications; Lymphocyte subpopulations; Perinatal outcome

1. Introduction vasoconstriction and a disturbance of platelet function and

Nitric oxide (NO) released by endothelial cells is a
potent vasodilator which contributes to the maintenance of
vascular tone and blood pressure regulation while inhib-
iting platelet aggregation and adhesion to the endothelium
[1,2].
Preeclampsia is associated with endothelial damage,
*Corresponding author. Tel.: 134 956 470276; fax: 134 956 830477;
e-mail: jbarthar@sego.es
0301-2115 / 99 / $ – see front matter  1999 Elsevier Science Ireland Ltd. All rights reserved.
PII: S0301-2115( 98 )00234-6
the hypothetical contribution of NO to the pathophysiology
of this disease, has been widely studied [3–10]. In animal
models, the inhibition of NO synthesis has been demon-
strated to produce signs similar to those found in pre-
eclampsia (i.e. sustained hypertension, proteinuria, throm-
bocytopenia and intrauterine growth retardation) [3,4].
In humans, several authors have reported low maternal
NO levels and the presence of an endogenous inhibitor of
NO synthesis in women with preeclampsia [5,6], but other
studies found diametrically opposed results. These studies
202 J.L. Bartha et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 82 (1999) 201 – 207
were primarily based on the in vitro evaluation of an
increase in nitrite production and NO synthase activity
after adding the serum of preeclamptic women to cultured
endothelial cells [7]. Furthermore, other authors found that
NO concentrations in fetoplacental circulation are in-
creased in preeclampsia [8,9]. Finally, some authors did
not find differences in NO levels between normal and
preeclamptic pregnant women [10].
Most of these studies are based on the desire to find a
definitive hypothesis to explain the pathophysiology of
preeclampsia. However, although it seems a disturbance in
maternal NO level is not the primary cause of the disease,
the relationships of this molecule to the important clinical
aspects of this pathology should be studied.
On the other hand, it has been demonstrated that
endothelium-dependent relaxation is decreased in the
setting of essential hypertension [11], but, at present, only
one study [12] has investigated maternal NO levels in
maternal chronic hypertension. Similarly, NO levels in
other kinds of hypertension in pregnancy, like gestational
hypertension, have not been well studied.
The present study has two objectives: firstly, to evaluate
the maternal serum NO level not only in preeclampsia, but
also in gestational hypertension and chronic hypertension
and secondly, to correlate the maternal serum NO level
with several clinical, hematological, biochemical and
immunological variables of clinical interest in these dis-
eases.
2. Materials and methods
Sixty women in four different groups were studied: 10
normotensive, 17 preeclamptic, 18 gestational hypertensive
and 15 chronic hypertensive pregnant women. Preeclam-
psia was defined as the development of blood pressure
$140 / 90 mm Hg after 20 weeks’ gestation occurring in
women with no prior history of hypertension or renal
disease whose blood pressure returned to normal within 3
months post-partum plus the presence of de novo
proteinuria .300 mg / day. Women with this kind of
hypertension who did not have proteinuria were catalogued
as having gestational hypertension. Women who were
hypertensive before 20 weeks’ gestation were considered
to have chronic hypertension.
Gestational age at the time of blood sampling did not
differ significantly: 34.5662.36 weeks’ gestation in the
normotensive pregnant group, 35.0663.24 in the pree-
clamptic group, 36.1162.92 in the gestational hyperten-
sion group and 29.3364.84 in the chronic hypertension
group.
The percentage of nulliparous in each group did not
differ significantly, 50% (5 / 10) in the normotensive group,
58.82% (10 / 17) in the preeclamptic group, 55.56% (10 /
18) in the gestational hypertensive group and 40% (6 / 15)
in the chronic hypertensive group.
Blood pressure, umbilical Doppler ultrasound using S / D
ratio, gestational age at birth, birthweight, mode of deliv-
ery, Apgar’s score and newborn gender were recorded.
Blood was collected from subjects at room temperature
into 10-ml silicone-coated Vacutainer blood collecting
tubes containing no additives. Blood was allowed to clot at
room temperature and was centrifuged for 20 min at 2000
g. Aliquots of the serum were then stored at 2808C until
they were required for the assay.
Serum nitrite levels were determined using the Griess
reaction. Because NO is spontaneously oxidized into both
nitrite and nitrate, the samples were analyzed after reduc-
tion with nitrate reductase as follows: 200 ml of serum was
incubated in a final volume of 998 ml containing 0.5 U of
nitrate reductase (50 ml) (Boehringer Mannheim), 5 mmol /
l flavin adenosine dinucleotide (50 ml), 56 mmol / l potas-
sium phosphate, pH 7.5 (400 ml), 50 mmol / l reduced
nicotinamide adenine dinucleotide phosphate (8 ml), 290
ml of water for 2 h at 378C. Excess reduced nicotinamide
adenine dinucleotide phosphate, which interferes with the
chemical detection of nitrite, was oxidized by continuation
of the incubation for a further 30 min at 378C after
addition of 5 mg (1 ml) of lactate dehydrogenase, 0.2
mmol / l (120 ml) pyruvate and 79 ml of water. Nitrite was
determined with the Griess reagent by mixing equal
volumes of the reduced samples with the Griess reagent:
0.1% a-naphtylamine in water–1% p-aminobenzene sul-
famide in 5% phosphoric acid (1:1, v / v). The samples
were allowed to stand for 15 min in the dark and then read
in a spectrophotometer at an absorbance of 550 nm. A
range of sodium nitrite standards was prepared, and a
standard curve was used to convert sample measurements
to micromoles per liter of nitrite [9].
Red blood cell count (RBC), hemoglobin, hematocrit,
mean corpuscular volume, mean corpuscular hemoglobin,
mean corpuscular hemoglobin concentration, leukocytes
and platelet count, and mean platelet volume, were mea-
sured by standard automated techniques (Coulter).
In maternal serum, total proteins, urea, creatinine, uric
acid, sodium, potassium, calcium, phosphorus, magnesium,
SGOT, SGPT, LDH, glucose, insulin, cholesterol, tri-
glyceride, HDL cholesterol, LDL cholesterol, apolipopro-
tein A, apolipoprotein B and iron were calculated using
colorimetric assay with autoanalyzer Hitachi 917. Sodium,
potassium, calcium and proteins in 24-h urine were
calculated by the same method.
Transferrin was measured by immunoturbidimetric
assay. Albumin was calculated by using the Behring
nephelometer analyzer II. Ferritin was measured by en-
zyme-immunoassay (Boehringer Mannheim) [13].
Blood for study of coagulation was collected into tubes
containing sodium citrate. Fibrinogen, activated partial
thromboplastin time (APTT) and prothrombin time were
calculated using automated standardized methods.
Peripheral blood lymphocytes were studied in all
women. Venous blood was collected by venipuncture
 J.L. Bartha et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 82 (1999) 201 – 207
between 7.00 and 9.00 in the morning in fasting state.
These cells were labelled using murine monoclonal anti-
bodies specific for different cell surface antigens conju-
gated with fluorescein isothiocyanate (FITC) and phyco-
erythrin (RDI) (Cyto-Stat / Coulter Clone T4-RDI / T8-
FITC and Cyto-Stat / Coulter Clone CD3 (IgG1)-FITC / B4-
RDI)). Cell count was performed by flow cytometry
(EPICS system). The results were recorded both in per-
centages and absolute numbers of stained cells. The
labellin procedures were performed on ice. Total T and B
lymphocytes and CD4 (recognize helper / inducer T cells),
CD8 (recognize suppresser / cytotoxic T cells) and CD4 /
CD8 ratio were analyzed [14].
Comparisons between groups were done using the
unpaired the Student’s t test. The Pearson’s correlation
coefficient and linear regression were used to evaluate the
relation between maternal NO levels and all of the studied
variables. However, when a variable was not normally
distributed, Spearman’s rank correlation was used. Signifi-
cant level was set at 95% (P,0.05).
3. Results
As shown in Table 1, preeclamptic women had a
significantly higher maternal serum nitrite concentration
(34.11614.36 vs. 25.3767.24 mmol / l, P50.04) while
women with chronic hypertension had a significantly lower
nitrite concentration than the control group (19.5666.46
vs. 25.3767.24 mmol / l, P50.04). Women with gestational
hypertension had a similar nitrite level to the control group
(26.9769.44 mmol / l).
Overall, we found significant positive correlations be-
tween serum nitrite levels and hematocrit (r50.29, P5
0.02) and mean corpuscular volume (r50.26, P50.04).
These correlations were greater in women with preeclam-
psia (r50.48 and r50.44 respectively) (Table 2). In
gestational hypertension, an important negative correlation
was found between serum nitrite levels and mean cor-
puscular hemoglobin (r50.48, P50.04). In contrast, the
trend in normotensive women was toward a negative
correlation, even though this relationship was not signifi-
cant for hematocrit (r520.42) and for mean corpuscular
volume (r520.39) while maintaining its significance for
mean corpuscular hemoglobin (r520.66, P50.03).
Lecucocytes were not correlated to nitrites in any of the
studied groups. Platelet count had a significant negative
Table 1
Maternal serum nitrite concentration (mmol / l) in the studied groups
Group n Mean S.D.
Control 10 25.37 7.24
Preeclampsia 17 34.11 14.36
Gestational hypertension 18 26.97 9.44
Chronic hypertension 15 19.56 6.46
*Comparison with control group; NS5not significant.
203
correlation with nitrite level in cases of preeclampsia
(r520.52, P50.02) and this trend was maintained in
cases of gestational hypertension even though it was of
borderline statistical significance (r520.43, P50.07). No
significant correlations were found between lymphocyte
subpopulations and nitrite levels in any of the studied
groups.
Coagulation was not related to serum nitrites level
except in chronic hypertension where a negative correla-
tion was found between nitrites and active partial throm-
boplastine time (r520.66, P50.03) (Table 2).
Overall, positive correlations were found between pa-
rameters of renal function (urea and creatinine) and
maternal serum nitrite levels (r50.32, P50.03, and r5
0.26, P50.04 respectively). Uric acid had one of the
highest correlations with maternal serum nitrite levels
(r50.37, P50.003).
In gestational hypertension serum nitrite levels had a
significant negative correlation with 24-h urine calcium
(r520.49, P50.03) and a positive one with 24-h urine
sodium (r50.47, P50.03).
Serum phosphorus levels had significant negative corre-
lations with nitrite levels in preeclampsia (r520.48, P5
0.04). No significant correlations were found between
serum nitrite levels and serum sodium, potassium, calcium
or magnesium level. Neither SGOT nor SGPT nor LDH
had significant correlations with maternal nitrite levels.
In pregnant women with preeclampsia, serum nitrite
levels had significant positive correlations with insulinemia
(r50.59, P50.01) and negative one with glucose:insulin
ratio (r520.60, P50.01) (Table 2).
There was a significant positive correlation between
apolipoprotein B and serum nitrite levels in the preeclamp-
tic group (r50.48, P50.04). No correlations were found
between serum nitrite levels and other lipid parameter.
Overall, gestational age at birth and neonatal birth
weight were negatively correlated to serum nitrite levels
(r520.31 for both, P50.01). The correlation with birth
weight was higher in cases of gestational hypertension
(r520.50, P50.03). There was a significant positive
correlation between maternal age and serum nitrite levels
in these cases (r50.53, P50.02).
Multiparous chronic hypertensive women had lower
nitrite levels than nulliparous ones (Table 3). There were
no differences in maternal serum nitrite levels depending
on mode of delivery and Apgar score (Table 3). Surpris-
ingly, mothers bearing male fetuses tended to have higher
nitrite levels, even though this difference was of borderline
statistical significance (P50.06 in total and P50.05 in
preeclampsia) (Table 3).
P*
0.04 4. Comment and conclusions
NS
0.04 We found a significantly higher maternal NO level in
women with preeclampsia and a significantly lower one in
204 J.L. Bartha et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 82 (1999) 201 – 207

Table 2
Significant correlations between hematological, immunological, biochemical and clinical parameters and maternal serum nitrite level
Total (n560) Control (n510) Pre (n518) GH (n518) CH (n515)
r P r P r P r P r P
HTO 0.29 0.02 0.48 0.04
VCM 0.26 0.04
MCH 20.66 0.03 0.48 0.04
Platelets 20.52 0.02
APTT 20.66 0.03
Urea 0.27 0.03
Creatinine 0.26 0.04
Uric acid 0.37 0.003
Na24 0.47 0.04
Ca24 20.49 0.03
P 20.48 0.04
Insulin 0.59 0.01
G/i 20.60 0.01
ApB 0.48 0.04
Age 0.53 0.02
Gest. a.b. 20.31 0.01
Birthweight 20.31 0.01 20.50 0.03
Abbrevitions: Pre, preeclampsia; GH, gestational hypertension; CH, chronic hypertension; HTO, hematocrit; MCV, mean corpuscular volume; MCH, mean
corpuscular hemoglobin; APTT, active partial thromboplastin time; Na24, Ca24, sodium and calcium in 24-h urine, g / i, glucose / insulin ratio; ApB,
apolipoprotein B; gest.a.b., gestational age at birth.

those with chronic hypertension in comparison to nor-
motensive pregnant women.
In support of our results, Nobunaga et al. [12] found that
women with preeclampsia who were at or near term, had
higher plasma total nitrites than normal pregnant women.
Other authors [15,16] have found evidence of endothelial
activation associated with an increased NO production. NO
modulates both vascular tone and vascular smooth muscle
reactivity, by activating soluble guanylate cyclase [17].
The relaxation response to NO is directly proportional to
the concentration of cGMP [18]. In additional support of
our results, Schneider et al. [19] found that the level of
plasma cGMP was higher in women with preeclampsia
compared with normal pregnant women. Together with
these studies, our research suggests that preeclampsia is
not primarily due to a decrease in NO production. Rather,
there may even be a compensatory increase in NO
synthesis, which probably works to counteract the vas-
oconstriction and the higher platelet aggregation that
characterise this disease. Admittedly, a chronic activation
of endothelial NO synthesis could lead to endothelial
damage as a secondary consequence.
Only one author [12] studied maternal serum NO level
in women with essential hypertension in pregnancy. As in

Table 3
Clinical parameters and maternal serum nitric oxide level: parity, mode of delivery, Apgar’s score and newborn gender
Parity Mode of delivery
0 .0 Cesarean section Vaginal
n Mean S.D. P n Mean S.D. n Mean S.D. P n Mean S.D.
Total 31 27.9 12.2 NS 29 25.4 11.2 26 26.7 11.3 NS 34 26.4 12.1
Controls 5 25.7 5.7 NS 5 25.0 9.2 5 25.8 7.8 NS 5 24.9 7.4
Pre 10 34.3 17.1 NS 7 32.3 12.7 8 34.6 12.1 NS 9 32.5 18.4
GH 10 24.0 9.4 NS 8 30.6 8.6 7 23.4 10.9 NS 11 29.2 8.0
CH 6 25.5 5.4 0.01 9 15.6 5.9 6 20.9 9.4 NS 9 18.6 6.2
Apgar’s score 59 Newborn gender
#7 $8 Female Male
Total 7 30.3 16.5 NS 53 26.2 11.0 37 23.9 10.2 0.06 23 31.1 12.7
Controls 0 10 5 21.2 4.4 0.06 5 29.5 7.4
Pre 3 41.6 15.5 NS 14 31.7 15.3 9 27.2 14.7 0.05 8 40.6 13.4
GH 2 16 11 28.1 8.4 ns 7 25.1 11.2
CH 2 13 12 18.7 7.4 ns 3 22.8 8.2
Abbreviations: ns, not significant; Pre, preeclamptic women; GH, gestational hypertension; CH, chronic hypertension.
In cases of controls, GH and CH, Student’s t test is impossible for Apgar score 59 due to a low number of cases in the #7 group.
 J.L. Bartha et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 82 (1999) 201 – 207
this study, significantly lower plasma concentrations were
found in women with essential chronic hypertension. This
might be related to the recognised failure of intravascular
volume expansion, associated with chronic hypertension.
In our study, a low nitrite level in these women is
associated with a higher coagulation state. Phenomena
such as intrauterine growth retardation and superimposed
preeclampsia may be dependent on this factor, but further
studies are needed to clarify the role of NO in complica-
tions of chronic hypertension during pregnancy.
NO contributes to maternal systemic vasodilatation and
reduced vascular reactivity during pregnancy. Moreover,
NO inhibits platelet activation and aggregation while NO
donors reduce platelet activation in preeclampsia [20]. We
have found a positive correlation between plasma nitrite
level and hematocrit and a negative relationship between
NO level and platelet count in women with preeclampsia.
Hemoconcentration, platelet activation and aggregation are
typical signs of preeclampsia. Therefore, it could be
suggested that an increase in NO synthesis may work as a
compensatory mechanism against these effects.
It is known that NO is involved in the mechanisms of
inflammation and immune response and that an altered
immunological mechanism has been described in the
pathogenesis of preeclampsia [21]. We found no correla-
tion between lymphocyte subsets and maternal serum NO
levels. Further studies, involving other aspects of the
inflammatory process, are needed to clarify if there is some
relationship between NO production and the immunologi-
cal changes described in preeclampsia. Overall, we found a
positive correlation between the parameters measuring
renal function and maternal serum NO level. It is logical to
assume that if renal function is altered, lower nitrites
excretion and higher serum levels may result. Begum et al.
[22] found a significant positive correlation between
creatinine clearance and urinary excretion of NO (nitrate /
nitrite) and negative relationship with blood pressure and
serum uric acid. Roberts et al. [23] hypothesised that
plasma nitrites in preeclampsia may act as an indicator not
only of NO production, but also of reduced renal clear-
ance. Davidge et al. found no differences in nitrate and
nitrite plasma concentrations between women with pre-
eclampsia and women with normal pregnancies. In women
with preeclampsia, plasma creatinine levels were elevated
indicating a reduced glomerular filtration rate while urine
concentrations of nitrate and nitrite were lower [24]. Thus,
one can see that with decreased renal function there are
higher urea, creatinine and NO levels.
In gestational hypertension, 24-h urine calcium is nega-
tively correlated with maternal serum NO level. It is
known that hypocalciuria is common in preeclamptic
women. We suspect that some pregnant women who are
diagnosed with gestational hypertension because they do
not present with proteinuria could actually have mild forms
of preeclampsia since other clinical and biochemical
characteristics of this disease are presented. In view of our
205
results, women with gestational hypertension and lower
calcium excretion tend to have higher nitrite levels, which
we found to be present in preeclampsia, and perhaps, these
women should be more strictly monitored. In the pree-
clamptic group, the negative correlation between 24-h
urine calcium and serum nitrite level was not statistically
significant (r520.21) but this could be explained by the
fact that in this group, almost all the women had severe
hypocalciuria and perhaps, within this extreme range, the
correlational level does not reach statistical significance.
Begum et al. [22] found a significant correlation be-
tween urinary NO metabolites (nitrate and nitrite) and
maternal serum triglycerides. In another study [25], a
positive correlation between urinary excretion of NO
metabolites and plasma HDL-cholesterol was found. The
importance of lipids and lipoproteins in NO production in
preeclampsia has been demonstrated [26]. Several studies
[8,12,26] support the hypothesis that the pathogenesis of
preeclampsia may be due to uncharacterised circulating
factors that not only do not inhibit but also activate the
production of NO by endothelial cells. In this way, several
authors [8,26] have provided evidence of in vitro activa-
tion of endothelial cells by plasma of preeclamptic women.
Davidge et al. [26] performing fractionation of plasma,
have determined that the factor (or factors) stimulating NO
generation was extractable by charcoal and present in lipid
extracts and lipoprotein isolates, with a molecular mass
greater that 1.5 million, which is characteristic of a
lipoprotein or lipoprotein aggregate. In preeclamptic
women, we found a positive correlation between maternal
serum nitrite level and apolipoprotein B. Moreover, in
these women, there is a positive correlation with in-
sulinemia and negative correlation with insulin sensitivity
measured by glucose:insulin ratio. Insulin has a significant
role in lipid metabolism and we have suggested that
hyperinsulinemia in a fasting state could be related to the
pathogenesis of this disease [27].
NO synthase activity in the uterus decreases at the end
of gestation while exogenous NO relaxes the myometrium,
but whether NO contributes to uterine quiescence during
pregnancy has yet to be confirmed [28]. However, in our
study, there was a negative correlation between maternal
oxide level and gestational age at birth which is probably
due to the fact that higher levels were found in preeclamp-
tic women, who delivered earlier. Also it has been
described that the local application of a NO donor induces
cervical ripening in pregnant guinea-pigs, but still con-
tradictions exist in the role of NO on uterine quiescence
[29].
There was a significant negative correlation between
maternal nitrite level and newborn weight. This is logical
when taking into account that lowest birthweights were
found in women with preeclampsia, who had highest NO
levels. However, the maintenance of this relationship in
women with gestational hypertension is very interesting.
Once again, a gestational hypertensive woman with higher
206 J.L. Bartha et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 82 (1999) 201 – 207
nitrite level shows a clinical pattern similar to preeclam-
psia tending to have babies with lower birthweights.
Umbilical vascular endothelium produces NO which
contributes to a low fetoplacental vascular resistance. In
our study, we did not find a relationship between umbilical
resistance measured by Doppler and maternal serum NO
level. However, we recognise that this relation would need
to be better investigated using fetal serum NO levels rather
than the maternal ones. Lees et al. [20] found that the
infusion of the NO donor, S-nitrosoglutathione, reduced
uterine artery resistance but umbilical and fetal Doppler
indices, in this study, showed no significant changes.
Therefore, maternal serum NO levels do not appear to be
related to umbilical resistance.
In multiparous women with chronic hypertension, ma-
ternal serum NO levels were lower than those in nullipar-
ous. We hypothesized the cardiovascular loads of several
previous pregnancies may affect the cardiovascular system
and produce increased endothelial damage and a lower
production of NO.
In conclusion: firstly, serum nitrite levels were higher in
preeclamptic women, lower in chronic hypertensive
women and similar in women with gestational hyperten-
sion in comparison to the control group. These results
agree with those of authors who presume that preeclamptic
women have primarily an endothelial hyperactivation that
may or may not be associated with endothelial damage.
Secondly, maternal serum NO levels had significant corre-
lation to variables of clinical interest. After the analysis of
these correlations, we suggest that in women with pre-
clampsia, a higher maternal NO level may act as a
compensatory mechanism against hemoconcentration and
platelet aggregation and that NO production may be related
to some carbohydrate and lipid metabolic parameters. In
women with gestational hypertension, higher serum nitrite
levels may be related to clinical and biochemical findings
common in preeclampsia (i.e.: hypocalciuria and low
birthweight). In chronic hypertension, a lower maternal
NO level is related to the status of coagulation.
5. Condensation
Maternal serum nitrite levels were higher in preeclamp-
tic women and lower in chronic hypertensive pregnant
women in comparison to normotensive pregnant women.
Maternal NO level seems to have an important link to
variables of clinical interest.
References
[1] Knowles RG, Moncada S. Nitric oxide synthesis in mammals.
Biochem J 1994;298:249–58.
[2] Radomski MW, Palmer RMJ, Moncada S. Endogenous nitric oxide
inhibits human platelet adhesion to vascular endothelium. Lancet
1987;2:1057–8.
[3] Yallampalli C, Garfield RE. Inhibition of nitric oxide synthesis in
rats during pregnancy produces signs similar to those of pre-
eclampsia. Am J Obstet Gynecol 1993;169:1316–20.
[4] Molnar M, Suto T, Toth T, Hertelendy F. Prolonged blockade of
nitric oxide synthesis in gravid rats produces sustained hypertension,
proteinuria, thrombocytopenia and intrauterine growth retardation.
Am J Obstet Gynecol 1994;170(5):1458–66.
[5] Seligman SP, Buyon JP, Clancy RM, Young BK, Abramson SB. The
role of nitric oxide in the pathogenesis of preeclampsia. Am J Obstet
Gynecol 1994;171:944–8.
[6] Fickling SA, Williams D, Vallance P, Nursey SS, Whitley GS.
Plasma concentrations of endogenous inhibitor of nitric oxide
synthesis in normal pregnancy and pre-eclampsia. Lancet
1993;342:242–3.
[7] Baker PN, Davidge ST, Roberts JM. Plasma from women with
preeclampsia increases endothelial cell nitric oxide production.
Hypertension 1995;26:244–8.
[8] Davidge ST, Baker PN, Roberts JM. NOS expression is increased in
endothelial cells exposed to plasma from women with preeclampsia.
Am J Physiol 1995;269:1106–12.
[9] Lyall F, Young A, Greer IA. Nitric oxide concentrations are
increased in fetoplacental circulation in preeclampsia. Am J Obstet
Gynecol 1995;173(3):714–8.
[10] Silver RK, Kupferminc MJ, Russell TL, Adler L, Mullen TA,
Caplan MS. Evaluation of nitric oxide as a mediator of severe
preeclampsia. Am J Obstet Gynecol 1996;175(4):1013–7.
[11] Panza JA, Wuyyumi AA, Brush Jr. JE, Epstein SE. Abnormal
endothelium-dependent vascular relaxation in patients with essential
hypertension. New Engl J Med 1990;323:22–7.
[12] Nobunaga T, Tokugawa Y, Hashimoto K, et al. Plasma nitric oxide
levels in pregnant patients with preeclampsia and essential hyperten-
sion. Gynecol Obstet Invest 1996;41:189–93.
[13] Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Seppanen R,
Salonen R. High stored iron levels are associated with excess risk of
myocardial infarction in eastern Finnish men. Circulation
1992;86:803–11.
[14] Matthiesen L, Berg G, Ernerudh J, Skogh T. Lymphocytes subsets
and autoantibodies in pregnancies complicated by placental dis-
orders. Am J Reprod Immunol 1995;33:31–9.
[15] Myatt L, Rosenfield RB, Eis AL, Brockman DE, Greer I, Lyall F.
Nitrotyrosine residues in placenta. Evidence of peroxynitrite forma-
tion and action. Hypertension 1996;28:488–93.
[16] Davidge ST, Signorella AP, Lykins DL, Gilmour CH, Roberts JM.
Evidence of endothelial activation and endothelial activators in cord
blood of infants of preeclamptic women. Am J Obstet Gynecol
1996;175:1301–6.
[17] Rappaport RM, Drazmin MB, Murad F. Endothelium-dependent
relaxation in rat aorta may be mediated through cyclic GMP-
dependent pretein phosphorylation. Nature 1983;306:174–6.
[18] Ignarro LJ, Kadowitz PJ. The pharmacological and physiological
role of cyclic GMP in vascular smooth muscle relaxation. Ann Rev
Pharmacol Toxicol 1985;25:171–91.
[19] Schneider F, Lutin P, Baldauf JJ, et al. Plasma cyclic GMP
concentration and their relationship with changes of blood pressure
levels in preeclampsia. Acta Obstet Gynecol Scand 1996;75:40–4.
[20] Lees C, Langford E, Brown AS, de Belder A, Pickles A, Martin JF,
Campbell S. The effect of S-nitrosoglutathione on platelet activa-
tion, hypertension, and uterine and fetal Doppler in severe pre-
eclampsia. Obstet Gynecol 1996;88:14–9.
[21] Sibai BM. Immunologic aspects of preeclampsia. Clin Obstet
Gynecol 1991;34:27–34.
[22] Begum S, Yamasaki M, Mochizuki M. Urinary levels of nitric oxide
metabolites in normal pregnancy and preeclampsia. J Obstet
Gynaecol Res 1996;22:551–9.
[23] Roberts JM. Plasma nitrites as an indicator of nitric oxide pro-
 J.L. Bartha et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 82 (1999) 201 – 207
duction: unchanged production or reduced renal clearance in pre-
eclampsia?. Am J Obstet Gynecol 1997;176:954–5.
[24] Davidge ST, Stranko CP, Roberts JM. Urine but not plasma nitric
oxide metabolites are decreased in women with preeclampsia. Am J
Obstet Gynecol 1996;174:1008–13.
[25] Begum S, Yamasaki M, Mochizuki M. The role of nitric oxide
metabolites during pregnancy. Kobe J Med Sci 1996;42:131–41.
[26] Davidge ST, Signorella AP, Hubel CA, Lykins DL, Roberts JM.
Distinct factors in plasma of preeclamptic women increase endo-
thelial nitric oxide or prostacyclin. Hypertension 1996;28:758–64.
207
[27] Bartha JL, Comino-Delgado R. Carbohydrate metabolism. Evalua-
tion in women with de novo hypertension in late pregnancy. J
Reprod Med 1997;42:489–96.
[28] Sladek SM, Magness RR, Conrad KP. Nitric oxide and pregnancy.
Am J Physiol 1997;272(2):R441–3.
[29] Chwalisz K, Shao-Qing S, Garfield RE, Beier HM. Cervical
ripening in guinea-pigs after a local application of nitric oxide. Hum
Reprod 1997;12:2093–101.