(Hypertension. 1999;34:1117-1122.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Effect of Estrogen Replacement on Vasoconstrictor Responses in Rat Mesenteric Arteries
From the Perinatal Research Centre, Departments of Ob/Gyn and Physiology, University of Alberta, Edmonton, Alberta, Canada.
Correspondence to Sandra T. Davidge, PhD, Perinatal Research Centre, 220 HMRC, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. E-mail sandra.davidge{at}ualberta.ca
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Abstract |
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Abstract—Recent studies have shown that estrogen can increase endothelial nitric oxide synthase expression and/or activity and that nitric oxide may play a role in attenuating vasoconstrictor responses. Yet there are still controversies in this field. Our hypothesis was that the role of nitric oxide in modulating vasoconstrictor responses in estrogen-replaced animals depends on the agonist. The aim of the study was to determine the effect of long-term estrogen replacement on vascular reactivity of resistance-sized mesenteric arteries in ovariectomized rats with the use of a variety of vasoconstrictors. Female Sprague-Dawley rats were ovariectomized at 11 weeks of age. 17ß-estradiol pellets (0.5 mg/pellet) were implanted in the estrogen-replaced group (n=9) for 4 weeks; placebo pellets were used in the ovariectomized group (n=10). Resistance-sized mesenteric arteries were dissected and mounted onto a dual-chamber arteriograph system. Estradiol replacement did not alter the response of mesenteric arteries to either arginine vasopressin or the thromboxane mimetic U46619. Inhibition of nitric oxide synthase with NG-monomethyl-L-arginine (100 µmol/L) did not modulate these vasoconstrictor responses in either group of rats. In contrast, the dose-response curve of the adrenergic agonist phenylephrine was significantly attenuated for the estradiol-replaced rats compared with the ovariectomized group (EC50=0.90±0.17 vs 0.44±0.08 µmol/L, P<0.05). After incubation with NG-monomethyl-L-arginine, the EC50 of phenylephrine significantly decreased in both groups, but a significant difference remained between the 2 groups (EC50=0.41±0.08 vs 0.28±0.02 µmol/L, P<0.05). Importantly, Western immunoblotting demonstrated that the expression of
1-adrenergic receptors was significantly suppressed by
estradiol replacement. We conclude that estrogen may have a specific
effect on adrenergic vasoconstriction by modulating its receptors.
Key Words: steroids • nitric oxide • receptors, adrenergic, alpha • vasopressin • thromboxanes
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Introduction |
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Epidemiological studies have shown that the incidence of cardiovascular disease in premenopausal women is lower than that in men and postmenopausal women.1 2 This is believed to be due to the protective effect of circulating estrogen because estrogen replacement therapy significantly reduces the incidence of cardiovascular disorders in postmenopausal women.3 4 The vascular wall has been shown to contain specific high-affinity receptors for estrogen both in humans5 6 and in animals,7 8 9 providing strong biological evidence that the cardiovascular system is one of the targets of estrogen. However, the exact mechanisms of the protective effect of estrogen are still unknown.
Estrogen treatment in animal models increases systemic and uterine blood flow10 11 12 13 and attenuates the pressor response to phenylephrine (PE) in mesenteric14 and aortic arteries.15 Many of these studies have implicated nitric oxide (NO) as the mediator of the altered vascular response resulting from estrogen treatment. This theory is supported by the data showing that estrogen can induce endothelial NO synthase (eNOS) expression and increase eNOS activity.16 17
However, there are still controversies in this field. Although some
studies have demonstrated that long-term treatment with estrogen
enhances NO-dependent modulation of vascular
function,11 13 14 other studies do not
concur.18 Further, the specificity of the vasoconstrictor
studied may influence the role of NO in modulating vascular response.
The aim of the current study was to investigate the effect of long-term
estrogen replacement on vascular reactivity of resistance-sized
mesenteric arteries in ovariectomized rats with the use of a variety of
vasoconstrictors including PE, an 1-adrenergic
receptor agonist; arginine vasopressin (AVP), a neurohypophyseal
hormone; and U46619, a thromboxane mimetic. The effect of
NO to modulate the vasoconstrictor responses was also tested by use of
the NOS inhibitor
NG-monomethyl-L-arginine
(L-NMMA).
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Methods |
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Animal Model
Female Sprague-Dawley rats were obtained at 10 weeks of age (weight range 200 to 225 g) from Harlan, USA. All animals were allowed to recover from the trip and acclimatize to the university facility for 1 week. Ovariectomy was performed following the university standard procedure. At the time of ovariectomy, one group of rats (n=9) received a 17ß-estradiol pellet (0.5 mg/60-day release, Innovative Research of America) subcutaneously; the control group (n=10) received a placebo (Innovative Research of America). After 4 weeks, the rats were euthanized under light anesthesia with methohexital sodium (50 mg/kg body wt). Blood samples were collected from the right atrium, allowed to clot, and centrifuged at 3000 rpm for 10 minutes. Sera were stored at -80°C for later assay of serum 17ß-estradiol levels. The animal protocols were examined by the University of Alberta Animal Welfare Committee and found to be in compliance with the guideline issued by the Canada Council on Animal Care.
Vessel Preparation and Equipment
A section of the mesentery 5 to 10 cm distal to the
pylorus was rapidly removed and placed in ice-cold
N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic
acid]–buffered physiological saline solution
(HEPES-PSS). The composition of HEPES-PSS was as follows (in
mmol/L): NaCl 142, KCl 4.7, MgSO4 1.17,
Ca2Cl 1.56,
KH2PO4 1.18, HEPES 10, and
glucose 5.5. Resistance-sized mesenteric arteries were dissected from
the fat tissue transferred to a dual-chamber arteriograph (Living
Systems Instrumentation). The proximal end of an artery was tied to the
glass cannula of the arteriograph, and with the use of a Servo pump,
arteries were gently flushed with HEPES-PSS buffer to remove residual
blood. The distal end of the artery was then mounted to the second
glass cannula. Intraluminal pressure was gradually increased to 75
mm Hg to approximate the in vivo pressure of the arteries. All
arterial measurements, including inner diameter and wall
thickness, were collected by a video camera mounted on the microscope,
a dimension analyzer (Living Systems Instrumentation), and a
monitor.
Experimental Protocol
The mesenteric arteries were equilibrated in warm (37°C)
HEPES-PSS buffer for 30 minutes at the intraluminal pressure of 75
mm Hg. Prestretching of the arteries was achieved by increasing the
intraluminal pressure from 75 to 100 mm Hg and immediately
returning it to 75 mm Hg. This pressure was maintained throughout
the experiment. The arteries were equilibrated for another 30 minutes.
All the experiments were started with the dose-response of 1 of 3
vasoconstrictors in the absence of the NOS inhibitor.
Cumulative doses of AVP (0.1 nmol/L to 100 nmol/L), U46619 (1 nmol/L to
100 µmol/L), or PE (0.1 to 10 µmol/L) were conducted. Only
one type of vasoconstrictor was applied to any one mesenteric
preparation. With a 30-minute interval and 3 washes, the arteries were
then incubated with L-NMMA (100 µmol/L) for 15 minutes. This
concentration of L-NMMA has been shown to be an effective
inhibitor of eNOS.19 In addition, we tested
our mesenteric arteries with a dose-dependent vasoconstriction to
L-NMMA (3 to 300 µmol/L). Maximal constriction response occurred
with 100 µmol/L, with no further effect with higher doses of
L-NMMA. The arterial diameter was taken immediately before
and at the end of the L-NMMA incubation period to determine the effect
of L-NMMA on vasoactivity at basal condition. Vasoconstrictor dose
responses were then repeated in the presence of L-NMMA. The
reproducibility of repeating curves had been determined in preliminary
experiments.
The vessel diameter changes in response to the different doses of vasoconstrictors were normalized to the maximal constriction of each vasoconstrictor (AVP, U46619, and PE) in each experiment.
Western Immunoblot
Mesenteric arteries were dissected free of surrounding adipose
tissue and homogenized. Protein concentrations were
determined with the use of the method of Bradford.20
Western immunoblot procedures were conducted as previously
described in detail.21 Samples containing 4.6 µg of
protein were loaded on 10% polyacrylamide gels, and
1-adrenergic receptor expression was
evaluated. Because the 1D-adrenergic receptor
subtype is the predominant type in mesenteric arteries,22
we used polyclonal antibodies to 1D-adrenergic
receptors (1:1000; Santa Cruz Biotechnology, Inc).
Radioimmunoassay
Rat serum 17ß-estradiol was assayed with the materials and
methods provided by Diagnostic Products Corp. The limit
of detection for the assay was 1.4 pg/mL. In this experimental period,
the interassay variability and intra-assay variability were 2% and
2.7%, respectively, for the 2 sets of radioimmunoassays.
Data Analysis and Statistics
The data from 3 vasoconstrictor dose-response curves were fitted
to the Hill equation, from which a straight line was generated by
linear least regression analysis. The effective concentration
that produced a 50% response (EC50) was
determined from this line and expressed as the geometric mean±SE.
ANOVA with the post hoc Tukey’s test was used to determine statistical
difference among the groups. Data were considered significantly
different at values of P<0.05.
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Results |
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Animal Model
As anticipated, there was a significant increase in plasma 17ß-estradiol levels in the estradiol-replaced rats that were in the physiological range of cycling proestrus and pregnancy levels. Uterine weight, which provides a biological marker of estrogen replacement, was also significantly elevated in the estradiol-replaced group (Table).
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Basal Conditions
The inner diameters of unpressurized (0 mm Hg) arteries were
not significantly different between ovariectomized control (n=10) and
estradiol-replaced (n=9) rats (205±16.4 and 182±7.95 µm,
respectively). In addition, the diameters of the arteries at 75
mm Hg in fully relaxed arteries (ie, inactivation of vascular smooth
muscle with papaverine and removal of extracellular calcium from the
buffer) were not different in ovariectomized rats compared with
estradiol-replaced animals (306±24.8 and 337±13.2 µm,
respectively). For the experimental basal condition with HEPES-PSS
buffer, there was also no difference in vessel diameter at 75
mm Hg between the 2 groups (307±12.8 and 316±15.8 µm,
respectively). However, after L-NMMA incubation, arteries from
ovariectomized rats constricted significantly (307±12.8 vs
260±15 µm; P<0.05), whereas those from the
estradiol-replaced group did not (316±15.8 vs 294±18.2 µm,
NS). These data suggest that there is a higher basal level of NO in the
ovariectomized control animals that may reflect a compensatory
mechanism to ovariectomy.
Vessel Responses to AVP and U46619
There was no difference in either the sensitivity or the maximum
constriction to AVP (Figure 1) or U46619
(Figure 2) between the estradiol-replaced
and ovariectomized rats. L-NMMA did not modulate the vasoconstrictor
responses of the arteries from either group.
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Arterial Response to PE
In contrast to the vasoconstriction responses of AVP and U46619,
the vasoconstrictor response to PE was significantly altered by
long-term replacement of estrogen in ovariectomized rats. The
EC50 for PE was significantly greater in the
arteries from estradiol-replaced animals than that from ovariectomized
animals (EC50=0.90±0.17 vs 0.44±0.08 µM,
P<0.05, Figure 3A); however,
the maximal constriction did not differ between the 2 groups (Figure 3B). After incubation with L-NMMA, the maximal constriction was
enhanced and the EC50 of PE was significantly
decreased in both groups (Figure 3A). The extent of the shift of
EC50, however, was significantly greater
(P<0.05) in the estradiol-replaced animals compared with
that from ovariectomized control animals. This observation indicated
that the NO pathway was partly involved in the decreased sensitivity to
PE in estradiol-replaced animals. Nevertheless, a significant
difference remained between the 2 groups after NOS inhibition
(EC50=0.41±0.08 vs 0.28±0.02 µmol/L,
P<0.05).
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Western Immunoblot of 1-Adrenergic
Receptor
Because a significant difference between ovariectomized and
estradiol-replaced rats occurred only with adrenergic vasoconstriction,
1-adrenergic receptor density was evaluated
with the use of Western blot analysis. Figure 3C is a
representative immunoblot for
1D-adrenergic receptors in the mesenteric
arteries of ovariectomized (lanes 1 to 3) and estrogen-replaced (lanes
4 to 8) rats. A major immunoreactive protein band was observed at 
60
kDa from arteries of the ovariectomized rats. The expression of the
1-receptors was suppressed below detectable
limits in the estradiol-replaced group.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our study focused on the vascular responses to different receptor-mediated vasoconstrictors and the possible involvement of the NO pathway in modulating the response in estradiol-replaced ovariectomized rats. Physiological levels of estradiol attenuated vasoconstriction only in response to an adrenergic agonist (PE). Two other vasoconstrictors, AVP and U46619, were not affected by estradiol replacement in the rat. This difference may occur at the receptor level. Indeed, in this study, we show that
1-adrenergic receptor expression is decreased
in the estradiol-replaced rats compared with the ovariectomized
animals. In our study, the 3 vasoconstrictors (AVP, U46619, and PE) were chosen on the basis of their physiological roles in vivo. AVP is a neurohypophyseal hormone that induces vasoconstriction through V1 receptors.23 24 In contrast to our initial hypothesis, estradiol replacement in ovariectomized rats did not alter the vascular response to AVP, nor was the NO pathway involved. Information regarding this issue is controversial. One study demonstrated that long-term estrogen replacement in ovariectomized rats attenuated the pressor response to AVP in vivo.25 In contrast, another study showed that a short-term (1-day treatment) estradiol replacement increased the AVP pressor response in ovariectomized rats in vivo, and this was accompanied by an increase in the density of AVP binding sites.26
The role of the NO pathway in modulating an AVP response is also unclear. Some studies have demonstrated that NOS inhibition and denuded endothelium increased vasoconstriction responses to AVP in a variety of vascular beds.24 27 However, Martinez et al23 showed that denuded endothelium of human omental arteries had no effect on vessel contraction to AVP. In our study, NOS inhibition did not alter mesenteric arterial response in the ovariectomized or estradiol-replaced rats. It appears that data vary, depending on the animal model and vascular bed studied, with the mechanisms of all these complexities remaining unknown.
U46619 is a vasoconstrictor that acts through the thromboxane/PGH2 receptor. In our study, the vascular response to U46619 in the estradiol-treated group did not differ from the ovariectomized rats. These data are consistent with a report from Miller and Vanhoutte28 showing no effect of estrogen on modifying vascular responses to U46619 in rabbit aorta. However, previous studies have demonstrated that the effect of estrogen to modify U46619 is very complex. The maximal response of coronary and renal arteries to U46619 was higher in male dogs than in female dogs. Tamoxifen, an antagonist of estrogen, increased the pressor response to U46619 in the female dogs, and estrogen treatment in the male dogs decreased the pressor response.29 However, in the perfused rat lung, ovariectomy decreased the pulmonary pressor responsiveness to U46619, whereas 17ß-estradiol treatment induced an increased pressor responsiveness in a dose-dependent manner to U46619.30 Similarly, estrogen also potentiated the responsiveness of mesenteric arteries from male rats to U46619.31 Overall, the data indicate that U46619 is a vasoconstrictor for the coronary, renal, mesenteric, and pulmonary vasculature. However, whether estrogen attenuates or potentiates the pressor response to U46619 may be dependent on the gender and vascular bed studied. In these previous studies, however, the role of NO was not tested. Very recently, a study demonstrated that estrogen replacement decreases guinea pig coronary artery contractility to U46619 through NO.32 However, this effect only occurred with the lowest dose of estrogen (0.25 mg/pellet), but not in the doses of 0.5, 1.5, and 7.5 mg/pellet. These data are contradictory to our study, but the different species and vascular beds studied may explain the different observation. In addition, the doses of estrogen replaced may be a factor in the difference, as demonstrated by the lack of effect at the higher doses of estrogen in their study. Serum estradiol levels were not reported, nor was the physiological relevance of the estradiol dose in the guinea pig discussed. In our study, estradiol replacement achieved a physiological range of pro-estrus to pregnant levels for the rat, yet there was no significant effect on the NO pathway for modulating the response to U46619.
PE is an 1-adrenergic receptor agonist, and
adrenergic receptors serve a primary role in the maintenance of
arterial resistance.33 34 A previous study has
shown that the maximal pressor response to PE is greatly attenuated in
aortas from female rats as compared with that from male
rats.27 In addition, 17ß-estradiol has been shown to
significantly decrease the contractile response to PE in aortic rings
of male rats.35 Although our results do not demonstrate an
effect of estrogen to blunt the maximal response to PE, our data as
well as that of Meyer et al14 show that long-term
replacement of estrogen significantly blunted the adrenergic
sensitivity of mesenteric arteries.
The role of NO in modulating the blunted sensitivity to adrenergic
vasoconstriction has been evaluated in estradiol-replaced rats. NOS
inhibition with
N
-nitro-L-arginine
(L-NNA) significantly enhanced the vasoconstrictor response in only
the estradiol-replaced rats in the study of Meyer and
coworkers.14 In our present study, L-NMMA
significantly increased the sensitivity in both the ovariectomized and
estradiol-replaced groups. Although the extent of increased sensitivity
to PE was greater in estradiol-replaced animals, there remained a
significant difference between the groups. These data suggest that the
NO pathway was only partly involved in the mechanisms of blunting the
adrenergic response in our model of estradiol-replaced rats.
We next tested whether the expression of
1-receptors was reduced because of estrogen. A
previous study had shown that estrogen decreased
2-adrenergic receptor expression in the
central nervous system36 ; however, little is known about
the modulation of adrenergic receptors by estrogen in the resistance
vascular system. Our data clearly indicate a suppression of
1-adrenergic receptors in the mesenteric
arteries of the estradiol-replaced rats compared with
placebo-controlled ovariectomized rats. Because the
1-adrenoreceptor is a major
regulator of vascular function, these data represent an
important mechanism for vascular control. Indeed, increased levels of
cardiac 1-receptors have been reported in
spontaneously hypertensive rats.37 Further, the maximal
binding of 1-adrenoreceptors
in cardiac ventricles has been found to be greater in male than in
female Dahl rats.38 Interestingly, these authors observed
that there was a greater variability in maximal binding in the female
rats that may have been related to the estrous cycle. Our data
demonstrate a novel role of estradiol on
1-adrenergic expression. Further studies
specifically to address the effect of estrogen on binding capacity and
molecular regulation are necessary.
In summary, estrogen modulation of vasoconstriction only occurred with
an adrenergic vasoconstrictor, which was, in part, mediated by NO.
Further, 1-adrenergic receptor expression was
reduced in the mesenteric arteries of the estradiol-replaced rats. AVP
and U46619, 2 other receptor-mediated vasoconstrictors, were not
affected by estrogen nor by the NO pathway. We conclude that estrogen
may have a specific effect to modulate adrenergic vasoconstriction by
modulating its receptors.
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Acknowledgments |
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Dr S.T. Davidge is a scholar of the Heart and Stroke Foundation of Canada and the Alberta Heritage Foundation for Medical Research. This research is supported by the Medical Research Council of Canada.
Received April 1, 1999; first decision April 30, 1999; accepted June 24, 1999.
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P. J Fadel, W. Zhao, and G. D Thomas Impaired vasomodulation is associated with reduced neuronal nitric oxide synthase in skeletal muscle of ovariectomized rats J. Physiol., May 15, 2003; 549(1): 243 - 253. [Abstract] [Full Text] [PDF]
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A. P. McKee, D. A. Van Riper, C. A. Davison, and H. A. Singer Gender-dependent modulation of alpha 1-adrenergic responses in rat mesenteric arteries Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1737 - H1743. [Abstract] [Full Text] [PDF]
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Y. Zhang, K. G. Stewart, and S. T. Davidge Endogenous estrogen mediates vascular reactivity and distensibility in pregnant rat mesenteric arteries Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H956 - H961. [Abstract] [Full Text] [PDF]
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S. P. Rao, H. L. Collins, and S. E. DiCarlo Postexercise alpha -adrenergic receptor hyporesponsiveness in hypertensive rats is due to nitric oxide Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2002; 282(4): R960 - R968. [Abstract] [Full Text] [PDF]
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