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1 Department of Medicine, To identify the
E-prostanoid (EP) receptors that mediate the hemodynamic actions of
PGE2, we studied acute vascular
responses to infusions of PGE2
using lines of mice in which each of four EP receptors
(EP1 through
EP4) have been disrupted by gene
targeting. In mixed groups of males and females, vasodepressor
responses after infusions of PGE2
were significantly diminished in the
EP2
prostaglandin receptors; blood pressure; knockout mice; sex
differences; mice
THE LIPID MEDIATOR
PGE2 is a product of the
cyclooxygenase pathway of arachidonic acid metabolism (29).
PGE2 has diverse effects in a
variety of physiological responses including inflammation, pain,
gastric acid secretion, and vascular homeostasis (8). The biological
actions of PGE2 are mediated by
specific G protein-coupled receptors. These receptors for
PGE2, by convention designated EP
(E prostanoid) receptors, can be divided into four distinct pharmacological classes, EP1
through EP4 (8). EP receptors from
each of these classes have been cloned from a variety of species (2, 6,
14, 25). The subclasses of EP receptors couple to distinct signaling
pathways. The EP1 receptor is
coupled to intracellular Ca2+
signaling (14), whereas the EP2
and EP4 receptors are coupled to
Gs and signal by stimulating
adenylate cyclase (2). The EP3
receptor is more complex, because multiple
EP3-receptor isoforms have been
identified that are generated by alternative splicing of the
EP3-receptor gene (6, 25).
Moreover, these EP3-receptor isoforms couple to different signaling pathways including
Gi (inhibition of intracellular
cAMP formation), Gs (stimulation
of intracellular cAMP formation), and
Gq (stimulation of intracellular
Ca2+ release) (25). The existence
of a series of EP receptors coupled to distinct intracellular signals
provides a molecular basis for the diverse and complex physiological
actions of PGE2.
The vascular effects of PGE2
contribute to the control of both systemic and regional hemodynamics
(18, 19, 24). For example, PGE2 is
the major cyclooxygenase metabolite produced in the kidney (4), where
it maintains renal blood flow during hemodynamic compromise (39). In
the renal circulation, PGE2 opposes the actions of vasoconstrictors such as angiotensin II, norepinephrine, and thromboxane A2
(TxA2) that are released in response to reductions in effective arterial blood volume (10, 24, 32).
Acute renal failure after administration of nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit production of PGE2, has been attributed to
interruption of these homeostatic effects of
PGE2 (39). In addition to
regulating regional blood flow,
PGE2 may also contribute to the
maintenance of systemic blood pressure, and dysregulation of
PGE2 synthesis has been suggested to play a role in the pathogenesis of hypertension (26).
The vascular actions of PGE2 have
been studied in a series of in vivo and in vitro settings. Some
differences in the net effects of
PGE2 in regulating systemic blood
pressure have been reported (1, 17, 26). Chronic infusion of
PGE2 into the kidney causes mild
hypertension in dogs (17). Similarly, central administration of
PGE2 also increases blood pressure
in rats (15). In contrast, intravenous infusions of
PGE2 reduce blood pressure in a
number of species (1, 26). Moreover, reduced synthesis of
PGE2 has been demonstrated in
several models of hypertension (13, 22, 34). For example, in the
Okamoto-Kyoto strain of spontaneously hypertensive rats fed a
high-sodium chloride diet, urinary
PGE2 excretion is reduced compared
with controls. One interpretation of these studies is that a defect in
PGE2 production might contribute to salt-dependent hypertension (13, 22, 34). However, studies in this
area have been limited by the lack of potent and specific EP-receptor
antagonists, and the EP-receptor subtypes that mediate the vascular
actions of PGE2 are not known.
To define the role of individual EP receptors in mediating the
hemodynamic actions of PGE2, we
determined the effects of intravenous infusions of
PGE2 on blood pressure in lines of
mice in which the genes encoding the various EP-receptor classes had
been disrupted by gene targeting. By comparing the effects of
PGE2 in mice lacking individual
EP-receptor isoforms to wild-type controls, we have developed a
comprehensive view of the contribution of each of these receptors to
the vasodepressor actions of PGE2.
We find that the vascular effects of
PGE2 are mediated by a complex
interaction of the EP-receptor subtypes and that there are striking
differences in the roles of the EP-receptor subtypes in males relative
to those in females.
Establishment of animal lines.
The generation of mouse lines with targeted disruptions of the four
EP-receptor genes are described elsewhere (12, 27). The
EP1-null mutation
(EP1 Breeding and maintenance of mice.
Animals were maintained in the Durham Veterans Affairs Medical Center
animal facility, fed a normal diet (0.4% wt/wt NaCl), and provided
with water ad libitum.
Measurement of hemodynamic actions of
PGE2.
On the day of the study, mice were anesthetized with isoflurane
(0.8-1.3% vol/vol). Flexible plastic catheters (0.98-mm outer diameter, 0.61-mm inner diameter; Braintree Scientific, Braintree, MA)
were placed in the carotid artery to monitor arterial pressure and in
the jugular vein to administer
PGE2 (Cayman Chemical, Ann Arbor,
MI),
2-chloro-N6-cyclopentyladenosine
(CPA; adenosine-receptor agonist), or
S-( Data analysis.
Data are presented as means ± SE. The significance of differences
between the two groups was assessed using an unpaired
t-test. All data were analyzed and
plotted using the GraphPad Prism software package (GraphPad, San Diego, CA).
EP receptors and systemic blood pressure.
At the beginning of each experiment, baseline MAP was recorded for a
minimum of 180 s and averaged. This baseline blood pressure was
compared between each EP-receptor mutant and its genetically matched
control. There were no significant differences in MAP measured in this
way between any of the EP receptor-deficient lines and controls (data
not shown). This suggests that none of the EP-receptor isoforms play a
unique role in the maintenance of blood pressure in euvolemic,
anesthetized animals.
Vasodepressor effects of PGE2 in mice.
As shown in Fig. 1, the administration of
PGE2 to a mixed group of wild-type
male and female mice caused a marked and immediate fall in blood
pressure. Maximal blood pressure reduction occurred within
the initial 20 s after PGE2
infusion. This was followed by a recovery phase in which there was a
sustained reduction MAP that gradually returned toward baseline within
180 s. Whereas the pattern of the response was similar with each dose
of PGE2, the magnitude of the
maximal response and the dimension and duration of the sustained phase
of MAP reduction increased in proportion to the dose of
PGE2 that was administered (Fig.
1).
ABSTRACT
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
/ and
EP4 / lines but not
in the EP1 / or
EP3 /
lines. Because the actions of other hormonal systems that
regulate blood pressure differ between sexes, we compared the roles of
individual EP receptors in males and females. We found that the
relative contribution of each EP-receptor subclass was strikingly
different in males from that in females. In females, the
EP2 and
EP4 receptors, which signal by
stimulating adenylate cyclase, mediate the major portion of the
vasodepressor response to PGE2. In
males, the EP2 receptor has a
modest effect, but most of the vasodepressor effect is mediated by the
phospholipase C-coupled EP1
receptor. Finally, in male mice, the
EP3 receptor actively opposes the
vasodepressor actions of PGE2.
Thus the hemodynamic actions of
PGE2 are mediated through complex
interactions of several EP-receptor subtypes, and the role of
individual EP receptors differs dramatically in males from that in
females. These differences may contribute to sexual dimorphism of blood
pressure regulation.
INTRODUCTION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
/) was
introduced into the DBA/1J background by targeted disruption of this
gene using an embryonic stem (ES) cell line derived directly from
DBA/1J mice (28). Control mice were housed in the same colony. The
EP2 / and
EP3 / mutations were
produced in ES cells derived from 129/Ola mice (12). Chimeras derived
from these cells were bred with 129/SvEv mice to maintain the mutation
on a 129 genetic background (12). Controls for these studies were +/+
129/SvEv littermates. On inbred backgrounds, most
EP4-deficient mice
(EP4 /) die within
24 h from complications of patent ductus arteriosus (27).
However, by selective breeding on a mixed background,
EP4-deficient lines have been
produced in which the ductus closes and the animals survive normally
(27). EP4 / mice
from these selected mixed breedings were used in our experiments.
Controls for these studies are +/+ littermates. The genetic background
of these animals consists of a mixture of 129, C57BL/6, and DBA/2.
)-BAY K 8644 (L-type
Ca2+-channel agonist; Sigma
Chemicals, St. Louis, MO). Pulse waveforms were monitored and recorded
at a rate of 50 samples/s through the arterial catheter using Windaq
data acquisition and playback software (Dataq Instruments, Akron, OH).
After stabilization of the blood pressure and pulse wave, mean arterial
pressure (MAP) was recorded for 60 s and averaged to establish a
baseline. After this baseline determination, 60 µl of vehicle (0.9%
saline mixed with ethanol) were injected through the venous catheter
and MAP was monitored for 5 min. After the vehicle injection,
increasing doses of 10 and 100 µg/kg
PGE2 were injected as a bolus at
5-min intervals. Each injection was administered in a volume of 60 µl. The PGE2 solution was
prepared from a 100 mM stock solution in 100% ethanol. As based on the
weight of the mouse, the ethanol content was determined to be <0.2%
(vol/vol) in all cases. The vehicle preparation was prepared to reflect
the concentration of ethanol found in the 100 µg/kg
PGE2 injection solution. MAP was
calculated from the pulse waveforms at 1-s intervals.
RESULTS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
View larger version (25K):
[in a new window]
Fig. 1.
Mean arterial pressure (MAP) responses in
EP2 / and +/+ mice
after administration of 10 or 100 µg/kg
PGE2. MAP was recorded
continuously in anesthetized mice from 0 to 180 s after administration
of PGE2.
A: change in MAP (
mmHg from
baseline) after 10 µg/kg PGE2.
B: change in MAP after 100 µg/kg
PGE2. Shaded tracings,
EP2 / mice
(n = 12); solid tracings,
EP2 +/+ mice
(n = 12). Data are means ± SE.
Vasodepressor responses to PGE2 are
blunted in EP2 / mice.
The contribution of the EP2
receptor to the vasodepressor actions of
PGE2 is shown in Fig. 1. Whereas
the pattern of the alterations in MAP was similar to that in controls,
the maximum fall in MAP was significantly blunted in
EP2 / mice (Figs. 1
and 2). Even at the lowest dose of
PGE2 (10 µg/kg), the absolute
MAP nadir was significantly different from that in controls
(EP2 /: 5.1 ± 0.8 mmHg, n = 12;
EP2 +/+: 10.6 ± 1.6 mmHg, n = 12;
P = 0.006). As depicted in Fig. 2,
this difference was more marked at the 100 µg/kg dose
(EP2 /: 15.3 ± 1.7 mmHg, n = 12;
EP2 +/+: 26.5 ± 1.8 mmHg, n = 12;
P = 0.0002). The duration of the
vasodepressor effect was shorter in the
EP2 / mice than in
genetically matched controls (Fig. 1).
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Hemodynamic responses to PGE2 are also
altered in EP4-deficient mice.
As shown in Fig. 2, the maximum depressor response after 100 µg/kg
PGE2 was significantly greater in
the EP4 +/+ animals (26.2 ± 2.7 mmHg, n = 9) than in the
EP4 / animals
(16.8 ± 2.5 mmHg, n = 8;
P = 0.017). A similar trend was seen
with the 10 µg/kg dose of PGE2
(EP4 /: 7.1 ± 1.4 mmHg, n = 8;
EP4 +/+: 11.3 ± 2.6 mmHg, n = 9); however, this difference
did not achieve statistical significance.
/ and
EP3 / mice and their
genetically matched controls (data not shown). These results suggest
that both EP2 and
EP4 receptors mediate the
hemodynamic actions of PGE2 in
mixed groups of males and females.
The relative contribution of individual EP receptors to hemodynamic
actions of PGE2 is different in males and
females.
A number of previous studies (9, 11, 16, 37) have documented sex
differences in blood pressure regulation. Whereas there were
differences in baseline MAP between males and females, blood pressures
were similar between / and +/+ females or / and +/+ males of each strain (Table 1). To
determine whether there might be sex differences in the relative role
of EP receptors, we analyzed responses in separate groups of male and
female mice. Experiments were performed with both 10 and 100 µg/kg
PGE2, and the results were
qualitatively similar (Fig. 1). However, the responses to the higher
dose were more robust and more clearly highlight the differences
between the / and +/+ groups. To simplify the
presentation, only the experiments using 100 µg/kg
PGE2 are included here. As shown
by the composite pressure curves in Fig. 3,
there were obvious and significant differences in the roles of
individual EP receptors in males and females. For example, the
hemodynamic actions of PGE2 were
markedly reduced in male EP1
/ mice compared with male
EP1 +/+ mice (Figs.
3A and
4A). In
contrast, in the female EP1
/ and +/+ mice depicted in Fig. 3B, the effects of
PGE2 on MAP were identical.
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/ mice, as shown
in Fig. 3, C and
D. However, these differences were
much more pronounced between the female EP2 / and +/+ groups
(Fig. 4B). This was because of
differences in the maximal blood pressure reduction between male
EP2 / (17.9 ± 2.5 mmHg) and female EP2
/ mice (13.1 ± 1.9 mmHg) as well as a more
prominent effect of PGE2 in female
EP2 +/+ controls (male
EP2 +/+: 22.9 ± 2.2 mmHg; female EP2 +/+: 30.4 ± 2.0 mmHg; P = 0.030) (Fig. 4).
Accordingly, it appears that the
EP2 receptor plays some role in
mediating hemodynamic actions of
PGE2 in both males and females,
although the effect is more prominent in females.
We also found significant differences in the role of
EP3 receptors between sexes. As
shown in Fig. 3E, the vasodepressor
effect of PGE2 was actually more
marked in EP3 /
males than in wild-type (EP3 +/+)
males. This was manifested primarily by a delay in the recovery phase
of the response so that MAP remained lower in the male
EP3 / mice than in
controls for >180 s after the
PGE2 was administered (area under
curve from 21 to 120 s: EP3
/ = 2,603 ± 370 s · mmHg,
n = 9;
EP3 +/+ = 1,263 ± 210 s · mmHg, n = 6; P = 0.005). In contrast, the
vasopressor effects of PGE2 were virtually identical in the female
EP3 / and +/+
groups. Thus the EP3 receptor
appears to negatively modulate the vascular actions of
PGE2 in males but not in females.
Figure 3, G and
H, shows
PGE2 responses in
EP4 +/+ and / mice
separated by sex. Whereas there were no significant differences in the
response to PGE2 in male
EP4 +/+ and / mice,
the vasodepressor actions of PGE2
were significantly attenuated in female
EP4 / mice
(15.7 ± 2.7 mmHg) compared with those in female
EP4 +/+ mice (29.9 ± 2.5 mmHg; P = 0.002) (Fig.
4B). Similar to the
EP2 / group, the
differences in the response between the female EP4 +/+ and / mice
were caused by a blunted response in the EP4 / group and a
larger effect of PGE2 in the
wild-type EP4 +/+ females
(29.9 ± 2.5 mmHg) compared with that in the
EP4 +/+ males (20.7 ± 4.9 mmHg).
Responses to other vasoactive agonists are not altered in EP mutant
mice.
To determine whether the altered responses to
PGE2 in EP-deficient mice
represent a generalized defect in hemodynamic responsiveness, we
examined the effects of two additional vasoactive agents, CPA and
S-()-BAY K 8644. Our studies
had indicated altered vascular responses to
PGE2 in the cAMP-linked
EP2,
EP3, and
EP4 receptor-deficient mice as
well as in the Ca2+-linked
EP1 and
EP3 receptors. Thus we used an
adenosine
A1/A2-receptor agonist (CPA) and an L-type
Ca2+-channel agonist
[S-()-BAY K 8644]
to test the integrity of these signaling pathways in the EP-deficient
mice. In our experiments, we selected the sex of EP mutant mice on the
basis of groups that manifested altered responses to
PGE2. As shown in Table
2, CPA caused a marked vasodepressor effect
in all of the groups tested, and there were no differences in the
response among groups. S-()-BAY K 8644 caused equivalent elevations in MAP in all of the groups, and
there were no differences in this vasodepressor response among groups.
These results suggest intact signal-effector coupling between cAMP- and
Ca2+-mediated hemodynamic
responses in all EP mutant mice.
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ABSTRACT
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RESULTS
DISCUSSION
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One of the many functions of the cyclooxygenase pathway of arachidonic acid metabolism is the regulation of hemodynamics and vascular tone (18, 24). To carry out this regulatory function, various cyclooxygenase metabolites may have opposing effects on vascular tone. For example, PGE2 and PGI2 are vasodilators (8), whereas TxA2 is a potent vasoconstrictor (8). These lipid mediators regulate blood flow at sites of inflammation (10) and in the renal and cardiac circulations (36) and also may modulate systemic blood pressure (33). The actions of PGI2 and TxA2 are mediated by individual G protein-coupled receptors, the IP and TP receptors, respectively. In contrast, a family of receptors (EP1 through EP4) mediates the actions of PGE2. The contribution of these EP-receptor subtypes to the hemodynamic actions of PGE2 is not known. Moreover, depending on the circumstance and mode of administration, PGE2 has been reported to either increase (15, 17) or decrease blood pressure in vivo (24). Because PGE2 is the major cyclooxygenase product produced in organs such as the kidney, it represents a prominent effector of vascular regulation. To determine the contribution of each EP-receptor subtype to the hemodynamic actions of PGE2, we studied lines of mice in which the genes encoding the individual EP-receptor isoforms had been disrupted by gene targeting.
In wild-type mice, we found that intravenous administration of
PGE2 produces marked but transient
reduction in blood pressure. The characteristics of this response
resemble the hemodynamic effects of
PGE2 in other species, including
humans (10, 33). Our studies in mixed groups of males and females
suggest that the EP2 and
EP4 receptors both contribute
significantly to the hemodynamic actions of
PGE2. On the basis of the maximal
level of blood pressure reduction, their relative contributions are similar, because this vasodepressor response was similarly diminished in EP2 / and
EP4 / animals. Both
the EP2 and
EP4 receptors are coupled to
adenylate cyclase, and stimulation of these receptors in vascular
smooth muscle cells increases intracellular cAMP. This signaling
pathway is used by other vasodepressor ligands such as isoproterenol
(
2-adrenergic receptor),
adenosine (A2-adenosine receptor),
and ADP (P2-purinergic receptor).
Thus a vasodepressor effect of
PGE2 mediated by the
EP2- and
EP4-receptor isoforms is
consistent with previous observations linking increases in intracellular cAMP to relaxation of smooth muscle. However, when we
compared the effects of PGE2 in
males and females, we found differences that did not conform to this
simple pattern.
In the mixed groups of EP2
/ and EP4
/ animals and their controls, most of the difference in
the response in the mutant mice is caused by a marked attenuation of
the effects of PGE2 in the
EP2 / and
EP4 / females. Our
data suggest that EP2 and
EP4 receptors mediate the major
portion of the hemodynamic response to
PGE2 in females. The use of mice
with combined EP2 and
EP4 deficiencies should provide
direct confirmation of this question. The situation is quite different
in males. Whereas the EP2 receptor
contributes modestly to the response, the vasodepressor actions of
PGE2 in males are mediated
primarily by the EP1 receptor. The
finding that the EP1 receptor
causes hypotension is unexpected. The
EP1 receptor is generally coupled
to an intracellular Ca2+ signal, a
pathway commonly used by vasoconstrictor agents such as angiotensin II
or TxA2 (8, 35). Furthermore, as
based on classic pharmacological characterization of EP receptors,
stimulation of the EP1 receptor
was associated with smooth muscle contraction (8). Accordingly, the
mechanism of this vasodepressor effect is not clear. In some systems,
increased intracellular Ca2+ may
enhance nitric oxide production (3), although such a linkage has not
been demonstrated for the EP1
receptor. Alternatively, the EP1
receptor may modulate the activity of a second vasoactive system. For
example, increased intracellular
Ca2+ activates phospholipases (5)
and may cause further endogenous release of lipid mediators, including
PGE2.
We also observed differences in the relative effect of the
EP3 receptor in males compared
with that in females. The EP3
receptor contributes very little to the vasodepressor effects of
PGE2 in females. In contrast, the
EP3 receptor acts to constrain the
vasodepressor effects of PGE2 in
males. This is shown by the accentuated and prolonged vasodepressor
response in male EP3
/ mice compared with that in controls as shown in Fig.
3E. The
EP3 receptor is unique among
prostanoid receptors in that multiple
EP3-receptor isoforms are
generated by alternative splicing of the single
EP3-receptor gene (6, 25). These
isoforms are coupled to different intracellular signaling pathways,
either inhibition of adenylate cyclase or stimulation of intracellular
calcium release (25). As discussed earlier, such signals would be
expected to promote vasoconstriction or oppose vasodilation. In males,
but not in females, the observed effect of
EP3 receptors is consistent with
this paradigm.
Genetic background may have significant influence on the phenotype of
mice with targeted deletions of EP-receptor genes (27). Thus, in our
experiments, the genetic backgrounds were carefully matched between
wild-type controls and each EP receptor-deficient mouse line to
minimize these potential confounding effects. On the basis of this
design, differences between +/+ and / animals can be
attributed to the absence of the individual EP receptor. Because the
backgrounds of the EP2 and
EP3 mutant lines are identical (129 background), intergroup comparisons between
EP2 / and
EP3 / lines can also
be made without concerns about potential influences of background
genes. However, the background of the
EP4 / animals is
diverse and consists of random combinations of C57BL/6, 129, and DBA/2.
Therefore, the potential role of this genetic heterogeneity should at
least be considered in comparisons of the contributions of
EP4 receptors relative to
EP2 and
EP3 receptors, as well as to
EP1 receptors, which are on a
DBA/1J background. Nonetheless, our data suggest that the influence of
background genes on hemodynamic responses to
PGE2 is minimal. For example, the
maximal vasodepressor effects of
PGE2 were virtually identical in
male or female +/+ mice on each of the backgrounds: ~22 mmHg in
wild-type males and ~30 mmHg in wild-type females. In females, the
absence of EP2 reduces this
response by 50%, and the absence of
EP4 causes an equivalent
diminution of the response. Accordingly, despite the differences in
background genes in EP2
/ and EP4
/ females, the contributions of these receptors appear to
be additive and seem to account for the entire vasodepressor effect of
PGE2 in the female wild-type controls.
Our observation that individual EP-receptor subtypes have distinct vascular actions in males compared with females was not anticipated. However, evidence from a number of sources (16, 37) has demonstrated substantial differences in the regulation of blood pressure and in the incidence and mechanisms of hypertension between males and females. For example, epidemiologic studies show a lower incidence of hypertension in premenopausal women compared with age-matched men (37). In several animal models of hypertension, hypertension develops sooner and is more severe in males than in females (9). Whereas mechanisms to explain the different susceptibilities to hypertension in males and females have not been identified, sex hormones are known to affect the activity of vasoactive mediators such as vasopressin and angiotensin II. For example, Wang et al. (38) showed that the antidiuretic and pressor effects of arginine vasopressin were more pronounced in males than in females. In humans, men were more susceptible to the effects of infused angiotensin II than age-matched premenopausal women (11).
Potential differences in eicosanoid metabolism between males and females have also been demonstrated (7, 31). PGE2 was found to be more potent and efficacious in eliciting aorta-strip contraction of male compared with female rats (20). In these experiments, there was no attempt to distinguish EP-receptor subtypes, and aortic smooth muscle cells contribute very little to systemic vascular tone. Nonetheless, this study suggests that different patterns of EP-receptor expression in males compared with females might be one potential mechanism to explain our findings. Such differences have not been explicitly identified for EP receptors. However, Masuda and associates (23) have shown that testosterone enhances TP-receptor expression in rat aortic smooth muscle cells. Furthermore, the 5' regulatory sequence for the EP2-receptor gene contains a progesterone-response element (21). Alternatively, differences in signal-effector coupling between males and females could also explain differences in the hemodynamic effects of PGE2.
NSAIDs are potent inhibitors of the cyclooxygenase enzymes, and their anti-inflammatory effects occur through inhibition of the production of eicosanoids such as PGE2 (30). In settings in which PGE2 acts as a major determinant of vascular tone, alterations in PGE2 biosynthesis may have profound effects on blood pressure and circulatory homeostasis. In elderly patients and especially in patients with congestive heart failure or volume depletion, administration of NSAIDs can cause acute renal failure due to the inhibition of PGE2 production and the interruption of its actions in maintaining renal blood flow (39). Our study defines a relative hierarchy for EP receptors in determining the vasodepressor effects of PGE2 and suggests that the development of specific EP-receptor agonists and/or antagonists might provide an approach to maximize the anti-inflammatory effects of NSAIDs while avoiding their hemodynamic complications.
In summary, the role of individual EP-receptor subtypes in the vascular actions of PGE2 is complex and varies significantly between males and females. These variations may contribute to sex differences in circulatory homeostasis.
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ACKNOWLEDGEMENTS |
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We thank Dr. Michael Oliverio for helpful discussions, Norma Turner for secretarial assistance, and Dr. Robert Spurney for critical reading of the manuscript.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants P01-DK-38103, DK-38108, and HL-58554 and the Research Service of the Department of Veterans Affairs.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: T. M. Coffman, Div. of Nephrology, Box 3014, Duke Univ. Medical Center, Durham NC 27710 (E-mail: tcoffman{at}acpub.duke.edu).
Received 8 February 1999; accepted in final form 12 April 1999.
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RESULTS
DISCUSSION
REFERENCES
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