(Hypertension. 1999;34:914-919.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Influence of Female Sex Hormones on Endothelium-Derived Vasoconstrictor Prostanoid Generation in Microvessels of Spontaneously Hypertensive Rats
From the Laboratory of Hypertension, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, Brazil.
Correspondence to Maria Helena C. Carvalho, Laboratory of Hypertension, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, 05508-900, Av Prof Lineu Prestes, 1524, São Paulo, SP, Brazil. E-mail mahecaca{at}.icb.usp.br
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Abstract |
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Abstract—Although female sex hormones may attenuate endothelial dysfunction in spontaneously hypertensive rats (SHR) by increasing endothelium-derived relaxing factors (EDRFs), the influence of ovarian hormones on the generation of endothelium-derived contracting factors (EDCFs) remains unknown. The aim of this study was to evaluate the effect of estrogen and progesterone on the generation of vasoconstrictor prostanoids and superoxide anion (O2-) by microvessels from SHR. Vascular reactivity to norepinephrine (NE), acetylcholine (ACh), and sodium nitroprusside (SNP) were evaluated in the mesenteric arteriolar bed from estrous (OE) and ovariectomized (OVX) SHR. OVX-SHR were treated for 24 hours or 15 days with estradiol and for 15 days with estradiol+progesterone. The vascular reactivity was evaluated in the absence or presence of indomethacin (INDO, 10 µmol/L) and sodium diclofenac (DIC, 10 µmol/L), ridogrel (RID, 50 µmol/L), dazoxiben (DAZ, 10 µmol/L), or superoxide dismutase (SOD, 100 U/mL). Prostanoid levels in the arteriolar perfusate of mesenteries with or without endothelium were measured by enzyme immunoassay. An increased reactivity to NE and reduced sensitivity to ACh were observed in microvessels from OVX-SHR compared with OE-SHR. There were no differences in the responses to SNP. Treatments with estradiol and estradiol+progesterone similarly restored these altered responses. INDO, DIC, RID, and SOD also restored the NE and ACh responses in OVX-SHR. DAZ had no effect on the vascular reactivities. The release of PGF2
, but not of
TXB2 and 6-keto-PGF1, was greater in OVX-SHR
than in OE-SHR microvessels with endothelium when
stimulated by NE. This response was normalized by hormonal treatments.
Neither NE nor ACh stimulated prostanoid production by
microvessels without endothelium. These results suggest
that estrogen may protect female SHR against severe hypertension partly
by decreasing the synthesis of EDCFs such as
PGH2/PGF2 and O2-.
Key Words: estrogen • progesterone • SHR • endothelium-derived contracting factors • prostanoids • superoxide
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Introduction |
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Women in the reproductive age are less prone to hypertension and hypertension-related diseases than men or postmenopausal women.1 This observation suggests that ovarian hormones, especially estrogen, may confer premenopausal protection. Indeed, a reduction in estrogen levels after ovariectomy aggravates hypertension in spontaneously hypertensive rats (SHR).2 In addition, although some authors have reported that estrogen exerts no influence on blood pressure,3 several studies have demonstrated that estrogen replacement can decrease blood pressure in this model of hypertension,4 as well as in postmenopausal women.5
One hypothesis to explain the beneficial effects of estrogen in the cardiovascular system is that estrogen can modulate the generation of endothelium-derived relaxing factors (EDRFs) such as nitric oxide. In vitro studies of certain isolated vessels have demonstrated a relationship between estrogen levels and nitric oxide generation.6 7 In contrast, the influence of estrogen on the biosynthesis of endothelium-derived constricting factors (EDCFs) in hypertension remains unknown.
Endothelial dysfunction in essential hypertension is characterized by a normal release of EDRFs and an enhanced release of EDCFs.8 This imbalance has been associated with impaired endothelium-dependent vasodilatation in the blood vessels of adult SHR.8 The constricting factor released by the endothelium in hypertension is probably a vasoconstrictor prostanoid and/or superoxide anion, because the impairment of endothelium-dependent relaxation is restored by indomethacin, an inhibitor of cyclooxygenase,9 and by superoxide dismutase (SOD).10
Few studies have examined the influence of sex hormones on endothelial function in hypertension.4 6 Williams et al4 reported that 17ß-estradiol enhanced endothelium-dependent relaxation in the aorta of female SHR. Subsequently, Kauser and Rubanyi11 demonstrated important gender differences in the endothelial dysfunction of SHR. In a previous study of microvessels from SHR, we demonstrated that estrogen may have a beneficial effect on endothelial dysfunction.2
Although the influence of female sex hormones on endothelial dysfunction has been studied, the exact mechanism by which these hormones can interfere with the endothelial function in hypertension remains unknown. A few studies have shown that estrogen can modulate EDRF/nitric oxide (NO) generation in the endothelium, but nothing is known about the action of estrogen on the generation of EDCFs in hypertension. In this work, we evaluated the influence of estrogen and progesterone on the generation of vasoconstrictor prostanoids (EDCFs) in microvessels from SHR.
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Methods |
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The experiments were performed with 16- to 18-week-old female SHR obtained from the breeding stock at our own institute and housed according to institutional guidelines (constant room temperature, 12-hour light/dark cycle, 60% humidity, standard rat chow and water ad libitum). The rats were divided into physiologically estrous (OE) and ovariectomized (OVX) groups. At the age of 16 to 18 weeks, physiological estrus was determined by microscopic evaluation of vaginal smears. Ovariectomy was performed at 12 weeks of age under chloral hydrate anesthesia (450 mg/kg). After an abdominal incision, the ovaries were clamped and removed, and the skin was then sutured before the animals were returned to their cages. The rats were used 30 days after surgery. Thirty days after ovariectomy, OVX rats were treated for 24 hours with estradiol 140 µg/kg SC [OVX+E(24 hours)] or for 15 days with subcutaneously implanted 21-day release pellets containing estradiol 0.05 mg [OVX+E(15 days)] or estradiol 0.05 mg+progesterone 50 mg [OVX+E+P(15 days)].
To measure plasma hormone levels, the blood samples were collected from the abdominal aorta of anesthetized SHR and then centrifuged to separate the serum. Serum estrogen and progesterone levels were determined by enzyme immunoassay (Cayman Chemical Co), and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were measured by radioimmunoassay (Amersham Life Science) with 125I-labeled LH/FSH.
Measurement of Arterial Blood Pressure
Mean arterial pressure was determined in conscious,
freely moving rats. One day before the arterial pressure
was recorded, the rats were anesthetized with chloral
hydrate (450 mg/kg), and a Tygon catheter was inserted into the iliac
artery via the femoral artery. The catheter was tunneled
subcutaneously, exteriorized at the back of the neck, and connected to
a pressure transducer (Narco Bio-System). The mean arterial
pressure was recorded over a 30-minute period with a chart
recorder (Narco Bio-System).
Vascular Reactivity in the Perfused Arteriolar Bed
The perfused mesenteric arteriolar bed was prepared as
previously described.12 Concentration-effect curves (CECs)
to norepinephrine (NE, 0.1 to 30 µmol/L),
acetylcholine (ACh, 1 nmol/L to 30 µmol/L), and sodium
nitroprusside (0.01 nmol/L to 1 mmol/L) were obtained. All curves
were performed in the presence of desipramine (inhibitor of
NE uptake) (10 nmol/L). The vascular responses were evaluated as
changes in the perfusion pressure measured with a pressure transducer
(RP-1500i) and recorded on a chart recorder (Narco Bio-System).
The vasodilator responses to ACh and sodium nitroprusside were
calculated as percentages of the contractions induced by NE (5
µmol/L). To evaluate the influence of vasoconstrictor prostanoids on
the vascular reactivity of SHR, CECs were obtained in the presence and
absence of preparations treated with indomethacin
(10 µmol/L) or sodium diclofenac (10 µmol/L)
(cyclooxygenase inhibitors), ridogrel
(a thromboxane [TX]
A2/prostaglandin [PG]
H2 receptor antagonist, 50
µmol/L), or dazoxiben (a TXA2 synthetase
inhibitor, 10 µmol/L). To evaluate the influence of
superoxide anion (O2-) on the
vascular reactivity of SHR, the preparations were treated with SOD (100
U/mL). Each drug was added separately to the perfusing Krebs-Henseleit
solution 30 minutes before the CEC was obtained and was maintained
throughout the experiment. Another series of experiments evaluated the
generation of O2- after the
addition of arachidonic acid. The response to
arachidonic acid (0.01 to 500 µmol/L) was
examined in OE-SHR and OVX-SHR after preconstriction with NE (5
µmol/L) in the presence or absence of SOD (100 U/mL).
Measurement of Prostanoids
The ability of isolated perfused mesenteric vascular beds from
OE-, OVX-, and hormone-treated OVX-SHR to release
PGF2, TXA2, and
PGI2 (measured as TXB2 and
6-keto-PGF1, respectively) was assessed by
quantifying the levels of these prostanoids in 1-mL samples of
perfusate collected immediately before and after stimulation
with ACh (0.001 µmol/L) or NE (30 µmol/L). These
concentrations were chosen because of the hyposensitivity to ACh
(EC50) and hyperreactivity to NE (maximal
responses) in OVX-SHR compared with OE-SHR. The levels of
PGF2, TXB2, and
6-keto-PGF1 in perfusate from
preparations with or without endothelium were
determined with enzyme immunoassay kits (Cayman Chemical Co). The
inactivation of the endothelium from mesenteric
arteriolar bed was performed by superfusing the preparation with sodium
deoxycholate 0.3% as described by Cusma-Pelogia et
al.12
Drugs
The following drugs were used:
l-norepinephrine bitartrate, acetylcholine
chloride, desipramine, sodium nitroprusside,
arachidonic acid, indomethacin, sodium
diclofenac, sodium deoxycholate, and 17ß-estradiol bitartrate from
Sigma Chemical Co. Janssen, Cilag (Brazil) and Pfizer Co (Brazil)
kindly supplied ridogrel and dazoxiben, respectively. Twenty-one-day
release pellets containing 17ß-estradiol or
17ß-estradiol+progesterone were purchased from Innovative Research of
America. All drugs used in the CECs were diluted in
Krebs-Henseleit solution.
Statistical Analysis
The results are shown as mean±SEM for maximal responses or mean
and 95% confidence intervals (95% CI) for EC50.
Statistical analysis was performed with 1-way ANOVA followed by
the Tukey test for multiple comparisons. Values were considered
statistically significant when P<0.05.
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Results |
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The mean arterial pressure of freely moving rats was higher in OVX-SHR than in OE-SHR. Acute and chronic treatments with estradiol reduced the elevated blood pressure in OVX-SHR to levels similar to those observed in OE-SHR. The association of estradiol+progesterone did not change the responses observed with estradiol (Table). The Table also shows the changes in uterus weight relative to changes in estrogen/progesterone concentrations. The decrease in estrogen and progesterone levels after ovariectomy increased levels of LH but not FSH and decreased uterus weight. Acute treatment of OVX-SHR with estradiol increased estrogen levels and uterus weight. Chronic treatment with estradiol increased the concentration of serum estradiol and uterus weight to levels similar to those observed in OE-SHR. Estradiol+progesterone treatment increased the serum concentrations of estrogen and progesterone and enhanced uterus weight in OVX-SHR. The elevated LH levels in OVX-SHR decreased after hormonal treatments. These data demonstrate the effectiveness of the hormone doses used in OVX-SHR.
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Vascular Reactivity
In all experiments using a constant flow rate on a perfused
mesenteric arteriolar bed, we did not observe a change in basal
perfusion pressure (mm Hg) among the groups (data not shown). Compared
with microvessels from OE-SHR, the preparations from OVX-SHR were more
responsive to NE. This difference was abolished by treatment with
hormones (Figure 1A). Diclofenac
corrected the impaired response to NE in OVX-SHR but did not alter the
corresponding responses in preparations from OE-SHR (Figure 1B).
Indomethacin, another
cyclooxygenase inhibitor, also
corrected and even depressed the hyperreactivity of OVX-SHR to NE
compared with OE-SHR (Figure 1B). Ridogrel, but not dazoxiben,
decreased the hyperreactivity to NE of vessels from OVX-SHR (Figure 1C). SOD treatment reduced the reactivity in microvessels from
OVX-SHR to levels similar to those observed in OE-SHR (Figure 1D). Ovariectomy also impaired ACh-induced,
endothelium-mediated relaxation. The sensitivity, but
not maximum relaxation, to ACh was greater in arteriolar beds isolated
from OE-SHR (EC50, 11 nmol/L; 95% CI, 6 to 19)
than OVX-SHR (EC50, 30 nmol/L; 95% CI, 12 to 15;
P<0.05 versus OE). The treatments with estradiol (24 hours)
(EC50, 9 nmol/L; 95% CI, 6 to 13;
P<0.05 versus OVX), estradiol (15 days)
(EC50, 10 nmol/L; 95% CI, 8 to 12;
P<0.05 versus OVX), and estradiol+progesterone (15 days)
(EC50, 11 nmol/L; 95% CI, 7 to 19;
P<0.05 versus OVX) were equally effective in restoring the
altered sensitivity to ACh. Indomethacin, sodium
diclofenac (Figure 2A), and ridogrel
(Figure 2B) corrected the impaired response to ACh in OVX-SHR
but did not alter the corresponding responses in preparations from
OE-SHR. Dazoxiben (Figure 2C) had no effect on the sensitivity
to ACh. SOD (Figure 2D) was also effective in restoring the
endothelium-dependent relaxation in OVX-SHR. There were
no differences in the endothelium-independent
vasorelaxations induced by sodium nitroprusside in preparations from OE
(EC50, 0.12 µmol/L; 95% CI, 0.04 to 0.44)
and OVX-SHR (EC50, 0.10 µmol/L; 95% CI,
0.04 to 0.31). Treatment with female sex hormones or
indomethacin did not affect the sensitivity to sodium
nitroprusside (data not shown).
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P<0.05,
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Microvessels from OVX-SHR rats exhibited vasoconstriction in response to exogenous arachidonic acid, whereas microvessels isolated from OE-SHR exhibited vasodilation (Figure 3). Pretreatment with SOD (100 U/mL) decreased the vasoconstriction in OVX-SHR microvessels but did not change the relaxation in OE-SHR vessels (Figure 3).
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) and microvessels from OE-SHR (n=6, 
) and OVX-SHR
(n=6, 
) treated with SOD (100 U/mL). The responses are expressed as
the percentage of relaxation relative to the contractions induced by NE
(5 µmol/L). Each point represents the mean±SEM.
Release of Prostanoids
There were no significant differences in the basal
production of PGF2,
TXB2, and 6-keto-PGF1
measured in the perfusate from OE, OVX, and OVX-treated SHR
mesenteric arterioles with or without endothelium (data
not shown). Microvessel prostanoid production stimulated by NE
(30 µmol/L) and ACh (0.001 µmol/L) was increased in
preparations with, but not without, endothelium. NE,
but not ACh, markedly enhanced the release of
PGF2 by mesenteric preparations with
endothelium from OVX-SHR compared with OE-SHR. The
increased release of PGF2 observed in
preparations from OVX rats was corrected by hormonal treatments (Figure 4). In contrast,
TXB2 and 6-keto-PGF1
production in OVX-SHR was not affected by ACh or NE (Figure 4). In mesenteries with or without endothelium,
the release of TXA2 and
PGI2 was not affected by ovariectomy or
exogenously administered hormones. However, NE, but not ACh, markedly
enhanced the release of PGF2 by mesenteric
preparations with endothelium from OVX rats compared
with OE rats. The increased release of PGF2
observed in preparations from OVX rats was corrected by hormonal
treatments.
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Discussion |
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The present study demonstrates that the long-term depletion of ovarian hormones increases the mean arterial pressure in conscious OVX-SHR and aggravates the already existing hypertension. The treatment of OVX-SHR with estradiol (24 hours or 15 days) corrected the increase in blood pressure induced by ovariectomy. Concomitant treatment with progesterone did not modify the response to estrogen. These observations suggest that estrogen may be important in the cardiovascular regulation of certain physiopathological situations. In fact, a decrease in blood pressure of menopausal women5 and of gonadectomized animals13 treated with estrogen has been described.
The effects of estrogen are multiple, but the mechanism by which this hormone can interfere with the cardiovascular system in hypertension is still unclear. Although some studies have shown that estrogen may have a modulatory role on endothelial function in hypertensive animals4 6 and humans,14 a few reports have evaluated arterioles,6 the most important vascular territory that controls peripheral resistance. Earlier studies15 16 have suggested that the regulation of peripheral vascular resistance in females and males may not be the same and have proposed that female sex hormones may have an important role in the modulation of the peripheral resistance.
In this study, we examined whether ovarian hormones can regulate arteriolar tone by modulating endothelial function and thus contribute to the less pronounced hypertension observed in OE-SHR. Our results suggest that estrogen, but not progesterone, modulates the endothelial function of mesenteric arterioles isolated from female SHR. Conversely, these results may also be secondary to the differences in blood pressure. Similar findings in women have recently been reported.17 Postmenopausal women undergoing coronary angiography were found to have reversal of ACh-induced vasospasm when treated with infusions of estradiol.
Several studies have investigated the role of endothelium-derived NO in mediating the effects of estrogen on vasomotor tone. Estrogen stimulates the synthesis of NO in numerous tissues from normotensive animals7 and humans.18 Likewise, in hypertensive rats, estrogen affects the release and/or action of endothelium-derived NO.6 We have demonstrated recently that estrogen increases the activity of NO synthase in mesenteric microvessels from ovariectomized SHR, suggesting that this hormone modulates endothelial dysfunction in arterioles by preserving NO synthesis.19
However, endothelium-dependent contractions caused by ACh are smaller in aortic rings from female SHR than male SHR.11 16 Because endothelium-dependent contractions to ACh can be explained by the increased production of EDCFs,8 the stimulatory role of female hormones on EDRF/NO production is not sufficient in itself to account for the modulation of endothelial function in hypertensive rats. This observation suggests that ovarian hormones can modulate endothelial function in SHR by a concomitant increase of EDRF/NO and a decrease in the generation of EDCFs, such as prostaglandins. Indeed, Kähönen et al16 have demonstrated that the treatment of mesenteric arteries with diclofenac abolished the differences in the responses to ACh between female and male SHR previously described by Kauser and Rubanyi.11
Our study demonstrated an accentuated dose-dependent vasoconstriction to arachidonic acid in microvessels from OVX-SHR and a slight vasodilation in arterioles from OE-SHR. In addition, the results obtained after the treatment of mesenteric arterioles from OVX-SHR with cyclooxygenase inhibitors suggest that the removal of ovarian steroid hormones increases the generation of cyclooxygenase-derived vasoconstrictors. In agreement with our data, a recent study of mesenteric arteries from ovariectomized normotensive rats demonstrated that estrogen suppresses a cyclooxygenase-dependent vasoconstriction.20 Thus, the beneficial effect of estrogen in vascular function may be attributed, in part, to a direct action on cyclooxygenase-mediated responses. The decrease in the vasoconstrictor response to NE was more marked with indomethacin than with diclofenac. These results suggest that indomethacin may have activities other than cyclooxygenase inhibition. Indeed, it has been shown that indomethacin may inhibit calcium influx into stimulated smooth muscle cells.21
To identify the vasoconstrictor prostanoids involved in the altered reactivity in OVX-SHR, the possibility of TXA2 or PGH2 involvement was evaluated first. The effects of ridogrel on the vascular reactivity to NE and ACh were similar to those seen with cyclooxygenase inhibitors. Dazoxiben did not modify the vascular responses, suggesting that PGH2, but not TXA2, was the most likely EDCF involved in the altered reactivity after ovariectomy.
To confirm these results, the levels of various
PGH2 metabolites (PGF2,
PGI2, and TXA2) were
determined after stimulation with NE or ACh. In microvessels with
intact endothelium from OVX-SHR, NE, but not ACh,
increased the production of PGF2
compared with that observed in OE-SHR. In contrast, ovariectomy did not
alter the release of PGI2 and
TXA2 stimulated by NE or ACh. The increased
release of PGF2 in microvessels from OVX-SHR
was normalized by estradiol. Progesterone did not modify this effect of
estrogen. Neither NE nor ACh increased the release of these prostanoids
by microvessels without endothelium. Together, these
results indicate that endothelium-derived
PGH2 and/or PGF2 may be
involved in the more pronounced endothelial dysfunction
in SHR in the absence of estrogen. Compared with our data from OVX
rats, some reports have proposed the involvement of
endothelium-derived PGH2 in
endothelial dysfunction.9 Conversely,
whether and to what extent the increase of
PGF2 generation would account for the enhanced
endothelial dysfunction in OVX-SHR remains an open
question. Although very large, nonphysiological
concentrations of PGF2
(>10-7 mol/L) are necessary to cause
constriction of microvessels,22 some studies have shown
that physiological amounts of
PGF2, associated with low-estrogen conditions,
cause an intense endometrial vasoconstriction leading to the menstrual
discharge.23
Therefore, these EDCFs do not necessarily have to be prostanoids, because O2- can also be classified as a cyclooxygenase-derived EDCF.24 Cyclooxygenase-derived EDCFs at least partially impair endothelium-dependent vasodilation by inactivating NO, indicating that these factors may include oxygen free radicals, such as superoxide (O2-).25 It has been proposed that PGH2 may modulate the generation of O2- in the endothelium.26 In addition, oxygen free radicals produce contractions of the rat aorta that are augmented in SHR and are reduced in the presence of a cyclooxygenase inhibitor.27
Because the inactivation of endothelium-derived NO by O2- participates in endothelial dysfunction in hypertension,10 we also examined the influence of female sex hormones on cyclooxygenase-derived O2-. Many reports have related the protective effect of estrogen on endothelial function to its antioxidant property.28 The antioxidant effect of estrogen may be attributed to its phenolic structure, which scavenges oxygen free radicals.29 Estrogen may also exert its antioxidant action by regulating the action of antioxidant enzymes, such as SOD.30 Our data from the OVX-SHR in the presence of SOD suggest a role for O2- in the impaired endothelial function after ovariectomy. In addition, SOD decreased the vasoconstrictor response to exogenous arachidonic acid in OVX-SHR. Thus, the less pronounced endothelial dysfunction observed in estrous female SHR may reflect a decreased generation of cyclooxygenase-derived vasoconstrictor prostaglandins and O2-. Although we are tempted to associate O2- generation with the formation of endothelium-derived cyclooxygenase products in microvessels of OVX-SHR, we cannot discard the influence of estrogen on other sources of O2-, such as NADH/NADPH oxidases and xanthine oxidases in endothelial and smooth muscle cells. Further studies are necessary to elucidate the precise relationship between estrogen and O2- generation.
In conclusion, our results suggest that estrogen may exert a beneficial
effect on the generation of EDCFs, such as PGH2,
PGF2, and/or
O2-, in microvessels of female
SHR. Because O2- has been
proposed to directly inactivate NO, the decreased release
of cyclooxygenase-derived vasoconstrictor
products by microvessels from OE-SHR may favor the diminished
endothelial dysfunction not only by decreasing
vasoconstriction but also by preserving the beneficial effects of
endothelium-derived NO. Because
endothelial dysfunction plays an important role in
cardiovascular diseases, it is possible that these
effects could contribute to the lower incidence and slower progression
of hypertension in women.
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Acknowledgments |
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This study was supported by Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Pesquisa (CNPq), and Fundação de Amparo a Pesquisa de Estralo de São Paulo (FAPESP). The authors are grateful to Sonia Maria Rodrigues Leite and Hermes V. Barbeiro for technical assistance and Dr Stephen Hyslop for revising the English of the manuscript.
Received May 10, 1999; first decision June 15, 1999; accepted August 2, 1999.
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