Chronic Activation of Dorsal Hindbrain Corticosteroid
Receptors Augments the Arterial Pressure Response
to Acute Stress
Deborah A. Scheuer, Andrea G. Bechtold, Kathy A. Vernon
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Abstract—Augmented cardiovascular responses to acute stress can predict cardiovascular disease in humans. Chronic
systemic increases in glucocorticoids produce enhanced cardiovascular responses to psychological stress; however, the
site of action is unknown. Recent evidence indicates that glucocorticoids can act within the dorsal hindbrain to modulate
cardiovascular function. Therefore, we tested the hypothesis that the endogenous glucocorticoid corticosterone can act
in the dorsal hindbrain to enhance cardiovascular responses to restraint stress in conscious rats. Adrenal-intact animals
with indwelling arterial catheters were treated for 4 or 6 days with 3- to 4-mg pellets of corticosterone or silastic (sham
pellets) implanted on the dorsal hindbrain surface. Corticosterone pellets were also implanted either on the surface of
the dura or subcutaneously to control for the systemic effects of corticosterone (systemic corticosterone). The integrated
increase in arterial pressure during 1 hour of restraint stress was significantly (P⬍0.05) greater in dorsal hindbrain
corticosterone (912⫾98 mm Hg per 60 minutes) relative to dorsal hindbrain sham (589⫾57 mm Hg per 60 minutes) or
systemic corticosterone (592⫾122 mm Hg per 60 minutes) rats. The plasma glucose response after 10 minutes of stress
was also significantly higher in dorsal hindbrain corticosterone-treated rats relative to both other groups. There were no
significant between-group differences in the heart rate or corticosterone responses to stress. There were no differences
in baseline values for any measured parameters. We conclude that corticosterone can act selectively in the dorsal
hindbrain in rats with normal plasma corticosterone levels to augment the arterial pressure response to restraint stress.
(Hypertension. 2007;49:127-133.)
Key Words: glucocorticoids 䡲 hypertension 䡲 brain 䡲 autonomic nervous system 䡲 sympathetic nervous system
䡲 nucleus of the solitary tract
C
hronic elevations in glucocorticoids increase cardiovascular disease risk.1–3 Recent evidence suggests that
glucocorticoid-mediated changes in neuroendocrine control
of cardiovascular function could contribute to these adverse
actions of glucocorticoids. For example, glucocorticoids reduce the sensitivity and increase the midpoint of the arterial
baroreceptor reflex; similar changes in baroreflex function
are positively associated with increased cardiovascular disease risk.4 –7 Other studies have demonstrated that chronic
systemic elevations in glucocorticoids increase the arterial
pressure or norepinephrine response to acute stress.8,9 Similar
enhanced stress responses in humans have also been linked to
increased cardiovascular disease risk.10 However, the sites of
action for stimulatory effects of glucocorticoids on cardiovascular function remain unknown.
We demonstrated recently that, analogous to systemic
increases in glucocorticoids, chronic treatment of the dorsal
hindbrain (DHB) with the endogenous glucocorticoid corticosterone (Cort) attenuated the gain and increased the mid-
point of baroreflex control of heart rate.7 These alterations in
baroreflex function could promote the enhanced stress responses observed with elevated systemic Cort.8,9 The DHB
includes the nucleus of the solitary tract (NTS), an important
cardiovascular regulatory site in the central nervous system.11
The NTS receives direct input from arterial baroreceptor
afferents and has reciprocal connections with more rostral
sites involved in cardiovascular control.11 Both ascending and
descending pathways can activate NTS neurons in response
to acute stress, suggesting that neurons within the NTS
influence the arterial pressure response to stress.12–14 Therefore, we performed the present experiments to test the
hypothesis that elevated Cort within the DHB would enhance
the arterial pressure response to restraint stress.
Methods
General
Experiments were performed on male Sprague–Dawley rats purchased from Charles River Laboratories. Rats were housed under
Received January 4, 2006; first decision February 5, 2006; revision accepted October 4, 2006.
From the School of Medicine (D.A.S.), University of Florida, Gainesville; the School of Medicine (A.G.B.), University of California, Davis; and the
School of Medicine (K.A.V.), University of Missouri-Kansas City.
Correspondence to Deborah A. Scheuer, University of Florida, 1600 SW Archer Rd, Room M552, PO Box 100274, Gainesville, FL 32610-0274. E-mail
[email protected]
© 2006 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000250088.15021.c2
127
128
Hypertension
January 2007
standard housing conditions in an Association for Assessment and
Accreditation of Laboratory Care International–accredited facility.
They weighed 367⫾3 g. At the conclusion of all of the experiments,
the rats were humanely euthanized according to American Veterinary Medical Association guidelines. The University of Missouri
Kansas City Institutional Animal Care and Use Committee approved
all of the procedures, and the experiments were conducted in
accordance with the National Research Council Guide for the Care
and Use of Laboratory Animals.
Experimental Protocol 1: Effects of DHB Cort on
Responses to Stress
Data were obtained from 3 groups of rats: DHB sham (to control for
surgery and placement of a pellet on the brain, n⫽17), DHB Cort (to
treat the DHB chronically with Cort, n⫽15), and systemic Cort (to
control for systemic effects of the DHB Cort, n⫽13). The systemic
Cort group included both dura Cort (n⫽8) and subcutaneous Cort
(n⫽5) animals.
DHB Pellets
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To selectively and chronically activate DHB Cort receptors, small
pellets of Cort were implanted on the surface of the DHB, as has been
described previously and validated.15 Briefly, powdered Cort was
melted and pipetted into a mold to form pellets with the approximate
dimensions of 1.5 mm (length)⫻1.75 mm (width)⫻1.0 mm (height).
The pellets weighed between 3 and 4 mg. Sham pellets were made of
hardened silastic (Kwik-Sil, World Precision Instruments) and
carved to the same dimensions as the Cort pellets. To control for
systemic effects of the DHB Cort pellets, a 3- to 4-mg Cort pellet
was implanted outside the brain either on the surface of the dura or
subcutaneously.
Surgical Preparation
Pellets and arterial catheters were implanted on the same day under
Domitor (metatomidine hydrochloride, 0.5 mg/kg, IP, Pfizer Animal
Health) and ketamine (75 mg/kg, IP, Ft Dodge Animal Health)
anesthesia with prophylactic penicillin (Pen-Pro-G 600 000 U/kg,
SC, Henry Schein) as described previously.15 Briefly, catheters were
introduced into the femoral artery and advanced to the descending
aorta until the tip was estimated to be 1 to 2 cm below the left renal
artery. The catheter was tunneled subcutaneously to exit between the
scapulae, filled with sterile heparin (1000 U/mL), and closed with a
sterile obturator. Animals were then placed in a stereotaxic head
frame with the head slightly ventroflexed for implantation of DHB or
systemic pellets. A midline skin incision was made between the
caudal aspect of the occipital bone and the first vertebra. Subcutaneous Cort pellets were implanted at this location. For implantation
of Cort pellets on the surface of the dura, the muscles were separated
along the midline and retracted to expose the surface of the dura that
covers the hindbrain at the base of the skull. Dura pellets were placed
here. To implant Cort or sham DHB pellets, a small hole was made
in the dura, and the pia was removed from the dorsal surface of the
hindbrain. The bottom surface of the DHB pellet was coated with
mineral oil to facilitate diffusion of the pellet contents into the brain.
The pellet was placed on the surface of the hindbrain with one third
of the pellet caudal to calamus scriptorius. The pellet was secured in
place with a drop of Vetbond surgical glue and covered with a thin
layer of silastic gel (Quicksil, WPI). Six to 8 mL of saline were
administered subcutaneously to replace lost fluid, and Antisedan
(atipamezole hydrochloride, 1 mg/kg, IP) was administered to
reverse the anesthesia.
Experimental Protocol
Arterial pressure, heart rate, plasma glucose, and plasma Cort
responses to 60 minutes of restraint stress were determined 4 (n⫽25)
or 6 (n⫽20) days after implantation of the catheters and pellets.
Glucose is increased during stress by a mechanism that includes
glucocorticoids and sympathetic nervous system activation.16 Thus,
the glucose and Cort measurements provided indices of endocrine
and metabolic responses to stress.
The rats were brought to the laboratory in the morning in their
home cages. The arterial catheter was connected to a pressure
transducer that was connected in series to a bridge amplifier and a
Maclab computerized data acquisition system. Before this, the rats
were brought to the laboratory in their home cages and prepared for
the measurement of blood pressure for ⱖ2 days to accustom them to
the experimental procedures. Arterial pressure and heart rate were
recorded continuously for 3 hours until baseline arterial pressure and
heart rate were stabilized. The final 10 minutes of arterial pressure
and heart rate data were used to determine baseline values. Then, in
30 rats, 300 ␮L of blood were obtained from the arterial catheter for
the measurement of baseline plasma Cort and glucose. The animals
were observed for another 15 minutes. Each animal was then placed
in a clear plexiglas restrainer for 60 minutes. Additional blood
samples were obtained at 10 and 60 minutes during the period of
restraint. Plasma glucose was measured immediately in each sample
using a hand-held glucose meter (One Touch Ultra, LifeScan,
Johnson & Johnson). The animals were subsequently euthanized and
the adrenal glands removed, cleaned, and weighed. In 5 animals,
baseline arterial pressure or heart rate increased after the blood
sampling and did not return to control values within 15 minutes.
These animals were not included in the study.
Experimental Protocol 2: Plasma Cort
Measurements in Adrenalectomized Rats
In protocol 1, we measured Cort in adrenal-intact rats. In these
animals, the plasma Cort concentration is the sum of endogenous
Cort plus any exogenous Cort that may have diffused from the pellets
into the systemic circulation. Even with similar total plasma Cort
concentrations among the experimental groups, alterations in the
ratio of endogenous to exogenous Cort could affect the results.
Specifically, significant systemic leakage of Cort from the DHB
pellet could feedback on the brain to alter corticotropin-releasing
hormone and adrenocorticotropic hormone synthesis, potentially
influencing interpretation of the results.17,18 Thus, it was important to
determine whether a measurable amount of Cort diffused from the
implanted pellets into the systemic circulation and whether the amount
of Cort that entered the systemic circulation depended on the location
of pellet implantation. To achieve this, plasma Cort was measured at
5 to 6 days of treatment in 5 groups of adrenalectomized rats (n⫽4
per group): DHB sham, DHB Cort, dura Cort, SC 4-mg Cort, and, to
serve as a positive control, SC 200-mg Cort.
Surgical Preparation
Surgery was first performed as described above to implant an arterial
catheter and a DHB (silastic or Cort), dura, or SC 3- to 4-mg Cort
pellet. To provide a positive control using an additional group of rats,
a much larger dose of Cort pellets (2⫻100 mg) was implanted
subcutaneously in the flank region as has been described previously.19
Then with a dorsal approach a small incision was made on the flank
above the rostral pole of each kidney, and the adrenal glands were
excised. Each rat was given 6- to 8-mL of 0.45% sodium chloride
with 7% sucrose into the retroperitoneal space, and the incisions
were sutured. After adrenalectomy, rats were given both 0.45%
saline and 7% sucrose in water to drink ad libitum.
Experimental Protocol
After surgery for implantation of DHB or systemic pellets, on the
evening of day 5 (within 2 hours before lights off) and morning of
day 6 (within 2 hours after lights on) 300-␮L blood samples were
taken from the arterial catheters, except in 1 DHB sham rat from
which only the evening blood sample was obtained. The data from 1
dura Cort rat were excluded, because the plasma Cort concentrations
of 3.6 and 8.1 ␮g/dL in the morning and evening, respectively,
indicated that the adrenalectomy was incomplete. Because all of the
rats were adrenalectomized, morning and evening plasma Cort
concentrations, when available, were averaged to provide a single
value for each animal.
Scheuer et al
Glucocorticoids in Brain Enhance Stress Response
129
Figure 1. Changes in mean arterial pressure
averaged into 5-minute periods (left) or integrated over the 1-hour stress period (right) in
rats treated with DHB sham pellets (n⫽17),
DHB Cort pellets (n⫽15), or systemic (Syst)
Cort pellets (n⫽13). *P⬍0.05 relative to DHB
sham. ⫹P⬍0.05 relative to Syst Cort.
Measurement of Plasma Cort
Blood samples were immediately placed on ice in tubes containing 2 ␮L of heparin (1000 U/mL) and then centrifuged at 4°C for 15
minutes. The plasma was stored at ⫺20°C until being assayed for
Cort using a commercially available radioimmunoassay kit (rat Cort
125
I, MP Biomedicals) as described previously.20
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Data Analysis
Preliminary testing using ANOVA was performed on the results
from experiment 1 for data from the dura Cort and subcutaneous Cort
rats to determine whether there were any significant differences in
the effects of these systemic Cort treatments with respect to the
variables we measured. No significant differences were found, so the
results from the Dura and subcutaneous Cort were combined and
analyzed as a single systemic Cort group. Preliminary analysis also
demonstrated that the blood sampling protocol did not alter the
integrated arterial pressure and heart rate responses to restraint.
Mean arterial pressure and heart rate were calculated online by
the Maclab software. Heart rate was quantified as beats per
minute. The values during stress were averaged into 5-minute time
bins, and the changes from baseline were calculated. The results
(including the “0” time point) were analyzed by 2-way ANOVA
(between subjects for treatment group and repeated measures for time).
Because the analysis revealed that there was no interaction between
time and treatment, the total integrated increase from baseline for the
hour of stress was calculated from the 5-minute averages, and the
results were analyzed by 1-way ANOVA for group. Regression
analysis was used to determine whether the arterial pressure response
to stress was correlated to baseline arterial pressure in the DHB
Cort-treated rats. Changes in plasma Cort and blood glucose concentrations in response to stress were calculated and analyzed by
2-way ANOVA for time (repeated measures) and group. There was
a significant interaction between time and treatment group for
plasma glucose values, so 1-way ANOVA was then performed on
the 10- and 60-minute values separately. Baseline arterial pressure
and heart rate, adrenal weight, and plasma Cort in adrenalectomized
rats were analyzed by 1-way ANOVA. Duncan’s new multiple range
test was used for posthoc analysis. P values for the overall ANOVA
are provided in the Results section, with significant differences
accepted at Pⱕ0.05. All of the values are presented as mean⫾SE.
Results
Protocol 1: Cardiovascular Responses to Stress in
Adrenal-Intact Rats
There were no differences in baseline mean arterial pressure
among DHB Cort (105⫾2 mm Hg), DHB sham
(105⫾2 mm Hg), and systemic Cort (106⫾3 mm Hg) groups.
DHB Cort significantly increased the arterial pressure response to 60 minutes of restraint stress relative to both DHB
sham and systemic Cort animals (P⫽0.02 overall effect of
treatment group; Figure 1, left and right). There was also a
significant effect of time on the change in arterial pressure
(P⬍0.01; Figure 1, left). However there was no interaction
between the effects of time and experimental group
(P⫽0.28), indicating that the effect of Cort to increase the
stress response was present throughout the stress period.
Calculating the integrated arterial pressure response to 60
minutes of stress revealed that DHB Cort treatment increased
the stress response by 54% relative to both the DHB sham and
systemic Cort groups (Figure 1, right). The lack of an increase
in baseline arterial pressure in the DHB Cort–treated rats did
not account for the enhanced stress response in this group,
because there was no correlation between baseline arterial
pressure and the integrated arterial pressure response to stress
(r2⫽0.03; P⫽0.55).
Baseline heart rate was not significantly different among
DHB sham (328⫾5 bpm), DHB Cort (335⫾7 bpm), and
systemic Cort (352⫾10 bpm) groups (P⫽0.11). There was
also no effect of treatment group on the change in heart rate
in response to stress (Figure 2; P⫽0.22), although there was
a significant effect of time (P⬍0.01). There was no interaction between the effects of experimental group and time
(P⫽0.20).
Figure 2. Changes in heart rate averaged into
5-minute periods (left) or integrated over the
1-hour stress period (right) in rats treated with
DHB sham pellets (n⫽17), DHB Cort pellets
(n⫽15), or systemic (Syst) Cort pellets (n⫽13).
There were no significant effects of treatment
on the heart rate response to stress.
130
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January 2007
Figure 3. Changes in plasma glucose (left) and
plasma Cort (right) concentrations after 10 and
60 minutes of restraint stress. Rats were
treated with DHB sham pellets (n⫽8), DHB Cort
pellets (n⫽9), or systemic (Syst) Cort pellets
(n⫽13). *P⬍0.05 relative to DHB sham.
⫹P⬍0.05 relative to Syst Cort.
Protocol 1: Glucose Response to Stress in
Adrenal-Intact Rats
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There were no significant differences in baseline plasma
glucose concentration among the DHB Sham (87⫾4 mg/dL,
n⫽8), DHB Cort (92⫾3 mg/dL, n⫽9), and systemic Cort
(96⫾2, n⫽13) treatment groups. There were significant
effects of treatment group (Figure 3; P⫽0.01) and time
(P⬍0.01) on the glucose response to stress, with a significant
interaction between group and stress (P⫽0.01). Further analysis revealed that after 10 minutes of stress, plasma glucose
was elevated (P⫽0.02) in DHB Cort rats relative to both
DHB sham and systemic Cort groups. After 60 minutes of
stress, plasma glucose was significantly lower in the systemic
Cort compared with the DHB sham rats (P⫽0.03).
Protocol 1: Cort Response to Stress in
Adrenal-Intact Rats
Baseline plasma Cort concentration before the acute stress
was not different between treatment groups. The values were
6.8⫾2.5, 7.0⫾2.9, and 9.7⫾2.8 ␮g/dL in the DHB sham,
DHB Cort, and systemic Cort treatment groups, respectively.
There were no significant between-group differences
(P⫽0.321) for the increase (P⬍0.01) in plasma Cort concentration in response to stress (Figure 3). Adrenal weight was
measured to provide an index of the effect of treatment with
DHB or systemic Cort on baseline hypothalamic-pituitary–
adrenal axis activity. Adrenal weights were not significantly
different among DHB sham (65⫾2 mg), DHB Cort (69⫾3
mg), and systemic Cort (67⫾2 mg) treatment groups.
Protocol 2: Plasma Cort in Adrenalectomized Rats
In rats with the 200-mg SC Cort treatment, plasma Cort
averaged 24⫾1 ␮g/dL, ⬇10-fold higher than any other
group. This group served as a positive control, and the data
were not included in the between-group ANOVA for comparison of plasma Cort in the adrenalectomized rats. Average
plasma Cort concentrations in the other groups of adrenalectomized rats were: DHB sham, 1.30⫾0.16 ␮g/dL; DHB
Cort, 2.61⫾0.32; dura Cort, 2.67⫾0.29; and subcutaneous Cort,
2.83⫾0.24 ␮g/dL. All of the groups with 3- to 4-mg Cort
pellets had significantly elevated plasma Cort values relative
to the DHB sham rats (P⬍0.01). However, the plasma values
in the Cort-treated rats were low and did not exceed the
lowest plasma Cort concentrations normally observed in
adrenal-intact rats during the nadir of the diurnal cycle.15
Importantly, there were no differences in systemic Cort
values among the 3 groups of rats with 3- to 4-mg Cort
pellets, regardless of the site of implantation. These results,
combined with the data demonstrating no differences in
baseline plasma Cort among the groups of adrenal-intact rats,
indicate that systemic effects of Cort because of diffusion of
Cort from the DHB Cort pellet cannot account for the
increased arterial pressure and glucose responses to stress
observed in the DHB Cort-treated rats.
Discussion
Effects of Cort on Cardiovascular
Stress Responses
Arterial pressure and heart rate responses to psychological
stress are mediated primarily by the sympathetic nervous
system.21 Previous studies have examined the effects of
systemic elevations in or elimination of glucocorticoids on
the cardiovascular and/or sympathetic nervous system response to stress. Earlier studies reported that adrenalectomy
without corticosteroid replacement increased baseline and
stress-stimulated norepinephrine secretion,22–24 leading to the
conclusion that glucocorticoids restrain the sympathetic nervous system response to acute stress. However, adrenalectomy has variable effects on the heart rate and arterial
pressure responses to acute stressors.9,22 Furthermore, more
recent studies report that increases in systemic Cort elevate
arterial pressure, epinephrine, and/or norepinephrine responses to stress,8,9,25 although the role of the central nervous
system in this action of glucocorticoids is unclear. Investigations of central effects of glucocorticoids on arterial pressure
regulation have used intracerebroventricular administration
of agonists and antagonists26 –30 or acute microinjection of
drugs into the NTS.31 However, none of these studies investigated the effect of chronic elevations of central glucocorticoids on the cardiovascular response to acute stress. The
current results provide novel evidence indicating that chronically elevated Cort can act within the central nervous system to
enhance the arterial pressor response to acute stress. The effects
observed in this study were qualitatively similar to the effects of
elevated systemic Cort reported by van den Buuse et al.9
Effect of Cort on Baseline Arterial Pressure
Several studies have examined the effects of central Cort on
baseline arterial pressure. These studies indicated that higher
doses of Cort administered intracerebroventricularly produce
small increases in baseline arterial pressure, whereas low
doses were without effect.26 –28 We reported previously that
DHB Cort pellets increased baseline arterial pressure by 5 to
6 mm Hg after 4 days of treatment,7,15 although in the present
study there were no differences in baseline arterial pressure
between groups. This was not because of a difference in
Scheuer et al
duration of DHB Cort treatment, because baseline arterial
pressures in rats treated with DHB Cort for 4 days
(105⫾4 mm Hg, n⫽8) or 6 days (104⫾3 mm Hg, n⫽7) were
not different. We have no explanation for the lack of effect of
DHB Cort on baseline arterial pressure other than to point out
that even when it has been observed, it was not a robust
effect. Importantly, the arterial pressure response to acute
stress was not correlated with baseline arterial pressure in the
DHB Cort–treated rats, so the lack of an elevation in baseline
pressure does not account for the enhanced stress response in
these rats.
Glucocorticoids in Brain Enhance Stress Response
131
We have reported previously that implantation of small Cort
pellets on the surface of the DHB selectively increases Cort
levels in a circumscribed region of the DHB.15 Three brain
stem structures that influence autonomic control of the
cardiovascular system lie within this area: the NTS, the dorsal
motor nucleus of the vagus, and the area postrema. Immunohistochemical methods have not been able to demonstrate the
presence of mineralocorticoid receptors (MRs) or glucocorticoid receptors (GRs) in the area postrema, whereas the NTS
and the dorsal motor nucleus clearly express both MRs and
GRs.32–34 However, in rats, the dorsal motor nucleus has
minimal influence over cardiovascular autonomic efferent
activity.35 Thus, it is likely that primarily cells within the NTS
mediate the effects of Cort within the DHB, although a role
for the area postrema cannot be ruled out. Ascending and/or
descending inputs activate NTS neurons in response to a
variety of stressors, including restraint stress.12–14 At least
some of these stress-activated neurons are catecholaminergic
and express GRs.12–14,36 However, the role of the NTS in
mediating or modulating the cardiovascular responses to
acute psychological stress, such as restraint, is not known.
The present study reports novel findings that strongly suggest
that the physiological status of neurons within the DHB,
including the NTS, can influence the arterial pressure response to restraint stress.
pellet is both minimal and independent of the site of pellet
implantation. Thus, the systemic pellet implantation serves as
an adequate control for any systemic effect of the exogenous
Cort. Because there was no effect of DHB Cort on the Cort
response to stress, we also conclude that differences in
plasma Cort levels during stress did not contribute to the
enhanced arterial pressure response in the DHB Cort–treated
rats.
Because the arterial pressure and heart rate responses to
psychological stress are mediated primarily by the sympathetic
nervous system,21 these studies support the hypothesis that
chronic increases in glucocorticoids can enhance sympathetically mediated cardiovascular responses to an acute psychological stress. In a recent study, we reported that DHB Cort
treatment attenuated the gain and increased the midpoint of
the arterial baroreceptor reflex.7 Thus, it is possible that
attenuation in baroreflex control of sympathetic nerve activity
contributed to the effect of DHB Cort to enhance the arterial
pressure response to stress observed in this study. However,
if there was enhanced activation of the sympathetic nervous
system, it was not universal, because the heart rate response
to stress was not elevated in the DHB Cort rats. Measurements of plasma catecholamines and/or sympathetic nerve
activity will be required to determine the contribution of the
sympathetic nervous system.
Cort can activate both MRs and GRs.37 Cort has a higher
affinity for MRs than GRs so that at lower doses Cort
primarily activates MRs, whereas at higher doses both the
MRs and GRs are activated.37 van den Buuse et al9 reported
that in adrenalectomized rats low-dose Cort replacement only
enhanced the heart rate response to an acute stress, whereas
high-dose replacement selectively enhanced the arterial pressure response to the stress, suggesting an important role for
GRs. Chronic central infusion of the endogenous mineralocorticoid aldosterone also enhanced the arterial pressure
increase during acute novel stress, suggesting a role for
MRs.38 Also, a selective MR antagonist blunted the arterial
pressure response to stress but only after the animals had
repeated exposure to the same stress.39 A subpopulation of the
MR-expressing neurons in the NTS also expresses an enzyme
that degrades Cort (11-␤-hydroxysteroid dehydrogenase 2).34
Thus, the MRs in these neurons are activated primarily by
aldosterone, although it is possible that high levels of Cort
could exceed the capacity of the enzyme. These neurons are
involved in sodium appetite,40 but their influence on the
neurohumoral responses to psychological stress has not been
studied. Results from these various studies considered together suggest that chronic elevations in Cort act centrally to
increase cardiovascular responses to stress by complex interactions of MR- and GR-mediated effects that remain to be
elucidated.16,41
Mechanism of Cort Action
Perspectives
In the present experiments, we used a previously validated
method to selectively and chronically treat the DHB with
Cort.15 This method increases Cort levels locally in DHB
areas without altering plasma Cort concentration in adrenalintact rats.7,15 We now have shown in adrenalectomized
animals that the systemic spillover of Cort from the DHB
There is substantial evidence that elevations in glucocorticoids increase morbidity and mortality from cardiovascular
disease.1–3 These adverse actions of glucocorticoids have
important implications for human health, because many
people take glucocorticoids by prescription or have elevated
endogenous glucocorticoids. Many peripheral mechanisms
Effects of Cort on Glucose and
Hypothalamic–Pituitary–Adrenal Stress Responses
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Endogenous glucocorticoids combined with sympathetic activation promote the increase in blood glucose during stress.16
DHB Cort enhanced the glucose response after 10 minutes of
stress compared with both other groups. Because there were
no significant effects of treatment or time on the Cort
response to stress in these experiments, the effect of DHB
Cort to increase the glucose response to stress is likely
because of changes in sympathetic activation. However,
further experiments are needed to determine the role of the
sympathetic nervous system.
Site of Cort Action
132
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January 2007
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for detrimental cardiovascular effects of glucocorticoids have
been investigated.2 In contrast, actions of glucocorticoids on
central neural control of cardiovascular function have received little attention, in part because initial studies suggested
that elevated glucocorticoids acted centrally to reduce rather
than increase arterial pressure or sympathetic nervous system
activity.23,27 However, these studies were limited to single
doses of steroids. More recent work suggests that chronic
elevations in glucocorticoids can act centrally to elevate
arterial pressure.15,42 The present results extend recent findings to demonstrate that selective chronic increases in Cort in
the DHB enhance arterial pressure and glucose responses to
acute stress. Enhanced reactivity to stress is associated with
elevated risk for cardiovascular disease.10 Elevated cardiovascular stress reactivity is observed with chronic stress,
which also increases endogenous glucocorticoids.43– 45 For
example, the chronic stress of lower socioeconomic status is
associated with elevated glucocorticoids.45,46 Thus, elucidating common mechanisms of elevated stress reactivity is
critical for understanding the etiology of cardiovascular
disease.
Source of Funding
This work was supported by the National Institutes of Health,
National Heart, Lung, and Blood Institute grant 1R01HL076807.
Disclosures
None.
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Chronic Activation of Dorsal Hindbrain Corticosteroid Receptors Augments the Arterial
Pressure Response to Acute Stress
Deborah A. Scheuer, Andrea G. Bechtold and Kathy A. Vernon
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Hypertension. 2007;49:127-133; originally published online November 6, 2006;
doi: 10.1161/01.HYP.0000250088.15021.c2
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