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1 Department of Cell Biology and 2 The Vascular Biology and Hypertension Program of the Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In women, arterial pressure generally increases after menopause, but several studies suggest that women who eat large amounts of plant estrogens (phytoestrogens) experience a slower rise in the incidence of postmenopausal hypertension. This suggests that both ovarian hormones (principally estrogen) and phytoestrogens may protect at least some women from hypertension. The present study tests the hypothesis that phytoestrogens blunt hypertension in estrogen-depleted female spontaneously hypertensive rats (SHR). Three-week-old ovariectomized SHR were fed one of four diets that contained basal (0.6%) or high (8%) NaCl with or without dietary phytoestrogens for 9 wk. In SHR on the basal NaCl diet, arterial pressure was unaffected by the removal of dietary phytoestrogens. In contrast, in SHR on the high-NaCl diet, arterial pressure was significantly higher in rats on the phytoestrogen-free (204 ± 4 mmHg) compared with the phytoestrogen-replete (153 ± 4 mmHg) diet. Ganglionic blockade resulted in reductions in arterial pressure that were directly related to the dietary NaCl-induced increases in arterial pressure. Together, these data indicate that dietary phytoestrogens protect ovariectomized female SHR from dietary NaCl-sensitive hypertension and that the sympathetic nervous system plays an important role in this effect. Furthermore, these results demonstrate that dietary phytoestrogens can have a major impact on the interpretation of studies into the physiological role of estrogen in females.
phytoestrogen; ovariectomy; sympathetic nervous system
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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IN BOTH MALES AND FEMALES, hypertension is one of the primary contributors to cardiovascular disease (the leading cause of death in the United States), but there is a sexual dimorphism in the incidence of hypertension (26). Arterial pressure in males exceeds that in similarly aged women until the age of menopause, but after that age, arterial pressure in women increases rapidly and eventually equals or exceeds that in males (26). This suggests that there is an interaction between circulating estrogen and blood pressure control in women. Furthermore, compared with age-matched men, premenopausal women are resistant to the hypertensive effects of a high-NaCl diet, but following menopause, women and men display a similar incidence of salt-sensitive hypertension (36).
A similar sexual dimorphism is present in some of the most common rat models of hypertension [e.g., spontaneously hypertensive rats (SHR), Dahl NaCl-sensitive rat]. In these animals, hypertension develops more rapidly and severely in male compared with female rats (e.g., 11, 12, 37), and female rats display less pronounced NaCl-sensitive hypertension (7). Furthermore, in female Dahl salt-sensitive rats and DOCA-NaCl rats, the elimination of endogenous estrogen blunts this sexual dimorphism and accelerates the development of NaCl-dependent hypertension (12, 37). In female compared with male SHR, the hypertensive response to a high-NaCl diet is greatly decreased (7, 8), suggesting that estrogen may blunt NaCl-sensitive hypertension in female SHR. However, ovariectomy of young female SHR does not cause a large increase in blood pressure in rats on a basal or high-NaCl diet, suggesting that endogenous estrogen is not the sole contributor to the arterial pressure protection that female SHR display (8).
Recent studies suggest that plant estrogens (phytoestrogens) can have
important physiological effects. The two major phytoestrogens genistein
and daidzein are abundant in soy diets that are normally fed to rats
and appear to be the most physiologically active phytoestrogens in
mammals (6), likely due to their structural similarity
with estrogen and their high affinity binding to the 
-estrogen
receptor (ER-; Refs. 5, 10). Data from other
laboratories indicate that phytoestrogens in the normal diet mimic some
of the beneficial effects of estrogen in rats (10, 14,
22). The present study tests the hypothesis that both plant and
endogenous estrogens can protect female SHR from at least one form of
hypertension, i.e., NaCl-sensitive hypertension.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1
Three-week-old SHR (n = 8 per group, Harlan Sprague-Dawley) were ovariectomized and allowed ad libitum access to one of four diets: normal phytoestrogen-replete (PE+) diet containing either basal (0.6%; diet #8746, Teklad, Madison, WI) or high (8%; diet #5008, Teklad) NaCl, or a phytoestrogen-free (PE
) diet
containing either basal (0.6%; custom diet TD86369, Teklad) or high
(8%; custom diet TD86370, Teklad) NaCl. Independent assay demonstrated that the PE+ diet contained 0.06% phytoestrogen by weight and the PE
diet contained no detectable phytoestrogens (6). Rats were
maintained at constant humidity (65 ± 5%), temperature (24 ± 1°C), and light-dark cycle (0600-1800, lights on), and they were allowed ad libitum access to tap water and diet throughout the
experimental protocols. All experimental procedures were
conducted in accordance with institutional and National Institutes of
Health guidelines and under the approval of the University of Alabama at Birmingham's Institutional Animal Care and Use Committee.
At 10 wk of age, all rats were anesthetized with pentobarbital sodium (35 mg/kg ip), and each rat was instrumented with an implantable arterial pressure transducer/transmitter (TA11PA-C40; Data Sciences, St. Paul, MN) as described previously (8, 9). The catheter was inserted into the abdominal aorta immediately caudal to the renal arteries, and the body of the transmitter was sutured to the inside of the anterior abdominal wall. The rats were allowed at least 1 wk to recover from the operation and were housed in individual cages throughout the study. Each cage was placed on a receiver panel for recording data via the Dataquest IV software system (Data Sciences). Arterial pressure, heart rate, and activity data for each rat were recorded for a 10-s period every 5 min. After a 1-wk recovery period, arterial pressure, heart rate, and activity were recorded for 2 wk.
For analysis of the circadian rhythms of mean arterial pressure (MAP) and heart rate, mean values were calculated at 60-min intervals for each diet/strain group. The data from 3 consecutive days were subjected to rhythm analysis using a nonlinear fitting program PHARMFIT, as described previously (8, 9, 34), and the "best fit" model was defined as the one with the lowest number of harmonics that had a confidence value of at least 0.05, as determined by the subprogram SYNOPS (8, 34). The MESOR (rhythm-adjusted 24-h mean), amplitude (the peak to trough of the rhythm), acrophase (time at which each component cosine function reaches its peak), and the percentage to which the computed rhythm estimates the data were determined for all groups.
Experiment 2
By the end of experiment 1, MAPs of the ovariectomized SHR on the PE, high-salt diet were extremely high,
with some of the animals exceeding 260 mmHg. Therefore, we conducted a
second experiment in which arterial pressure and heart rate were
measured at an earlier age. Three-week-old female SHR
(n = 56, Harlan Sprague-Dawley) were ovariectomized or
received sham surgery (i.e., anesthetized and skin cut open; intact
controls), and they were placed on one of four diets as described above
(i.e., 8 groups). At 7 wk of age, all rats were again anesthetized, and
each rat was instrumented with catheters implanted in the right femoral
artery and vein. Three days later, arterial pressure and heart rate
were monitored by connecting the arterial catheter to a pressure
transducer connected to a personal computer (BioPac, Santa Barbara,
CA). MAP was measured at 0200-0400 and 1400-1600, time points
that approximate the nighttime peak and daytime nadir of the 24-h
arterial pressure rhythm as observed in experiment 1.
To test the role of the sympathetic nervous system in the arterial pressure response to the high-NaCl diet, we blocked sympathetic nervous system activity using the ganglionic blocker hexamethonium (10 mg/kg body wt iv) at 0200-0400, the approximate peak of the arterial pressure circadian rhythm in SHR. Arterial pressure was recorded 30 min before hexamethonium infusion and for 20 min following the treatment.
Statistical analysis. All data from both experiments were evaluated by analysis of variance (between-group MAP and heart rate comparisons) or repeated-means analysis of variance (within- and between-group comparisons of the hexamethonium responses) followed by appropriate post hoc tests (Newman-Keuls) to determine the source of main effects and interactions. The significance criterion for all experiments was P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1: 8-Wk Diet Exposure
In 12-wk-old ovariectomized SHR on basal NaCl, PE+ diet, the 24-h average MAP was 130 ± 2 mmHg (Fig. 1). The removal of phytoestrogens from the basal NaCl diet (PE group) was associated with no significant increase in MAP [136 ± 3 mmHg, not significant (NS); Fig. 1].
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Exposure to the high-NaCl diet for 8 wk (from 3 wk of age) increased
MAP to 153 ± 4 mmHg in the PE+ rats (an increase of 23 mmHg;
P < 0.05 vs. either group fed the basal NaCl diet).
The removal of phytoestrogen greatly exacerbated the MAP response to
the high-NaCl diet, i.e., MAP increased to 204 ± 4 mmHg in the
PE group (an increase of 68 mmHg; P < 0.05 vs. all
other groups; Fig. 1; all statistical comparisons were equally
significant whether the means of the arterial pressure were generated
directly from the raw data or from the individual MESORs). The
high-NaCl diet led to a similar increase in amplitude of the 24-h
pressure rhythm in both PE+ (4.38 mmHg) and PE (2.77 mmHg, NS; Fig.
1), and it did not alter the acrophase of the rhythm (time of peak).
In SHR fed the basal NaCl diet, the 24-h average heart rate was
significantly lower in PE+ compared with PE rats (339 ± 2 vs.
358 ± 3 beats/min, respectively; P < 0.05; Fig.
2). Exposure to the high-NaCl diet
resulted in a slight but significant reduction (9 beats/min;
P < 0.05) in 24-h average heart rate in the PE+ rats,
whereas heart rate slightly increased in the PE group (+9 beats/min;
P < 0.05; Fig. 2). At the end of the study, there were no significant differences in body weight between the groups.
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Experiment 2: 4-Wk Diet Exposure
Because MAP was extremely high in the high-NaCl, PE group in
experiment 1, and because no nonovariectomized rats were
included in experiment 1, arterial pressure responses to the
high-NaCl diet were tested at a shorter exposure to the diets (4 wk on
diet) in both ovariectomized and intact rats. Because rat telemetry probes cannot reliably be implanted in animals weighing <150 g, a
tethered catheter system was used for experiment 2. Body
weights were significantly greater in the PE rats (210 ± 3 g) compared with the PE+ group (191 ± 5 g; P < 0.05), although exposure to the 8% NaCl diet did not significantly
alter the body weights. However, animals on the PE diet (207 ± 4 g) tended to be heavier than those on the PE+ diet (194 ± 4 g; NS).
Nighttime measurement.
To assess MAP during the rat's active period, arterial pressure was
measured from 0200 to 0400 (the approximate peak of the arterial
pressure circadian rhythm in SHR). Intact, 7-wk-old female SHR on basal
salt, PE+ diet displayed a nighttime average blood pressure of 126 ± 4 mmHg, which was not significantly altered by removal of
phytoestrogens from the diet (121 ± 1 mmHg; Fig. 3). Ovariectomy had no effect on average
nighttime blood pressure in either the PE+ (121 ± 4 mmHg) or the
PE (126 ± 3 mmHg) group fed the basal NaCl diet (Fig. 3).
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group to 144 ± 3 mmHg (+23 mmHg;
P < 0.05; Fig. 3). In ovariectomized PE+ rats, the
high-salt diet increased nighttime MAP to 165 ± 5 mmHg (+44 mmHg;
P < 0.05 compared with all intact groups) and in the
ovariectomized PE rats to 190 ± 4 mmHg (+62 mmHg;
P < 0.05 compared with all other groups; Fig. 3).
Daytime measurement.
Arterial pressure was also measured from 1400 to 1600, the approximate
nadir of the arterial pressure rhythm in SHR. Blood pressures were
lower during the daytime than nighttime in all groups, and there were
no significant differences in daytime MAP among the four groups fed the
basal NaCl diet for 4 wk (Fig. 3). The high-NaCl diet induced a small
increase in daytime MAP in the intact PE+ rats (10 mmHg; NS) and a
significantly larger increase (25 mmHg; P < 0.05) in
the intact PE group (Fig. 3). In the ovariectomized rats, the
high-NaCl diet increased daytime MAP similarly in the PE+ and PE
groups (21 and 24 mmHg, respectively; Fig. 3).
Sympathetic blockade.
To assess the contribution of sympathetic nervous system to arterial
pressure, autonomic blockade was induced using hexamethonium during the
approximate peak of the arterial pressure circadian rhythm in SHR
(0200-0400). Acute hexamethonium blockade of sympathetic nervous
system activity significantly reduced nighttime arterial pressure in
all groups. The decreases correlated directly with the basal MAP and
were the greatest in the ovariectomized PE group fed the high-NaCl
diet (Fig. 4). The hexamethonium blockade eliminated the significant nighttime arterial pressure differences between the groups.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study demonstrates that dietary phytoestrogens protect ovariectomized SHR from dietary NaCl-sensitive hypertension. In ovariectomized SHR on a normal (PE+) diet, excess dietary NaCl causes a modest increase in arterial pressure, even when the NaCl challenge is initiated as early as 3 wk of age. However, in this model, the removal of phytoestrogens from the diet greatly exacerbates the hypertensive response to a high-NaCl diet. The results of the present study also indicate that the sympathetic nervous system contributes to the exaggerated response of arterial pressure to dietary NaCl.
These findings are consistent with evidence suggesting that circulating estrogen blunts hypertension and cardiovascular disease in human females. After menopause, arterial pressure rises, resulting in a significantly higher rate of hypertension (42), including NaCl-sensitive hypertension (36), greatly increasing the risk of cardiovascular disease and mortality (36). The present study demonstrates that circulating estrogen reduces NaCl sensitivity in female SHR, although it has little effect on arterial pressure in SHR fed a basal NaCl diet.
The present findings also indicate that dietary phytoestrogens
significantly reduce the increase in arterial pressure in response to
dietary NaCl. These results support a growing body of evidence that
indicates that both dietary phytoestrogens and endogenous estrogen have
a cardioprotective effect. It is well documented that Asian (compared
with Western) women have significantly lower rates of cardiovascular
morbidity and mortality; the postmenopausal rise in blood pressure
occurring in women from Western societies is significantly greater
compared with Japanese women (1), who consume much higher
levels of dietary phytoestrogens (24, 25, 39). These
observations suggest that dietary phytoestrogens can mimic some of the
effects of estrogen replacement therapy. Dietary phytoestrogens exert
their actions primarily through ER-
and ER- (18, 27, 28,
35), but their protective effects may also be mediated through
their ability to inhibit tyrosine kinase (23). Research
suggests that phytoestrogens preferentially bind to ER- (vs. ER-)
receptors. Genistein, the primary phytoestrogen in soy, has negligible
binding affinity for the ER- receptor but binds to ER- receptors
with only three times lower affinity than 17-estradiol
(27). Thus we hypothesize that the antihypertensive effects of phytoestrogens are mediated by the ER- receptor, leading to alterations in vascular compliance (2, 33, 46), renal function (40), and circulating lipid levels
(17), without inducing breast or uterine cancer (20,
21), the most serious potential side effects of estrogen
replacement therapy (3, 8, 21). However, clinical
studies have not convincingly demonstrated a beneficial effect of
phytoestrogen treatment in women (15, 19).
The means by which estrogen and phytoestrogens protect female SHR from
NaCl-induced changes in blood flow are unclear but probably include
both peripheral and central nervous system mechanisms. Estrogen's
vasoprotective effects include its ability to blunt vasoconstrictor
responses to norepinephrine by reducing intracellular free calcium
(4) and to enhance vasodilation by increasing nitric oxide
release (13). Similar effects have been reported in
response to phytoestrogen consumption (2, 33, 46).
Estrogen and phytoestrogens may also act centrally to reduce
sympathetic activity (43) and to increase parasympathetic
activity (30) by modulating baroreflex function and/or
altering brain control of arterial pressure (41). In the
present study, heart rate was slightly higher in PE rats fed the
basal NaCl diet compared with the PE+ group. Furthermore, in contrast
to PE+ rats, PE rats failed to reduce heart rate following exposure
to the high-NaCl diet. These observations are consistent with the
hypothesis that hypertension and NaCl-sensitive hypertension in SHR are
due, at least in part, to overactivity of the sympathetic nervous
system (9, 31, 47). We more formally tested this
hypothesis by using hexamethonium to block sympathetic outflow during
the peak period of the arterial pressure rhythm. The greatest decrease in arterial pressure in response to the hexamethonium challenge occurred in the ovariectomized SHR on the high-NaCl, PE diet, whereas
the second largest drop was found in the ovariectomized rats fed the
high-NaCl, PE+ diet. Furthermore, treatment with hexamethonium reduced
blood pressure in both groups to similar levels. These results indicate
that the sympathetic nervous system contributes to the NaCl-sensitive
hypertension in estrogen-depleted rats. Moreover, our data suggest that
both endogenous and exogenous estrogens blunt the sympathetic nervous
system response to the high-NaCl diet, which is consistent with other
evidence indicating that female sex hormones may reduce circulating
catecholamine levels (32) and suppress sympathetic nervous
system activity and hypertension in male SHR (16).
The present study demonstrates that after a 2-mo exposure to a
high-NaCl, PE diet, blood pressure increases significantly during
both nighttime and daytime periods in ovariectomized SHR. In contrast,
at an earlier time point (1 mo after exposure to the diet), nighttime
(but not daytime) arterial pressure is significantly increased. This is
similar to our findings in male SHR in which a high-NaCl diet increases
nighttime arterial pressure much sooner than it increases daytime
arterial pressure (8). Thus, in both male and
estrogen-depleted female SHR, a high-NaCl diet causes an eventual
increase in daytime arterial pressure, leading to a decreased amplitude
of the arterial pressure circadian rhythm (8). The failure
of arterial pressure to dip during the daytime in estrogen-depleted
female SHR chronically fed a high-NaCl diet (8) is similar
to the failure of arterial pressure to decrease during sleep periods in
many established hypertensive humans, i.e., nondippers (38, 44,
45) appear to accelerate both cardiovascular and renal disease
(29, 38, 44, 45).
Perspectives
The present results demonstrate that dietary phytoestrogens protect female SHR from NaCl-sensitive hypertension. Although a high-NaCl diet normally causes only a modest increase in arterial pressure in intact female SHR, removal of either endogenous ovarian estrogen or exogenous dietary phytoestrogens elicits NaCl-sensitive hypertension. The most important finding of the present study is that the depletion of both endogenous and exogenous estrogen dramatically exacerbates the hypertensive effect of a high-NaCl diet. Furthermore, this protective effect of both estrogen sources appears to be related to their ability to prevent sympathetic nervous system overactivity in response to a high-NaCl diet. These data suggest that research examining the biological role of estrogen should carefully consider the similar and synergistic actions that endogenous and exogenous estrogens may produce. They also suggest that the role of estrogens should be carefully examined in postmenopausal women who are under stress, whether that be dietary or emotional.| |
ACKNOWLEDGEMENTS |
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This work was supported by Grants HL-37722 and HL-07457 from the National Institutes of Health in Bethesda, MD.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. M. Wyss, Dept. of Cell Biology, Univ. of Alabama at Birmingham, Birmingham, AL 35294-0019 (E-mail: jmwyss{at}uab.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 23 January 2001; accepted in final form 3 August 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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