Hypertension. 2001;37:1199-1208
(Hypertension. 2001;37:1199.)
© 2001 American Heart Association, Inc.
Gender Differences in the Regulation of Blood Pressure
Jane F. Reckelhoff
From the Department of Physiology and Biophysics and the Center for
Excellence in Cardiovascular-Renal Research, University of Mississippi Medical
Center, Jackson.
Correspondence to Jane F. Reckelhoff, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505. E-mail jreckelhoff{at}physiology.umsmed.edu
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Abstract
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Abstract—Men
are at greater risk for cardiovascular and
renal
disease than are age-matched, premenopausal women. Recent
studies using
the technique of 24-hour ambulatory blood pressure
monitoring have
shown that blood pressure is higher in men
than in women at similar
ages. After menopause, however, blood
pressure increases in women to
levels even higher than in men.
Hormone replacement therapy in most
cases does not significantly
reduce blood pressure in postmenopausal
women, suggesting that
the loss of estrogens may not be the only
component involved
in the higher blood pressure in women after
menopause. In contrast,
androgens may decrease only slightly, if at
all, in postmenopausal
women. In this review the possible mechanisms by
which androgens
may increase blood pressure are discussed. Findings in
animal
studies show that there is a blunting of the
pressure-natriuresis
relationship in male spontaneously hypertensive
rats and in
ovariectomized female spontaneously hypertensive rats
treated
chronically with testosterone. The key factor in controlling
the pressure-natriuresis relationship is the
renin-angiotensin
system (RAS). The possibility that
androgens increase blood
pressure via the RAS is explored, and the
possibility that
the RAS also promotes oxidative stress leading to
production
of vasoconstrictor substances and reduction in
nitric oxide
availability is
proposed.
Key Words: sex characteristics • hypertension • angiotensin II • nitric oxide • oxidative stress
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Introduction
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In this review
gender differences in blood pressure control
are explored, including
possible mechanisms by which androgens
may increase blood
pressure.
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Gender Differences in Blood Pressure
Regulation in Humans
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Men are generally at greater risk for
cardiovascular and renal
disease than are age-matched,
premenopausal women. Recent studies
using the technique of 24-hour
ambulatory blood pressure monitoring
have shown that blood pressure is
higher in men than in women
at similar ages. As shown in
Figure 1
, Wiinber and
colleagues
1 studied 352
normotensive (for age) Danish men and women, aged
20 to 79 years, and
found that blood pressure increased with
aging in both men and women,
but that men had higher 24-hour
mean blood pressure, by approximately 6
to 10 mm Hg, than did
women, until the age of 70 to 79 years,
when blood pressure
was similar for men and women. Khoury and
colleagues
2 performed
ambulatory blood pressure monitoring on 131 men and women,
aged 50 to
60 years, and found that men had higher blood pressure
than did
women. Findings were similar in a meta-analysis study
performed by Staessen et al.
3
In addition, the Third National
Health and Nutrition Evaluation Survey
(NHANES III) showed
that, in general, men had higher blood pressure
than women
through middle
age.
4 Furthermore, the
incidence of uncontrolled
hypertension is also greater in men than in
women.
5
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Figure 1. Effect of aging and gender on blood pressure (BP) measured by 24-hour ambulatory technique in a Danish cohort. Data are presented as mean±SEM. *P<0.05 compared with women of similar age. Data presented with permission from Am J Hypertens.1
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After menopause, however, blood pressure increases in women
as well. The data from NHANES III, shown in
Figure 2, confirmed that by 60 to 69 years of age,
non-Hispanic black and Hispanic women developed higher blood pressure
than men of similar ethnic
background.4 However, the
mechanisms responsible for the hypertension in these populations are
complicated by comorbid conditions of obesity and type II diabetes,
both of which lead to increases in blood
pressure.4 In the
non-Hispanic white population, in which the incidence of obesity and
type II diabetes with aging is not as high, blood pressure also
increased after the average age of menopause (51.4 years). Therefore,
by 60 to 69 years of age, non-Hispanic white women had blood pressure
similar to that of men, and by 70 to 79 years of age, this population
of women had higher blood pressure than did
men.4
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Figure 2. Effect of aging and gender on prevalence of hypertension (in percentage) in non-Hispanic blacks, non-Hispanic whites, and Mexican Americans compiled from the NHANES III cohort. With advancing age (postmenopause), the prevalence of hypertension in women increases to levels higher than in age-matched men. *Too few individuals available for statistical evaluation. Data presented with permission from Hypertension.4
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Gender Differences in Blood Pressure Regulation
in Animals
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The gender-associated differences in blood pressure
observed
in humans have also been documented in various animal models.
In hypertensive rat models, many investigators have found that
males
have higher blood pressure than do females. For example,
as shown in
Figure 3
, male spontaneously hypertensive rats
(SHR) have
higher blood pressure than do females of similar
ages.
6 7 8 9
Similar gender differences in development of
hypertension are also
found in Dahl salt-sensitive (DS)
rats,
10 11
deoxycorticosterone-salt hypertensive
rats,
12 and the
New Zealand
genetically hypertensive
rat.
13 Therefore, as
found
in humans and hypertensive rat models, males have higher
blood pressure
than age-matched females.
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Figure 3. Mean arterial blood pressure (MAP) measured in anesthetized SHR, aged 17 to 19 weeks, during the established phase of hypertension. Some males and females were castrated (cast) or ovariectomized (ovx) at 7 weeks of age. Some ovariectomized females were given testosterone (T) by implantation of silicone elastomer pellets for the last 5 to 6 weeks before blood pressure was measured. *P<0.01 compared with males and/or testosterone-treated ovariectomized females;  P<0.01 compared with females, castrated males, or ovariectomized females. Data presented with permission from Hypertension.27
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To date there have been no studies in which a
consistent gender difference in blood pressure in normotensive
animals has been documented. Contrary to data in humans, Calhoun and
colleagues14 reported that
24-hour blood pressure measured at 12 weeks of age in male Wistar-Kyoto
rats (WKY) was lower than in female WKY by approximately 9 mm Hg
(males, 96±3; females, 105±1 mm Hg). However, by 14 weeks of
age there was no difference in blood pressure over 24 hours between the
genders (males, 101±3; females, 106±1
mm Hg).14 It is possible
that averaging blood pressure over 24 hours would diminish gender
differences that would be exposed when blood pressure is evaluated
during the day or night individually. In any case, from the small
differences in blood pressure found in normotensive human subjects, it
is clear that blood pressure measurement in conscious rats during acute
studies is not sufficient to be able to detect the small differences
one would expect to find between normotensive male and female rats.
Thus, it will be necessary to measure telemetric blood pressure in
normotensive rats over a prolonged (months) period of time to determine
whether there are in fact gender differences with increasing age in
normotensive rats, as found in normotensive
humans.
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Mechanisms for Gender Differences in Blood
Pressure Control: Role of Testosterone
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Although the mechanisms responsible for the gender
differences
in blood pressure control are not clear, there is
significant
evidence that androgens, such as testosterone, play an
important
role in gender-associated differences in blood pressure
regulation.
For example, studies using ambulatory blood pressure
monitoring
techniques in children have shown that with increasing age,
blood pressure increases in both boys and girls. However, after
the
onset of puberty, boys have higher blood pressure than
do age-matched
girls.
15 16 At
ages 13 to 15 years, systolic
blood pressure was approximately
4 mm Hg higher in boys than
girls, and at ages 16 to 18 years,
boys had higher systolic
blood pressures than girls by 10 to
14 mm Hg.
16 The blood
pressure in postpubescent boys also does not dip as low at
night as in
girls.
15 16 A
reduction in nocturnal dipping
is recognized as a hallmark of early
dysfunction in blood pressure
regulation.
15 16
These data clearly show that in adolescence
and puberty, when androgen
levels are increasing, blood pressure
is higher in boys than in
girls.
Another line of evidence that testosterone may play an
important role in higher blood pressure in males is castration studies
in male rats. Castration at a young age (3 to 5 weeks) attenuates the
development of hypertension in SHR
(Figure 3), in DS male rats, in male rats subjected to
2-kidney, 1 clip (Goldblatt)
maneuver,6 7 9 10 11 17 18
and in male rats subjected to reduced renal
mass.19 20
Furthermore, as shown in
Figure 4, we have found that chronic blockade of the
androgen receptor with the antagonist flutamide attenuates
blood pressure in male SHR to the level found in female
SHR.21 Both testosterone and
dihydrotestosterone (DHT) bind to the androgen receptor, and DHT rather
than testosterone is the androgen involved in such conditions as male
pattern baldness and benign prostatic
hypertrophy.22 23
When treated with finasteride, the inhibitor of the
conversion of testosterone to DHT, baldness of this type is attenuated,
and the prostatic hypertrophy is
reversed.22 23
However, conversion to DHT was not found to be important in promoting
hypertension in male SHR because chronic treatment with finasteride did
not have an effect on the
hypertension.21
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Figure 4. Androgen receptor antagonism in intact male SHR reduced mean arterial blood pressure at 14 to 16 weeks of age to the same level as found in castrated males and intact female SHR of similar ages. Male SHR were given daily injections of vehicle (control) or flutamide (8 mg/kg per day) for 5 to 6 weeks. For purposes of illustration, data from untreated intact female and castrated SHR of similar ages are also presented. *P<0.01 compared with untreated males. Data presented with permission from Hypertension.21
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On the other hand, increases in androgens in humans and
animals increase blood pressure. Women with polycystic ovary syndrome
or adrenal virilizing tumors, which are characterized by elevated
testosterone levels, experience
hypertension.24 25 26
In animal studies testosterone treatment increases blood pressure in
ovariectomized female and castrated male SHR
(Figure 3).9 27
Furthermore, chronic testosterone treatment of normotensive,
uninephrectomized female rats increases arterial blood
pressure that was found not to be reversible, depending on the length
of time the testosterone was
given.28 29 Thus,
increases in androgens in humans and in normotensive and hypertensive
rats lead to higher blood pressure.
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Mechanisms for Gender Differences in Blood
Pressure Control: Role of Estrogens
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Because men and male rats have higher blood pressures
than
do females, it is possible that female hormones may play a role
in
protecting females from developing higher blood pressures.
In women
menopause is characterized by increases in blood pressure,
as
determined by the NHANES III study and others
(Figure 2
).
4 30 31
Interestingly, the blood pressure does not increase
during the
transitional phase from perimenopause to
menopause,
32 but rather the
increase in blood pressure after menopause
takes an average of 5 to 20
years to develop,
4 suggesting
that lack of female hormones may not be the only contributing
factor
for the elevated blood pressure.
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Hormone Replacement Therapy in Postmenopausal
Women
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The possibility that lack of female hormones may not be
the
only factor contributing to the increase in blood pressure after
menopause is supported by the numerous studies in postmenopausal
women
given hormone replacement therapy (HRT), in whom blood
pressure was
measured by ambulatory blood pressure monitoring
techniques. In these
studies, blood pressure was not affected
by
HRT,
33 34 35
was only minimally affected by
HRT,
36 37 38
or the reduction in blood pressure with HRT was evident
only at
night
38 or only in
normotensive individuals.
39
Furthermore,
the route of delivery was important in whether HRT was
effective
in lowering blood pressure, with transdermal HRT being more
effective than oral
preparations.
34 38
Importantly, the
Heart and Estrogen/Progestin Replacement Study (HERS)
also
found that there was no overall beneficial effect on secondary
prevention of coronary heart disease in postmenopausal women
during the 4.1 years of
study.
40
Estrogen has been shown to stimulate nitric oxide (NO)
production.41 42
Thus, loss of estrogen with menopause could play a role in the
increased blood pressure in women after menopause. However, since
estrogen replacement therapy has not been shown to decrease blood
pressure, it is doubtful that the effect of estrogen on NO is the
protective mechanism by which blood pressure is lower in premenopausal
women. We have shown in previous studies that aging in rats is
associated with a reduction in NO substrate
(L-arginine) and excretion
of NO metabolites.43 Thus,
it is also possible that the effect of advanced age on other components
of the NO overwhelms the effect of estrogen on NO production in
postmenopausal women.
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Androgens in Postmenopausal Women
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With regard to androgen levels after menopause, there
is some
controversy since studies have shown that serum testosterone
levels in postmenopausal women may decrease slightly, may not
change at
all, or may actually
increase.
44 45 46 47
A recent
report from the Rancho Bernardo Study, a community-living,
population-based
study in Rancho Bernardo, Calif, emphasized that in
685 women,
aged 50 to 89 years, the status of whether or not the women
had undergone hysterectomy with or without oophorectomy affected
serum
testosterone levels.
48 These
investigators found that
in intact women serum testosterone levels
decreased immediately
after menopause but increased with aging to
premenopausal levels
by 70 to 79 years of
age.
48 In women who had
undergone hysterectomy
with bilateral oophorectomy, both total and
bioavailable testosterone
levels were reduced by 40%. Postmenopausal
women who had undergone
hysterectomy without oophorectomy had
intermediate serum testosterone
levels.
48 These data show
that the ovary is a very important
source of androgens after menopause
in women. Since increased
androgen levels have been shown to increase
BP in women with
polycystic ovary syndrome and in animal models, it is
possible
that with the loss of estrogens at menopause, the unopposed
effect of androgens in postmenopausal women may contribute
to their
elevated BP. This hypothesis remains to be tested
in both women and
female animal models.
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Role of Female Hormones in Blood Pressure
Control in Animal Models
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Studies in female SHR have supported the notion that
female
hormones do not cause protection against the higher blood
pressure
found in male SHR. As shown in
Figure 3
, ovariectomy of female
SHR at 4 to 5 weeks of age
does not result in higher blood
pressures than in intact females at 18
to 20 weeks of
age.
27 49
However, androgen treatment of ovariectomized female SHR
causes an
increase in blood pressure that is dose
dependent.
27 49
These data suggest that it is not female hormones but rather
lack of
testosterone that may protect female SHR from the higher
blood pressure
found in males.
There are differences in rat models of hypertension with
regard to the role that ovariectomy plays in the control of blood
pressure in female rats. Hinojosa-Laborde and
colleagues50 found that
ovariectomy of DS rats resulted in higher blood pressure than in either
males or females. When rats were maintained on a high salt diet, blood
pressure increased in all rats, but to a greater extent in males and
ovariectomized females than in intact females. Surprisingly, reversal
of the diet to low salt in these animals reversed the hypertension in
intact male and female DS rats but not in ovariectomized DS
rats.50 Similar effects of
ovariectomy in causing an increase in blood pressure compared with
intact females have also been found in females in the model of
deoxycorticosterone-salt
hypertension.51 It is not
clear why loss of female sex hormones results in elevation of blood
pressure in these models.
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Abnormal Pressure-Natriuresis in Hypertension:
Role Played by Testosterone
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Substantial evidence supports the theory that some form
of
renal dysfunction plays a role in the development and
maintenance
of
hypertension.
52 53
Providing the strongest support for
this theory are observations that
transplantation of prehypertensive
kidneys from SHR to WKY produces
hypertension.
53 Similar
results
have been obtained in renal transplantation studies between
DS
and Dahl salt-resistant
rats.
53 Of particular
relevance
to human hypertension is the study by Curtis et
al,
54 which
demonstrated
that blood pressure returns to normal in hypertensive
patients who
receive kidneys from normotensive donors. The
results indicate that a
defect within the kidney may play a
crucial role in the pathogenesis of
hypertension. A common
defect that has been characterized in several
forms of hypertension
is a shift in the pressure-natriuresis
relationship.
53 The
pressure-natriuresis relationship refers to the fact that increased
arterial pressure elicits a marked increase in sodium
excretion.
55 56
According to the renal body fluid feedback concept, a long-term
increase in arterial pressure or hypertension occurs as a
result
of reduction in renal excretory function or a rightward shift
in
the pressure-natriuresis
relationship.
55 56
As shown in
Figure 5, we have recently reported that the
pressure-natriuresis relationship is blunted in male SHR compared with
females.27 Castration of the
male SHR restored the pressure-natriuresis relationship, whereas
ovariectomy of female SHR had no
effect.27 Testosterone
treatment of ovariectomized female SHR resulted in an increase in blood
pressure and a concomitant blunting of the pressure-natriuresis
relationship.27 Preliminary
data have shown that the androgen receptor is located predominantly in
proximal tubule segments of the
nephron.57 These data
provide initial support for the notion that androgens may have a direct
effect on sodium reabsorption in the proximal nephron.
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Figure 5. Acute pressure-natriuresis relationship comparison in male, female, castrated male, untreated ovariectomized (ovx) female, and ovariectomized female SHR treated chronically for 5 to 6 weeks with testosterone (ovx+T). Acute pressure-natriuresis studies were conducted in anesthetized SHR, aged 17 to 19 weeks. Renal perfusion pressure was reduced by tightening a snare around the aorta above the renal arteries in a stepwise fashion. *P<0.05 compared with males. Data presented with permission from Hypertension.27
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As mentioned above, many studies have demonstrated that
"hypertension follows the kidney"; accordingly, when the kidney of
SHR is transplanted into a normotensive rat, the blood pressure in the
previously normotensive rat
increases.53 However, Harrap
and colleagues58 reported
that when the kidney from male SHR was transplanted into female SHR,
this maneuver did not result in a significant rise in blood pressure
such that female SHR with male kidneys had blood pressure similar to
that in female SHR with female kidneys. However, when the kidney from
female SHR was transplanted into male SHR, blood pressure was not
attenuated in the male with female kidneys compared with blood pressure
in a male SHR with male
kidneys.58 These data
indicate that the 25 to 30 mm Hg higher blood pressure in the
male SHR compared with the female is not due to an intrinsic defect of
the male kidney but rather is due to some external factor in the male
that further increases blood pressure, perhaps because of a reduction
in pressure-natriuresis. We hypothesize that androgens are the factor
in males by which the pressure-natriuresis relationship is blunted and
higher blood pressure results.
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Testosterone-Induced Reduction in
Pressure-Natriuresis: Role of the Renin-Angiotensin
System
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The key system for controlling blood pressure and body
fluid
volume (ie, pressure-natriuresis) is the
renin-angiotensin
system
(RAS).
55 56 For
example, under normal conditions,
any perturbation that increases
arterial pressure will also
provoke an increase in sodium
and water excretion via pressure-natriuresis.
This will lead to a
decrease in extracellular fluid volume,
venous return, and cardiac
output, and blood pressure will
return to normal. Long-term
pressure-natriuresis is modulated
by the RAS. Angiotensin
II (Ang II) increases proximal sodium
reabsorption by the kidney by
stimulating epithelial
transport.
56 In the event of
abnormal Ang II levels for the level of volume
in the body, the blood
pressure will increase with abnormal
sodium and water reabsorption,
leading to blunting of the pressure-natriuresis
relationship.
Similarly, if total body fluid volume levels
are "perceived"
incorrectly, and thus Ang II levels do not
respond appropriately,
increases in blood pressure will also
occur.
59
Gender differences in components of the RAS have been shown
to exist that may play a role in the control of blood pressure. James
and colleagues60 measured
plasma renin activity (PRA) in men and women over a 9-year period and
documented that in this normotensive population, PRA was 27% higher in
men than in women regardless of age and ethnic heritage. Kaplan and
associates61 reported
similar findings. Other studies in older individuals have shown that
PRA is higher in postmenopausal women than in premenopausal women but
that PRA is still higher in men than in women of similar
age.62 Thus, renin activity
is greater in men than in women. The cause of this gender difference is
unclear. However, these data lend credence to the hypothesis that the
RAS may play a role in mediating the gender difference in blood
pressure regulation.
In animal studies, male SHR have higher PRA than do
females,63 testosterone
treatment of ovariectomized female rats causes increases in
PRA,64 65 and PRA
decreases with castration in male
rats.64 65
Furthermore, as presented in
Figure 6, we have found that there is a linear
correlation (r=0.904) between
the level of serum testosterone and PRA in Sprague-Dawley rats treated
chronically (2 weeks) with increasing doses of testosterone. Blood
pressure also increases with chronic testosterone in normotensive rats.
Therefore, these data suggest that testosterone stimulates the RAS. The
mechanism by which androgens increase PRA is not clear, but data from 2
groups have independently shown in SHR and normotensive WKY that
castration decreases renal angiotensinogen mRNA and chronic
testosterone increases renal angiotensinogen
mRNA.64 66
Chronically increased renal angiotensinogen could increase
renal tissue Ang II if renin enzyme is not working at maximal velocity,
which has been reported in both humans and
rats.67 In support of this
hypothesis, studies in mice have demonstrated that an increase in
angiotensinogen gene copy numbers causes increases in blood
pressure.68 Alternatively,
if testosterone plays a role in directly increasing proximal sodium
reabsorption, as hypothesized above, the reduction in tubular sodium
would be perceived by the macula densa and would therefore result in
renin release, causing an increase in PRA. Future studies will be
necessary to determine the exact mechanism by which androgens increase
PRA.
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Figure 6. In normotensive rats, increasing serum testosterone causes an increase in PRA. Castrated male Sprague-Dawley rats (n=9) were implanted with testosterone pellets of increasing concentration (Innovative Research). After 2 weeks, rats were anesthetized, and plasma was taken for measurement of renin activity and testosterone by radioimmunoassays, as previously described.27 Each point represents the data from an individual rat. Rats with 0 testosterone (n=3) were placebo-implanted castrated males. Statistical analyses were performed with Origin software (Microcalc). R=0.904. AI indicates angiotensin I.
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To test the hypothesis that the RAS plays a role in
mediating the gender difference in blood pressure in SHR, we found that
chronic blockade with the Ang II–converting enzyme
inhibitor enalapril resulted in normalization of the blood
pressure regardless of
gender,49 thus removing the
gender-induced difference in blood pressure in SHR
(Figure 7). In male SHR and ovariectomized female SHR treated
with testosterone, in which blood pressure was elevated by
30 mm Hg, blood pressure was reduced by 65% with enalapril,
whereas in female, castrated male, and untreated ovariectomized female
SHR, blood pressure was only reduced by
40%.49 These data suggest
that the RAS plays an important role in mediating the hypertension in
SHR regardless of gender, but, more importantly, that the
androgen-promoted exacerbation of the blood pressure in male and
testosterone-treated ovariectomized female SHR is also mediated by the
RAS.
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Figure 7. Chronic treatment of SHR with angiotensin-converting enzyme inhibitor removes the gender difference in blood pressure but decreases blood pressure more in male and ovariectomized female SHR treated chronically (6 weeks) with testosterone (ovx+T) than in rats in the other 3 groups. SHR were treated for 6 to 8 weeks with the Ang II–converting enzyme inhibitor enalapril (250 mg/L) in the drinking water. *P<0.05 compared with control males; **P<0.05 compared with control rats of same sex; P<0.05 compared with control females, castrated males (cast), and ovariectomized females (ovx). Data presented with permission from Hypertension.49
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Mechanism(s) by Which Ang II May Increase Blood
Pressure in Males: Role of Oxidative Stress
|
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Both supraphysiological and
physiological doses of Ang II can
cause oxidative
stress. For example, Rajagopalan and
colleagues
69 found that
pharmacological doses of Ang II (0.7 mg/kg per
day SC by minipump)
increased blood pressure and superoxide
levels in aortic segments of
rats, while infusion of norepinephrine,
which resulted in
an increase in blood pressure similar to
that of Ang II, had no effect
on superoxide levels. These data
suggested that infusion of Ang II at
pharmacological doses
was capable of inducing oxidative stress
independent of elevated
blood pressure. In addition, these
investigators found that
increased superoxide levels could be
normalized with losartan,
the Ang II receptor
antagonist, or with liposomes containing
superoxide
dismutase.
69 In additional
experiments they also
reported that Ang II increases superoxide
production via increased
NAD(P)H oxidase
activity.
70
Superoxide is known to interact with NO to produce
peroxynitrite, one of the most potent oxidative compounds
known.71 72
Thermodynamically speaking, the reaction of NO and superoxide is
preferential since the rate of reaction is more rapid than the reaction
rate of superoxide and its scavenger, superoxide
dismutase.73 Although
peroxynitrite itself is a vasodilator, Villa and
colleagues74 demonstrated
that tachyphylaxis occurs at peroxynitrite concentrations of 3
µmol/L, which is subthreshold as a vasodilator in coronary
circulation; this not only prevents further response to its own
vasodilator actions but also causes long-lasting impairment of the
response to other vasodilators. In support of this notion, Benkusky and
colleagues75 found that the
development of tachyphylaxis to peroxynitrite attenuated the
hemodynamic vasodilator effect produced by systemic
administration of acetylcholine and prostacyclin in hindquarter, renal,
and mesenteric circulation. Furthermore, Kooy and
Lewis76 reported that after
tachyphylaxis to peroxynitrite infusion, blood pressure in rats
increased by 20% and renal vascular resistance increased by 93%,
along with increases in hindquarter and mesenteric vascular
resistances. Therefore, the vasodilator action of peroxynitrite will
play only a minimal role in control of vascular tone, if at all.
However, not only will quenching of NO by superoxide increase the
vascular tone, but the increase in peroxynitrite could potentiate this
effect by causing tachyphylaxis to residual NO.
It may not be surprising that high doses of Ang II could
cause oxidative stress since Ang II is a powerful vasoconstrictor;
however, we have recently shown that chronic infusion of subpressor
doses (ie, doses that do not elicit an immediate blood pressure
response) of Ang II (10 ng/kg per minute) for 14 days to normotensive
rats that were given enalapril to block endogenous Ang II
formation resulted in the slow-onset development of hypertension and an
increase in plasma F2-isoprostanes, an indicator
of oxidative stress.77 Two
factors suggest that the increase in blood pressure in this model may
require a secondary mechanism in addition to Ang II itself. The first
is the time delay required for the increase in blood pressure to
develop (5 to 10 hours, typically reaching a maximum in 4 to 5
days),77 78 and
the second is lack of a significant increase in plasma Ang II
levels accompanying the increase in blood
pressure.59 79
Peroxynitrite, by virtue of its potent oxidative ability, can produce
oxidation of lipids and produce other products that have
vasoconstrictive actions. One such group of compounds
are the isoprostanes, which are prostaglandin-like
compounds produced by nonenzymatic, free radical–induced peroxidation
of arachidonic
acid.80 One of the F-ring
isoprostanes (8-iso-prostaglandin
F2
or F2-isoprostanes)
has been shown to be a very potent renal vasoconstrictor, mainly by
increasing afferent resistance, and can also raise blood pressure at
higher
doses.80 81 In
addition, Sametz and
colleagues82 recently
reported that coinfusion of F2-isoprostane and
Ang II resulted in significant potentiation of the vasoconstrictor
effect of Ang II. Furthermore, F2-isoprostanes
have been shown to increase
endothelin,83 which would
also contribute to renal vasoconstriction. We hypothesize that
androgens stimulate the RAS and increase Ang II, which causes oxidative
stress with increased superoxide production, quenching of NO
(leading to a further increase in blood pressure), and
production of peroxynitrite, which causes a reduction in the
renal vascular response to vasodilators, including residual NO, and
production of vasoconstrictor
F2-isoprostanes, which will in turn potentiate
the vasoconstrictor effects of Ang II and stimulate endothelin
production to increase blood pressure even further. To extend
this hypothesis, thromboxane receptor number has been shown
to increase with testosterone treatment in aortic vascular smooth
muscle cells.84
Thromboxane receptors have been shown to mediate at least in
part the biological action of
F2-isoprostanes.85
Thus, androgens could also increase the number of
thromboxane receptors by which the
F2-isoprostanes cause vasoconstriction. It is
doubtful that thromboxanes themselves play any role in
mediating the higher blood pressure in male SHR since, as shown in
Figure 8, we have found that male SHR excrete less
thromboxane B2, the stable
metabolite of thromboxane A2, than
do females.
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Figure 8. Male SHR excrete less thromboxane B2 than do females. Male and female SHR, aged 3 to 4 months, were maintained for 24 hours in individual metabolism cages, and urine was collected on ice for thromboxane B2, as measured by radioimmunoassay. Data are expressed as mean±SEM. Statistical differences were determined by Student’s t test. *P<0.01 compared with males.
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In support of the hypothesis that oxidative stress, and more
directly superoxide, plays a role in the hypertension in male SHR, we
have preliminary data in which SHR were chronically treated with the
chemical scavenger of superoxide, TEMPOL, for 6
weeks.63 With TEMPOL
treatment, the mean arterial pressure of SHR males was
attenuated to the level found in untreated female SHR. Chronic TEMPOL
also decreased PRA in male SHR to levels found in untreated female SHR.
In contrast, there was no effect of TEMPOL on blood pressure or PRA in
female SHR.63 Together with
the data from our enalapril studies in SHR discussed above, these
preliminary data provide strong evidence that Ang II and oxidative
stress play important roles in the higher blood pressure in male
SHR.
Figure 9 serves to illustrate the possible mechanisms by
which oxidative stress could play a role in at least partially
mediating androgen-induced increases in blood pressure. Androgens could
stimulate superoxide production either directly or via the
effect of Ang II on NAD(P)H oxidases. Superoxide production
would quench NO, leading to vasoconstriction. The combination of
superoxide and NO produces peroxynitrite, which would oxidize
arachidonic acid to produce
F2-isoprostanes.
F2-isoprostanes, mediated by
thromboxane receptors, which are upregulated by androgens,
would cause renal vasoconstriction directly and indirectly by
potentiating the vasoconstrictor actions of Ang II and stimulating
endothelin production, which in turn would cause further renal
vasoconstriction. These hypotheses remain to be
tested.
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Figure 9. Schematic diagram describing the speculation of the possible mechanisms by which androgens may increase oxidative stress and thus renal vasoconstriction and lead to increases in blood pressure (BP). O2·- indicates superoxide; Tx, thromboxane.
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Other Mechanism(s) by Which Androgens May
Influence Blood Pressure: Role of Ang II Receptors
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One mechanism by which androgens may affect the
sensitivity
to Ang II is by exerting an effect on Ang II receptors in
the
kidney. In contrast to female SHR and female rats subjected
to
reduced renal mass, female DS rats on a high salt diet exhibit
an
increase in blood pressure after
ovariectomy.
86 87
Nickenig
and colleagues
88
reported that ovariectomy of normotensive
rats results in an increase
in angiotensin type 1 (AT
1) receptor
number in the aorta. In preliminary studies by Harrison-Bernard
and
Raij,
86
AT
1 receptor concentration in the kidney was
found to be higher in ovariectomized female DS rats. It is
possible
that the increase in blood pressure in DS rats after
ovariectomy may
result from the increase in renal AT
1 receptor
number. Angiotensin type 2 (AT
2)
receptors are thought to
be associated with the vasodilatory actions of
Ang II, which
may be mediated by
NO,
89 and it is possible
that male SHR
also have lower AT
2 receptor
numbers than females, which could
contribute to the higher blood
pressure in males than in females.
To date there have been no studies
to determine whether androgens
affect the Ang II receptor subtypes,
numbers, or affinity.
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Other Mechanism(s) by Which Androgens May
Influence Blood Pressure: Role of Aldosterone
|
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Ang II stimulates the production of
aldosterone, which is responsible
for increasing sodium
reabsorption in the distal nephron. It
is possible that androgens could
increase sodium reabsorption
via Ang II–mediated or androgen-mediated
increases in
aldosterone. There is evidence to suggest that
this may be
the case, since Miller and
colleagues
90 found higher
blood
pressure and aldosterone levels in men than in women,
and Schunkert
et al
91 found
a positive correlation between dehydroepiandrosterone
sulfate (a
metabolite of testosterone), aldosterone levels,
and blood
pressure in a population of hypertensive men. However,
Kau and
colleagues
92 reported that
testosterone replacement
in castrated male rats decreased
corticotropin-stimulated aldosterone
release.
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Mechanistic Scheme
|
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This review has attempted to critically examine large
numbers
of fragmentary observations to create a coherent set of
hypotheses
(albeit complicated) by which gender differences in blood
pressure
control may be explained. The speculative hypotheses described
in
Figure 9
represent the possible mechanisms by which
androgens,
mediated via Ang II, could induce oxidative stress to
potentiate
renal vasoconstriction. In
Figure 10
are illustrated the mechanisms
by which
androgen-mediated increases in Ang II could lead to
a shift in the
pressure-natriuresis relationship and renal
vasoconstriction, both of
which are known to affect blood pressure.
As we have shown in animal
studies, androgens could promote
an increase in blood pressure
in males by stimulating renin
activity and Ang II formation, either by
stimulating renin
release and/or by increasing renal renin activity.
Androgens
may stimulate renin release by reducing
glomerular filtration
rate, directly stimulating sodium
reabsorption, and thus decreasing
delivery of sodium to the macula
densa. Alternatively, renin
activity (and thus Ang II) could also be
increased if androgens
cause a chronic increase in renal
angiotensinogen and renin
enzyme is working below its
maximal velocity. Androgens may
affect the number and affinity of
receptors for Ang II, thereby
affecting sodium reabsorption and/or
renal vasoconstriction.
Ang II via AT
1 receptors
may directly cause renal vasoconstriction
and may also stimulate
proximal tubule sodium reabsorption
and/or stimulate
aldosterone-mediated distal tubule sodium
reabsorption,
blunt pressure-natriuresis, and increase blood
pressure. The
combination of increased sodium reabsorption
and renal vasoconstriction
would lead to the increase in blood
pressure.
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Figure 10. Schematic diagram by which androgens could affect the RAS to cause an increase in blood pressure (BP).
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If androgen levels are similar in normotensive and
hypertensive rats and yet blood pressure differences are difficult to
detect in normotensive rats but are very obvious in hypertensive rat
strains, this may suggest that hypertensive rats may exhibit an
exaggerated response to androgens that normotensive rats do not. This
is intriguing because increasing responsiveness to androgens may be an
important factor in why postmenopausal women experience increases in
blood pressure, if in fact androgen levels are not significantly
reduced with aging in
women44 45 46 47
and are left unopposed because of lack of estrogen. The increasing
response to androgens could be mediated by changes in Ang II receptors,
aldosterone, and/or oxidative stress. Future studies will
be necessary to investigate these
possibilities.
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Acknowledgments
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This work was supported by National
Institutes of Health grant
HL-51971 and by an Established Investigator
Award from the
American Heart Association. We also thank Dr Manis
Smith, University
of Mississippi Medical Center, Jackson, for
measurement of
urinary thromboxane
B
2. The author would also like to thank
Dr J.C.
Romero, Mayo Clinic and Foundation, Rochester, Minn,
for helpful
suggestions and commentary during the preparation
of the
manuscript.
Received August 21, 2000;
first decision October 24, 2000;
accepted October 24, 2000.
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References
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Wiinber N,
Hoegholm A, Christensen HR, Bang LE, Mikkelsen KL, Nielsen PE, Svendsen
TL, Kampmann JP, Madsen NH, Bentzon MW. 24-h Ambulatory blood pressure
in 352 normal Danish subjects, related to age and gender.
Am J Hypertens. 1995;8:978–986.[Medline]
Top
Abstract
Introduction