Vol.2, No.8, 897-905 (2010)
doi:10.4236/health.2010.28133
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
HEALTH
Sex differences in cardiovascular control by nitric
oxide in normotensive and hypertensive rats
Oxana Semyachkina-Glushkovskaya*, Tatyana Anishchenko, Sergey Kapralov,
Roman Novikov, Konstantin Skvorcov, Yana Kuznecova, Antonina Kuznecova
Saratov State University, Saratov, Russia; *Corresponding Author:
Received 21 November 2009; revised 7 January 2010; accepted 9 January 2010.
ABSTRACT
R Nitric oxide probably plays an important role
in mechanisms determining sexual dimorphism
in the development of cardiovascular diseases,
including hypertension. Because stress together
with gender are significant cardiovascular risk
factors, we studied the role nitric oxide in car-
diovascular regulation in male and female nor-
motensive and hypertensive rats under normal
and stress conditions. Experiments were per-
formed in mongrel normotensive and hyperten-
sive (two kidney, one clip) rats of both sexes,
weighing 200-250g. The study of mean arterial
pressure and heart rate was carried out: 1) under
control condition; 2) during nitric oxide blo- ckade
by NG-nitro-L-arginine-methyl ester (L-NAME, 10
mg/kg, iv) 3) during 60 min immobilization
stress and recovery; 4) during 60 min immobi-
lization stress + L-NAME and recovery. We
found that the severity of hypertension in fe-
males was lower than in males. We also ob-
served that both normotensive and hyperten-
sive females demonstrated more favorable pat-
tern of cardiovascular responses to stress. At
rest, nitric oxide blockade increased the mean
arterial pressure and decreased the heart rate
more effectively in female normotensive and
hypertensive rats than in male groups. During
stress, nitric oxide blockade modified the stress-
induced cardiovascular responses more sig-
nificantly in female normotensive and hyper-
tensive rats compared with male groups. Our
data show that both normotensive and hyper-
tensive females demonstrated the more effec-
tive nitric oxide control of cardiovascular activ-
ity under normal and especially stress condi-
tions than male groups. This male-female dif-
ference may be important mechanism respon-
sible for greater in females vs. males of cardio-
vascular resistance to stress and development
of hypertension.
Keywords: Nitric Oxide; Stress; Cardiovascular
Stress-Reactivity; Sex-Differences
1. INTRODUCTION
The clinical and experimental studies show that nitric
oxide (NO) plays an important role in regulation of the
cardiovascular homeostasis. So, NO inhibits platelet
aggregation and adhesion [1], prevents neointimal plaque
progression [2], NO is also involved in the baroreflex
mechanism [3]; increases cholinergic [4] but inhibits
sympathetic influences on the heart [5]. NO deficiency
contributes to the pathogenesis of different cardiovascu-
lar diseases including hypertension [6,7] and NO donors
used in cardiovascular therapeutics [8].
It is known that incidence of cardiovascular diseases
such as hypertension is significantly lower in women of
reproductive age compared with age-matched men. Al-
though the mechanisms underlying this “cardioprotec-
tion” of females are not fully elucidated, the enhanced
vascular production of NO has been shown to have a
potential role in both humans and rats. In women, whole
body NO production and NO-dependent vasodilatation is
greater than in men [9,10]. In vitro experiments have
demonstrated that the aorta, as well as coronary, cerebral
and skeletal muscle arteries from female rats appear to
produce a greater amount of NO compared with those
from males [11-14].
In our studies we observed that female compared with
male rats demonstrate higher basal and stressed levels of
NO [15] that is associated with more favorable pattern of
cardiovascular responses to stress in females vs. males
[16]. This fact may be due to cardioprotective role of
NO during stress. Indeed in some investigations it has
been reported that NO possesses stress-limiting activity
[17] and produces a regional vasodilatatory effect [18].

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Thus, an enhanced function of the NO system in fe-
males may contribute to a lower incidence of vascular
disease. Despite the well-documented gender-differences
in the development and severity of hypertension in hu-
mans and in animal models, as well as the increasing
evidence supporting the cardioprotective role of NO
during stress and cardiovascular pathology, the gender
particularities in activity of the NO-ergic system during
cardiovascular dysfunction and stress remain little stud-
ied.
2. METHODS
2.1. Animals
Experiments were performed in mongrel normotensive
(NT) and hypertensive (HT) rats of both sexes, weighing
200 to 250 g. All procedures were performed in accor-
dance with the Guide for the Care and Use of Laboratory
Animals published by the US National Institutes of
Health (NIH Publication No. 85-23, revised 1996).
2.2. Surgical Preparation
To induce two kidney, one clip (2K1C) hypertension rats
were clipped at the left renal artery with a silver clip
having an inner gap of 0.25 mm under anesthesia with
ketamine (40 mg/kg, ip). Seven weeks after clipping
hypertensive rats were used in all sets of experiment.
The day before the experiment, both NT and HT rats
were instrumented with polyethylene catheters for
monitoring mean arterial pressure (MAP) and heart rate
(HR). For implantation of catheters, rats were anesthe-
tized with ketamine (40 mg/kg, ip) supplemented with
xylazine (5 mg/kg, ip). Polyethylene catheter (PE-50
with a PE-10 tip, Scientific Commodities INC., Lake
Havasu City, Arizona) was inserted into the left common
carotid artery. In addition, the left femoral vein was
catheterized with PE-50 tubing fused PE-10 for drug
infusion.
2.3. Experimental Procedure
HR and MAP were recorded in the home cages of con-
scious, unrestrained rats. Blood pressure signals were
acquired on PowerLab system (ADInstruments, Austra-
lia) using pressure transducer. The control group in-
cluded intact, but not sham-operated animals since we
found that the basal and stressed values of MAP and HR
didn’t differ significantly between sham-clipped rats and
NT (nonclipped) group or between sexes within each
group and also the blood corticosterone level returned to
normal 1 day after surgery (laparotomy) [19].
Protocol 1: Influences of immobilization stress (IS)
on cardiovascular activity in NT and HT male and
female rats. After base-line measurement, HR and MAP
were recorded continuously during 60 min immobiliza-
tion and 60-min recovery. This protocol was adminis-
tered to a group of NT male (n = 10), female (n = 10)
and to a group of HT male (n = 10), female (n = 10) rats.
Protocol 2: Effect of NO synthesis inhibition on
MAP and HR in NT and HT rats of both sexes at rest.
After base-line measurement, changes in hemodynamic
responses to inhibition of NO synthesis were evaluated
by intravenous administration of NG-nitro-L-arginine
methyl ester (L-NAME, Sigma Chemical Co, 10 mg/kg,
iv). HR and MAP were recorded continuously during
120 min after L-NAME injection. This protocol was
administered to a group of NT male (n = 12), female (n
= 15) and to a group of HT male (n = 12), female (n = 12)
rats.
Protocol 3: Effect of NO synthesis inhibition on
MAP and HR in NT and HT rats of both sexes under
IS condition. After base-line measurement, male and
female rats of both groups were treated L-NAME. Then
rats were subjected to 60-min immobilization. HR and
MAP were recorded continuously during 60 min IS and
60-min recovery. This protocol was administered to a
group of normotensive male (n = 10), female (n = 10)
and to a group of hypertensive male (n = 10), female (n
= 10) rats.
After performance of all experiments the animals
were killed with an intravenous overdose of ketamine
(150 mg/kg). The kidneys were then removed and
weighed.
Results were reported as mean ± standard error of the
mean (SEM). The changes in MAP and HR were ex-
pressed as percentage changes from control values. The
differences from the initial level in the same group were
evaluated by Wilcoxon test. Inter-group differences were
evaluated using Mann-Whitney test and ANOVA-2 (post
hoc analysis with Duncan’s rank test). Significance lev-
els were set at p < 0.05 for all analyses.
3. RESULTS
The development of renovascular hypertension (two-
kidney, one clip, 2K1C) observed 7 weeks after clipping
of left renal artery became more severe in males vs. fe-
males. So, in all sets of experiment the baseline MAP
values were significantly higher in HT males relative to
HT females (Table 1). Furthermore, the weight of
clipped kidneys in males and females decreased by 10, 6
(p < 0.05) and 6, 2 (0.05) times, respectively.
3.1. The Hemodynamic Effects of is in
Normotensive and Hypertensive
Male and Female Rats
The IS caused the significant tachycardia and increase in

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Table 1. The baseline mean arterial pressure (MAP, mmHg) and heart rate (HR, beats/min) values in normotensive and hypertensive
male and female rats.
Normotensive Hypertensive
Female Male Female Male
Sets of experiments
MAP HR MAP HR MAP HR MAP HR
1. immobilization
stress 102 ± 2 349 ± 4† 105 ± 3371 ± 4118 ± 4† □ 354 ± 10 140 ± 3 □ 362 ± 7
2. NO blockade with
L-NAME injection at
rest
101 ± 2 361 ± 7 103 ± 3358 ± 6131 ± 2† □ 370 ± 11 148 ± 3 □ 377 ± 9
3. NO blockade with
L-NAME injection
under immobilization
stress
102 ± 3 353 ± 5 105 ± 3365 ± 6137 ± 3† □ 367 ± 8□ 151 ± 4 □ 376 ± 10
□－p < 0.05 vs. normotensive rats; †－p < 0.05 vs. males
MAP in both NT and HT rats. The effects of IS on car-
diovascular activity were different in females and males
of both groups.
In NT females the HR increased more significantly
(22-32% vs. 13-24%, p < 0.05) and recovered more rap-
idly than in NT males (Figure 1). The basal values of
HR were lower in NT females vs. NT males (Table 1).
Important notice that despite more severe tachycardia
under IS in NT females, the amplitude and duration of
MAP elevation were lower than in NT males (Figure 1).
Moreover, only in NT females, short-lasting stress-in-
duced MAP increase was followed by transient hypoten-
sion. There was no significant sex difference in the basal
MAP values in NT group (Table 1).
Openly accessible at
3.2. Hypertension Versus Normotension
In HT rats in comparison with NT ones, cardiac and
vascular responses to IS were decreased in females but
increased in males (Figures 1 and 2). So, in females,
hypertension was accompanied by decrease in stress-
evoked tachycardia in comparison with NT females: in
HT females during IS the HR increased by only 10-16%
(p < 0.05), while in NT females this parameter increased
by 22-32% (p < 0.05). In HT females, HR returned to
normal 5 min after IS, while in NT females it returned to
normal 40 min after the end of IS. The pressor responses
in HT and NT females observed at 1 min of IS and did
not differ by the amplitude. However, in HT females the
significant MAP increase was replaced by long-lasting
(more than 120 min) compensatory hypotensive state.
In contrast to HT females, in males hypertension was
accompanied by an increase in cardiac and vascular re-
activity to IS. Really, the positive chronotropic effect of
IS was significantly higher in HT males (28-21%, p <
0.05) than in NT males (24-13%, p < 0.05) over the en-
tire stress period. As for MAP, despite the same of am-
plitude of stress-induced increase in MAP in both groups
the pressor reactions were more prolonged in HT males
than in NT males: in NT males the elevated MAP levels
were observed during 15 min of IS, in HT males - during
40 min of IS and it remained tendentionally higher at the
end of IS.
(a) (b)
Figure 1. The changes of mean arterial pressure (MAP, %－a) and heart rate (HR, %－b) in normotensive male and female rats dur-
ing immobilization stress and recovery period. Here and in Figures 2-6: －females, －males; p < 0.05: －vs.
basal level; †－vs. males.

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The decrease in the chronotropic component of IS in
HT females and its increase in HT males inverted the
sex-related difference in the degree of stress-induced
tachycardia (Figure 2). In HT rats, in contrast NT ani-
mals, the HR response to IS was more pronounced in
males vs. females (28% vs. 16%, p < 0.05). Notice that
basal values of HR didn’t differ reliably between sexes
in HT group.
3.3. The Hemodynamic Effects of No Blockade
in Normotensive and Hypertensive Male
and Female Rats at Rest and During
Stress
In both NT and HT rats, NO blockade with L-NAME
caused an increase in MAP with a decrease in HR and these
changes depended upon the gender and the state of rat.
Female NT rats in comparison with male ones were
more sensitive to NO blockade with L-NAME under
normal and especially stress conditions. Actually, at rest,
L-NAME induced a greater MAP increase with a greater
HR decrease in females than in males (25% vs. 17%, p <
0,05 for MAP; 18% vs. 10%, p 0 < 0,05 for HR). This
sex difference in cardiovascular response to L-NAME
was occurred within 30 min after L-NAME injection
(Figure 3). There were no statistical differences in base-
line MAP and HR values between NT females and NT
males (Table 1).
Cardiovascular responses to IS have been significantly
modified by L-NAME in NT males and especially in NT
females (Figures 1 and 4). Indeed, IS against NO block-
ade induced a higher elevation in MAP than IS alone did
(34% vs. 18%, p < 0.05 in NT males and 57% vs. 11%, p
< 0.05 in NT females). As a result, sex difference in vas-
cular responses to IS was greater in the L-NAME treated
group (57% vs. 34%, p < 0.01) than in untreated one
(18% vs. 11%, p < 0.05) and observed during 60 min of
IS and 40 min of recovery period. In both sexes, espe-
cially in NT females, stress-evoked MAP elevation was
much more continued when compared with IS alone.
Actually, the elevated MAP occurred within 60 min of
IS and the MAP didn’t reach the basal values even at 60
min after stress-off.
(a) (b)
Figure 2. The changes of mean arterial pressure (MAP, %－a) and heart rate (HR, %－b) in hypertensive male and female rats dur-
ing immobilization stress and recovery period.
(a) (b)
Figure 3. The effects of NO synthesis inhibition by L-NAME on mean arterial pressure (MAP, %－a) and heart rate (HR, %－b) in
normotensive male and female rats at rest.

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(a) (b)
Figure 4. The effects of NO synthesis inhibition by L-NAME on mean arterial pressure (MAP, %－a) and heart rate (HR, %－b) in
normotensive male and female rats under stress condition.
Cardiac effects of IS were also modified by L-NAME
in NT males and especially in NT females (Figures 1
and 4). Actually, in NT males, tachycardic response to IS
was significantly suppressed by L-NAME. In NT fe-
males, tachycardic effects of IS were abolished com-
pletely and replaced by bradycardic effects of L-NAME,
that were more pronounced in stressed females com-
pared with unstressed ones (Figures 3 and 4). Notice
that basal values of MAP and HR didn’t differ reliably
between sexes in NT group (Table 1).
Thus, in NT rats, acute effects of NO blockade with
L-NAME on the MAP and HR were more pronounced in
female than in male rats at rest and especially during
stress.
3.4. Hypertension Versus Normotension
Renovascular hypertension was accompanied by a de-
crease in vascular sensitivity to NO blockade at rest,
which was similar in both sexes (Figures 3 and 5). In-
deed, the vasoconstrictor response to NO blockade was
attenuated in HT rats compared with NT animals of both
sexes (17% vs. 25%, p < 0.05 for females; 10% vs. 17%,
p < 0.05 for males, respectively). However, despite less
pronounced pressor reactions after L-NAME injection in
HT vs. NT rats, the MAP didn’t normalize even at 120
minutes of experiment in female and male HT animals.
Unlike vascular reactivity, cardiac responses to L-NAME
in NT and HT rats were comparable. As a result, in HT
rats as in NT ones, pressor and cardiac effects of L-
NAME were greater in females than in males (17%
against 10%, p < 0.05 for MAP; 26% against 12%, p <
0.05 for HR).
Pressure responses to IS against L-NAME compared
with IS alone were significantly changed in HT females
and slightly changed in HT males (Figures 2 and 6).
Actually, in HT females, NO blockade induced more
significant stress-evoked elevation in MAP than IS alone
did (24% vs. 12%, p < 0, 05) and abolished completely
the long-lasting hypotensive state observed after short-
lasting pressor response during IS alone. As for HT
males, NO blockade didn’t affect the amplitude of MAP
response to IS but it increased the duration of stress-
induced hypertension. As a result, in contrast to IS alone,
IS against NO blockade induced the similar MAP re-
sponses pattern in male and female HT rats.
In both male and female HT rats, NO blockade abol-
ished completely the tachycardic effect of IS (Figures 2
and 6). Note, that in HT females, tachycardic effect of IS
was replaced by slight non-significant but long-lasting
(120 min) bradicardic effect of L-NAME. There were no
statistical differences in baseline HR values between HT
females and HT males in this experiment (Table 1).
4. DISCUSSION
In this study we examined the effect of NO blockade by
L-NAME on MAP and HR in conscious NT and HT
male and female rats at rest and during IS. The results
show that the cardiovascular sensitivity to L-NAME
depended upon the following factors: resting MAP (nor-
motension vs. hypertension), gender (male vs. female),
and state (rest vs. stress).
We have, for the first time, demonstrated that the se-
verity of hypertension associated with impairment of
renal blood flow was lower in females than in males.
These findings are in agreement with our previous re-
ports [15,16] and results of other studies [20,21] in
which showed the sexual dimorphism in development of
several forms of hypertension in both humans and ani-
mals.
In addition, we found that both NT and HT females
demonstrated more favorable pattern of cardiovascular
responses to IS. Actually, in NT females the chrono-
ropic effects of IS were more pronounced, while the t

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(a) (b)
Figure 5. The effects of NO synthesis inhibition by L-NAME on mean arterial pressure (MAP, % －a) and heart rate (HR, %－b) in
hypertensive male and female rats at rest.
(a) (b)
Figure 6. The effects of NO synthesis inhibition by L-NAME on mean arterial pressure (MAP, %－a) and heart rate (HR, %－b) in
hypertensive male and female rats under stress condition.
pressor effects were weakened compared with males.
Hemodynamic parameters in females returned to normal
more rapidly than in males. The more pronounced hy-
pertension in males vs. females was associated with in-
creased cardiovascular stress-reactivity in males and
with decreased cardiovascular stress-reactivity in fe-
males. Moreover, only in NT and HT females short-
lasting stress-induced MAP elevation was replaced by
transient hypotension indicating the activation of com-
pensatory mechanisms.
In so far as heightened pressure stress responses had
been linked to the development of cardiovascular dis-
eases [22], from our result, we concluded that more fa-
vorable pattern of cardiovascular responses to stress,
observed in NT and especially HT females compared
with male groups may be an important mechanism re-
sponsible for greater resistance of females to hyperten-
sion and other cardiovascular diseases. Indeed, our pre-
vious observation demonstrated that NT male vs. NT
female rats have been shown to exhibit heightened pres-
sure stress-reactivity and lower cardiovascular and cere-
brovascular resistance to stress-induced damages [23,
24].
In order to investigate the role of NO in gender-related
differences in the severity of renovascular hypertension
and in cardiovascular stress responses in NT and HT rats,
we studied the effect of NO blockade on hemodynamic
parameters at rest and during stress.
The results of the present study show that in both NT
and HT rats, NO blockade by L-NAME caused an in-
crease in MAP with a decrease in HR and these changes
depended upon the gender and the state of rats.
At rest, NO blockade increased the MAP and de-
creased the HR more effectively in female NT and HT
rats than in male groups. During stress, NO blockade
modified the stress-induced MAP and HR responses
more significantly in female NT and HT rats compared
with male groups. Our results are consistent with reports
of in vitro observations that showed stronger nitrergic
control of various vessels of female than in male rats in
normotensive state [11-14]. These data, along with re-
port of higher NO production [25] and plasma arginine
levels [26] in female gender compared with male gender
are in accordance with our previous report of greater
blood NO concentration in both NT and HT females vs.
male groups under normal and stress conditions [15].
This male-female difference suggesting the more ef-
fective NO control of cardiovascular activity in females

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vs. males may be an important mechanism responsible
for more favorable stress-induced pattern of MAP and
HR changes observed in NT and especially HT females
compared with NT and HT males.
In the work of some investigators [6,7] it has been
demonstrated that the decrease in NO activity is a nega-
tive factor promoting hypertension development and
increasing the risk of cardiovascular complications. In-
deed, we found that renovascular hypertension being
more severe in males than in females was accompanied
by a decrease in effectiveness of NO control of MAP at
rest and during stress. Moreover, our previous report
demonstrated that more pronounced hypertension in
male vs. female rats was accompanied by more signifi-
cant decrease in NO production in males than in females
[15]. These findings led to a suggestion that a decrease
of function of the NO-ergic system as a major factor
contributing to hypertension.
Our results are consistent with reports of diminished
availability of basal NO in blood [15], urine [27], kidney
[28] and in vessels [29] in hypertensive state. Yet some
investigators have not revealed any differences in ni-
trite/nitrate plasma concentration [30] and hemodynamic
responses to NO blockade [31] between NT and HT rats.
But others have found enhanced endothelial NO syn-
thase (eNOS) activity in endothelial cells from isolated
aorta [32] and elevated hemodynamic responses to NO
blockade [33] in HT vs. NT rats, suggesting that NO
production is increased rather than decreased in the HT
animals. This conclusion seems to contradict the results
of the present study. However, the involvement of NO
synthesis and release in the hypertensive state remains
obscure. The enhanced NO production in the vascular
beds in hypertensive state may represent a compensatory
mechanism to blood pressure increasing. So, McIntary
et al. [32] observed that in both NT and HT male rats
compared with females the higher baseline blood pres-
sure was associated with greater eNOS activity in aorta.
The increased sympathetic activity being important fac-
tor in pathogenesis of hypertension was accompanied by
an increase in activity of neuronal isoform of NO syn-
thase that tonically inhibits the sympathetic outflow
from the specific area of the brain involved in the neu-
rogenic control of blood pressure [34]. These facts are
further evidence that NO production is increased as a
compensatory mechanism. It therefore seems likely that
the reduced NO availability in hypertensive state ob-
served in many studies is due to increased scavenging.
Furthermore, discrepant results among studies may be
due to the fact that above experiments was done by
topical application of the pharmacological agents which
modulate of NO activity in different section of the pial
vessels. The results could be different from those ob-
tained in the whole vascular beds or in local circulation.
High nitrergic control of cardiovascular activity in
females may be due to estrogens that stimulate eNOS
function and NO production, potentiate the endothe-
lium-dependent effect of acetylcholine [35]. On the con-
trary, androgens through a mediated increase in angio-
tensin II, which causes oxidative stress with enhanced
superoxide production, quenching of NO, contribute to
decrease in NO availability [20]. In addition, androgens
appear to play an inhibitory role in small intestinal en-
dothelial function [36]. The reciprocal stimulatory ef-
fects of NO and cholinergic influences being more pro-
nounced in females vs. males [37] may be an additional
mechanism responsible for enhanced NO activity in fe-
males compared with males. Notice, that the augmented
parasympathetic activity has protective effects during
myocardial infarction and coronary sudden death [38,
39]. Based on these data one may suggest that specific
relationship between NO activity and cholinergic system
reduces risk of progressive hypertension and cardiovas-
cular disorders in females.
5. CONCLUSIONS
In summary, our results indicate that both NT and HT
females demonstrated the more effective NO control of
cardiovascular activity under normal and especially
stress conditions than male groups. This male-female
difference may be important mechanism responsible for
greater in females vs. males of cardiovascular resistance
to stress and development of hypertension observed in
experimental animal models and in humans.
6. ACKNOWLEDGEMENTS
This studies were supported in part by a Grant from Russian Ministry
of Science and Education within program “Scientific and scientific and
pedagogical staff of innovative Russia” 2009-2012, in the field of
“Fundamental Medicine and Physiology”, GK- 1257P and GK-144P
Conflict of Interest. Conflict of Interest: none declared.
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