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Department of Pharmacology, The University of Missouri-Kansas City, Kansas City, Missouri 64108
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The effect of glucocorticoids on arterial baroreceptor reflex control of heart rate (HR) was determined in conscious rats. Corticosterone (Cort) treatment for 4-6 days doubled plasma Cort in Cort-treated relative to control rats. Cort had no significant effect on mean arterial pressure (MAP) or HR. Ramped changes in MAP were produced using infusions of phenylephrine and nitroprusside. Baroreflex control of HR was analyzed using a four-parameter logistic function. The midpoint of the baseline baroreflex function curve was significantly increased in Cort-treated (n = 14) relative to control (n = 14) rats (112 ± 2 vs. 98 ± 2 mmHg, n = 14), and the slope was significantly decreased (0.065 ± 0.002 vs. 0.091 ± 0.007). Three hours after the glucocorticoid type II receptor antagonist mifepristone (Mif) was administered to Cort-treated rats (n = 8), the midpoint of the baroreflex function was significantly reduced from 113 ± 4 to 99 ± 2 mmHg, and the slope was significantly increased from 0.061 ± 0.004 to 0.083 ± 0.005. Mif decreased HR in Cort-treated rats from 355 ± 17 to 330 ± 14 beats/min (P = 0.04) but did not alter MAP (111 ± 2 to 107 ± 3 mmHg, P = 0.14). Mif had no significant effects on baroreflex function in control rats. Therefore, a moderate elevation in Cort for several days causes pressure-independent modulation of baroreflex control of HR.
hypertension; autonomic regulation; blood pressure
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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GLUCOCORTICOIDS PLAY AN IMPORTANT role in arterial pressure homeostasis (9). However, elevated glucocorticoids can produce hypertension, and abnormalities involving glucocorticoids are implicated in the pathogenesis of human hypertension (2, 9, 22, 28-30). Recently it was demonstrated that elevated glucocorticoids during critical prenatal periods result in both an increased risk for hypertension and elevated glucocorticoids in adulthood (19). Thus understanding the effects of glucocorticoids on mechanisms of arterial pressure regulation is of increasing clinical importance.
A number of studies demonstrated that glucocorticoids can enhance vascular responses to adrenergic agonists and angiotensin II (15). The hypertensive actions of glucocorticoids have largely been attributed to these and other peripheral actions of glucocorticoids. In contrast, the effects of glucocorticoids acting in the central nervous system to influence arterial pressure regulation are controversial and remain poorly understood (3, 11, 13, 25). Recent data from this laboratory demonstrated that glucocorticoids influence neural control of the circulation by acting to modulate baroreflex control of renal sympathetic nerve activity (RSNA) in anesthetized rats (18). In that study, corticosterone (Cort) treatment for 2-3 wk significantly increased the midpoint and decreased the slope of the baseline baroreflex function curve. Furthermore, acute administration of the glucocorticoid type II receptor antagonist mifepristone (Mif) significantly increased the slope and decreased the midpoint of the baroreflex function curve within 2 h. In control rats, Mif significantly decreased the midpoint within 3 h but had no effect on the slope. However, two important issues could not be addressed by that study. First, the effect of Cort on baroreflex control of heart rate (HR) could not be determined, because the combination of anesthesia and neuromuscular blockade greatly reduced the range of baroreflex control of HR. Second, the effect of baseline Cort concentrations in control rats on the arterial baroreceptor reflex could not be established in the anesthetized animals, because anesthesia and surgery on the day of the experiment increased baseline Cort in control rats.
Therefore, the present experiments were performed to test the hypothesis that Cort modulates baroreflex control of HR in conscious rats. Rats were prepared with indwelling catheters at least 4 days before experiments were performed. Baroreflex control of HR was determined in conscious rats that were either treated with a subcutaneous Cort pellet for 4-6 days or left untreated (control rats). Baroreflex control of HR was determined before and 3 h after administration of the glucocorticoid type II receptor antagonist Mif (30 mg/kg sc) or vehicle (protocol 1). The effect of glucocorticoid type II receptor blockade on baseline arterial pressure and HR was also determined in the absence of baroreflex function testing (protocol 2). Cort-treated rats used in those experiments were treated for either 4-6 days or for 10 or more days.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiments were preformed using 58 male Sprague-Dawley rats housed in American Association for Accreditation of Laboratory Animal Care-accredited animal care facilities at either The University of Texas-Health Science Center, San Antonio (n = 11), or at the University of Missouri, Kansas City (n = 47). Access to food and water was provided ad libitum. The rats were on a normal sodium diet (0.12 mmol/g in San Antonio and 0.17 mmol/g in Kansas City).
Surgery
General. Animals were allowed to acclimatize in the animal care facility for at least 1 wk before any surgery was performed. All surgical procedures were performed using aseptic technique. Animals were anesthetized with either isoflurane or methoxyflurane gas or a combination of Domitor (metatomidine hydrochloride, 0.5 mg/kg ip, Pfizer Animal Health, Exton, PA) and ketamine hydrochloride (75 mg/kg ip) (6). The dose of anesthesia was adjusted to maintain a depth of anesthesia at which there was no reflex response to a pinch of the hindpaw or to any surgical manipulation. All incisions were sutured closed. After surgery with the Domitor-ketamine combination, Antisedan (atipamezole hydrochloride, 1 mg/kg ip) was administered to speed the recovery from anesthesia (6).
Corticosterone treatment. Rats were treated for 4 days to 3 wk with Cort to produce increases in plasma Cort concentration (n = 31). The Cort pellets were either made in the laboratory as previously described (17) or 100-mg Cort pellets were purchased from Innovative Research of America (Sarasota, FL). Briefly, Cort was liquefied and pipetted into a mold designed specifically for manufacturing the pellets (Ted Pella, Redding, CA). The pellets were implanted subcutaneously through a small incision over the dorsal lumbar region at the time of catheterization or in a previous surgery. Control rats were either subjected to sham surgery or left untreated.
Catheter implantation. Catheters were implanted for measurement of arterial pressure and administration of drugs. A small skin incision was made over the femoral artery and vein, and the vessels were isolated. An arterial catheter made of 23-gauge Tygon tubing with a 28-gauge Teflon tip was advanced into the abdominal aorta via the femoral artery for measurement of arterial pressure. Venous catheters made of PE-50 tubing pulled to a finer tip were inserted into the femoral veins and advanced into the vena cava for administration of drugs. A subcutaneous catheter, used to administer Mif or vehicle, was made by cutting four or five small holes along the bottom inch of 18-gauge Tygon tubing. The subcutaneous catheter was positioned so that the tip lay under loose skin in the area of the hip. All catheters were tunneled under the skin to exit between the scapulae and secured in place with silk suture. The dead space in the arterial catheter was filled with sterile heparin (1,000 U/ml), and the venous catheter was filled with sterile heparinized saline (20 U/ml).
Adrenalectomy. Mif, the glucocorticoid type II receptor antagonist used in these experiments (7), also acts as a progesterone antagonist. To determine the selectivity of Mif as a glucocorticoid receptor antagonist in these experiments, the effects of Mif on arterial pressure and HR were determined at least 3 days after endogenous Cort was eliminated by bilateral adrenalectomy (n = 3) under methoxyflurane anesthesia. A small skin incision was made above each adrenal, and the gland was quickly removed. Adrenalectomized rats were given free access to both 0.45% saline and water to drink.
Experimental Protocol
General. Experiments were conducted in the laboratory with the animals in their home cages. All animals were brought to the laboratory in the morning and allowed at least 1 h for arterial pressure and HR to stabilize. Between 9:00 AM and noon, a 200-µl blood sample was obtained from the arterial catheter for measurement of baseline plasma Cort concentration in most experiments. After the collection of the blood sample, at least 15 min elapsed before initiation of the experimental protocol. After a period in which baseline data were collected, either Mif (30 mg/kg sc) or vehicle (100 µl dimethyl sulfoxide and 100 µl proplylene glycol) was administered through the subcutaneous catheter. Mif was either purchased or provided as a gift (National Institute of Mental Health synthesis program) from Research Biomedicals.
Protocol 1. Experiments were performed to test the hypothesis that Cort modulates baroreflex control of HR in conscious rats. After the baseline blood sample was obtained, a baseline arterial baroreflex function curve was generated using intravenous infusion of phenylephrine (10 µg/ml) and nitroprusside (100 µg/ml). The rates of infusion were adjusted so that arterial pressure changed by ~1-2 mmHg/s. Baseline arterial pressure and HR were recorded for 30 min, then either Mif or vehicle was administered. A second baroreflex function curve was obtained at 3 h. In both protocols, some animals were used for a Mif experiment at least 1 day after a vehicle experiment. Due to the long duration of action of Mif, no animal was used in another experiment after receiving Mif. All Cort-treated animals used in protocol 1 were treated with Cort for 4-6 days.
Protocol 2. In protocol 1 the changes in arterial pressure required for the determination of the baseline baroreflex function curve could influence the subsequent effect of Mif on resting arterial pressure and HR. Therefore, experiments were performed to determine the effects of Mif on baseline arterial pressure and HR in the absence of any other perturbations. In this protocol the baseline blood sample was obtained as in protocol 1. Baseline arterial pressure and HR were then recorded for 30 min. Either Mif or vehicle was then administered as in protocol 1, and arterial pressure and HR were measured continuously for the next 3 h. A second blood sample was obtained at the end of the experiment. Three of the Cort-treated rats used in protocol 2 were treated for 4-6 days, and the rest were treated for 10 days or more.
Methods of Measurement and Analysis
Cardiovascular data. Arterial pressure was measured by connecting the arterial catheter to a bridge amplifier (World Precision Instruments, Sarasota, FL) with a pressure transducer (Maxxim Medical, Athens, TX). The output from the bridge amplifier was fed into a MacLab (ADInstruments) analog-to-digital processor connected to a Macintosh computer. Mean arterial pressure (MAP) and HR were determined online from pulsatile pressure using the MacLab software. For protocol 1, average resting values for MAP and HR were determined just before each of the two baroreflex curves (the baseline curve and the curve 3 h after Mif or vehicle). For protocol 2, average values for MAP and HR were determined for the baseline period and then averaged into 10- and 30-min bins after administration of Mif or vehicle. Values for MAP and HR were analyzed by one- and two-way ANOVA as appropriate. Repeated-measures ANOVA was used for analysis of time as a factor, and between-subjects ANOVA was used to compare groups. For post hoc analysis, Tukey compromise for between-subjects variables and least-square means for within-subjects variables were used as needed. In some cases, regression analysis was used to determine the significance of relationships between variables. Significance was accepted at P < 0.05. Changes from baseline were calculated and used for graphical presentation only.
Baroreceptor reflex curves.
For analysis of baroreflex function, values for HR were averaged into
1-mmHg MAP bins. The data were then analyzed using a sigmoid logistic
function curve according to the equation HR = P4 + P1/{1 + exp[P2(MAP
P3)]}, where P1 is the range of HR, P2 is the slope of HR as a function of pressure, P3 is the pressure at the
midrange of the curve, and P4 is the minimum value for HR
(10). The best-fit curve was calculated using SigmaPlot
software (SPSS). The fit of the data to the calculated curve was
estimated by calculating an r2 value. Values
ranged from 0.91 to 0.99. Parameter values were averaged for each group
and used to generate average curves. Statistical analysis was performed
on the parameter values using ANOVA as described above.
Plasma Cort.
Blood samples were taken to determine plasma Cort concentration. Two
hundred microliters of blood was drawn from the arterial catheter and
added to tubes containing heparin (1,000 U/ml). Samples were
centrifuged at 3,000 g for 15 min. The plasma was then
removed and stored at 4°C until being assayed with a commercially
available radioimmunoassay kit (I125 RIA kit, ICN
Biomedicals, Costa Mesa, CA). For rats in which more than one
experiment was performed, baseline plasma Cort concentrations were
averaged. The results were analyzed by ANOVA.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Average plasma Cort concentration during the baseline period was significantly elevated in Cort-treated rats (6.8 ± 0.7 µg/dl, n = 28) relative to control rats (2.9 ± 0.5 µg/dl, n = 23, P < 0.01). This approximate doubling in plasma Cort is similar to previous reports from this laboratory (16, 18). In protocol 2, in which plasma Cort was also measured at the end of the experiment, there were no significant changes in Cort during the experiment in any experimental group. There were significant decreases in thymus (578 ± 47 vs. 818 ± 48 mg thymus weight/kg body wt, P < 0.01) and adrenal weights (109 ± 7 vs. 178 ± 7 mg adrenal wt/kg body wt, P < 0.01) in Cort rats relative to control rats, demonstrating physiological efficacy of the Cort treatment. At the time of the experiments, body weight did not differ significantly between control (389 ± 8 g) and Cort-treated rats (368 ± 8 g, P = 0.057). Some of these variables were affected by the duration of Cort treatment, and for further analysis Cort-treated rats were divided into two groups: rats treated for 6 days or less (short duration, n = 16) and rats treated for 10 days or more (long duration, n = 15). Body weight was significantly lower in rats treated for a long duration than in rats treated for a short duration (351 ± 9 vs. 381 ± 11 g, P = 0.03). Adrenal weight normalized to body weight was significantly lower in rats treated for a short duration (94 ± 5 mg/kg) compared with those treated for a long duration (127 ± 12 mg/kg, P = 0.01). Some of this difference was due to the lower body weight in the long-duration treatment group, because the difference in absolute adrenal weights between the short- and long-duration treatment groups was only of borderline significance (36 ± 1 vs. 45 ± 5 mg, P = 0.050). The duration of treatment did not significantly affect thymus weight normalized to body weight (528 ± 61 vs. 658 ± 62 mg/kg for short vs. long duration, P = 0.15). Plasma Cort concentration was also unaltered by the duration of Cort treatment (7.5 ± 1.0 vs. 5.8 ± 1.1 µg/dl for short vs. long duration, P = 0.30).
The duration of Cort treatment affected baseline arterial pressure. Average values for MAP for all control and all Cort-treated rats used in this study were 107.6 ± 1.1 and 111 ± 2 mmHg, respectively (P = 0.18). Average MAP for the long-duration Cort treatment group (114.0 ± 2.4 mmHg) was significantly greater compared with MAP for both the control and short-duration (107.2 ± 1.9 mmHg) groups (P = 0.017). Regression analysis of the duration of treatment (regressor) vs. baseline MAP (dependent variable) revealed that the relationship was significant (P < 0.01) and the r2 value was 0.30. Baseline HR was 347 ± 7 beats/min for control rats. Although HR tended to be higher in long-duration Cort-treated rats (364 ± 11 beats/min) than in either short-duration Cort-treated rats (348 ± 7 beats/min) or control rats, the difference was not significant. Regression analysis for baseline HR (regressor) vs. baseline MAP (dependent variable) demonstrated a significant relationship for Cort-treated rats (P < 0.01, r2 = 0.29) but not control rats (P = 0.39).
In protocol 1, all Cort-treated rats were treated for a
short duration. MAP was not different in control (107.2 ± 1.6 mmHg) vs. Cort-treated (108.2 ± 2.2 mmHg) rats. Similarly, there
was no significant difference in HR between control (333 ± 7 beats/min) and Cort-treated rats (349 ± 7 beats/min,
P = 0.12). The average baseline baroreflex function
curves for control and Cort-treated are illustrated in Fig.
1. Cort treatment significantly decreased the slope (P2) from 0.091 ± 0.007 to 0.065 ± 0.002 (P < 0.01). Cort treatment also shifted the baroreflex
curve to the right, as indicated by a significant increase in midpoint
(P3) in Cort-treated rats (111.9 ± 1.9 mmHg) relative to control
rats (98.3 ± 1.8 mmHg, P < 0.01). The minimum HR
of the curve (P4) tended to be reduced in Cort-treated rats (261 ± 10 beats/min) relative to control rats (287 ± 9 beats/min),
but the difference was not statistically significant (P = 0.062). The range of HR (P1) was not significantly different between
control (143 ± 13 beats/min) and Cort-treated (157 ± 11 beats/min) rats.
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In control rats, treatment with neither vehicle (n = 9)
nor Mif (n = 8) had a significant effect on any curve
parameter or on resting arterial pressure and HR. The curves are
illustrated in Fig. 2, and the curve
parameters are provided in Fig. 3 and Table 1. Resting values for MAP and HR
are illustrated in Fig. 2 and provided in the legend.
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In Cort-treated rats, the vehicle (n = 11) had no
significant effect on any curve parameter or on resting MAP or HR. The
curves are illustrated in Fig.
4A, and parameter values are
provided in Fig. 3 and Table 1. Three hours after administration of Mif to Cort-treated rats (Fig. 4B; n = 8) there
was a significant increase in the baroreflex curve slope (P2) from
0.061 ± 0.004 to 0.083 ± 0.005 (P = 0.03).
In Cort-treated rats, Mif also decreased the arterial pressure midpoint
of the curve from 113.0 ± 3.7 mmHg in the baseline curve to
99.4 ± 2.2 mmHg 3 h after administration of Mif
(P < 0.01). The values for the slope and arterial
pressure midpoint after Mif in Cort-treated rats were not significantly different from the corresponding parameters in control animals during
the baseline period (see Fig. 3). HR was significantly decreased 3 h after Mif in Cort-treated animals from 355 ± 17 to 330 ± 14 beats/min (P = 0.04); however, MAP was not
significantly reduced (from 111.0 ± 2.2 to 107.3 ± 2.6 mmHg, P = 0.14).
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In animals used in protocol 2, baseline MAP and HR were not
significantly different in control (108.8 ± 1.5 mmHg and 365 ± 10 beats/min, n = 10) compared with Cort-treated
rats (112.5 ± 2.2 mmHg and 354 ± 11 beats/min,
n = 18). Cardiovascular responses to vehicle and/or Mif
showed a biphasic response: an initial increase in some groups followed
by a decrease in some groups. Because of the complex nature of the
response, values for MAP and HR were analyzed by within-subjects ANOVA
over time for each group separately. Administration of vehicle or Mif
caused an initial increase in MAP that was significant in Cort-treated
rats only and was apparently due to the sensation of feeling the
vehicle under the skin (Fig. 5A). In Cort-treated rats
receiving vehicle (n = 11), there were no further
significant increases or decreases in MAP. After the initial increase
in arterial pressure in Cort-treated rats receiving Mif at time
0 (n = 9), arterial pressure fell, and the
decrease became statistically significant during the period from 120 to 150 min (P < 0.01). Further analysis of the data
averaged into 10-min periods demonstrated a significant decrease in
pressure starting at 120 min. Arterial pressure remained significantly reduced for the remainder of the experiment (130-180 min,
P < 0.01 for each 10-min average). In control rats,
vehicle (n = 9) had no significant effects on arterial
pressure at any time during the experiment, but Mif (n = 8) significantly decreased arterial pressure during the 150- to
180-min period. Analysis of data averaged into 10-min periods showed
significant reductions in pressure at 150 (P = 0.02),
170 (P = 0.02), and 180 min (P = 0.03).
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Administration of either vehicle or Mif tended to produce an initial increase in HR in all four groups of rats, but the increase was significant only in control and Cort-treated rats that received vehicle (Fig. 5B). HR remained elevated for a prolonged period in the Cort-treated rats receiving vehicle. A significant reduction in HR was only observed in the control rats receiving Mif during the period of 120-150 min. In the three adrenalectomized rats, baseline MAP was 105.8 ± 6.0 mmHg, which was not significantly different from control or Cort-treated rats. Resting HR was 426 ± 12 mmHg, which was significantly greater than both control and Cort-treated rats. When the data were averaged into 30-min periods, neither MAP nor HR fell below baseline in adrenalectomized rats given Mif (data not shown).
Both short- and long-duration Cort treatments were used in
protocol 2, and the duration of treatment affected the
changes in arterial pressure and HR observed after Mif (Fig.
6). For short-duration Cort-treated rats
receiving Mif (n = 3), arterial pressure increased significantly during the first 30 min after Mif, then pressure returned
to baseline and remained there. In rats with long-duration Cort
treatment (n = 6), pressure fell from baseline after
Mif, and the reduction was significant starting with the 90- to 120-min period. HR did not change significantly in response to Mif in either
group of Cort-treated rats, although it tended to fall in the
short-duration treatment group (P = 0.09). The
responses to vehicle could not be compared between short- vs.
long-duration treatment groups, because the short-duration group had an
n = 2.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of Cort Treatment on Arterial Baroreflex Control of HR
The fact that elevated glucocorticoids can cause hypertension has been recognized for many years (9). However, surprisingly little is known regarding the effects of glucocorticoids on neural control of the circulation. A recent report from this laboratory demonstrated that a mild elevation in plasma glucocorticoid concentration for 2-3 wk increased arterial pressure by 13 mmHg and decreased the slope and increased the midpoint of baroreflex control for renal sympathetic nerve activity in anesthetized rats (18). In the present study, the effect of glucocorticoids on baroreflex control of HR was determined in conscious rats treated with glucocorticoids for 4-6 days. Despite the fact that the glucocorticoid treatment did not increase baseline arterial pressure in these rats, Cort treatment significantly decreased the slope of the baroreceptor reflex from 0.091 ± 0.007 to 0.065 ± 0.004 and increased the midpoint of the curve from 98 ± 2 to 112 ± 2 mmHg. In addition, administration of the glucocorticoid type II receptor antagonist Mif to Cort-treated rats reversed the effects of Cort, significantly increasing the slope from 0.061 ± 0.004 to 0.083 ± 0.005 and decreasing the midpoint of the baroreflex function curve from 113 ± 4 to 99 ± 2 mmHg. These results demonstrate that subacute elevations (i.e., of moderate magnitude and duration) in glucocorticoids cause a pressure-independent modulation of baroreceptor control of HR.Effects of Basal Concentrations of Cort in Control Rats
Blockade of glucocorticoid type II receptors in control rats with low resting plasma glucocorticoid concentration had no effect on baroreflex control of HR within 3 h. In control rats in the absence of baroreflex testing, Mif produced a decrease in arterial pressure that was small and delayed relative to the long-duration Cort-treated rats. Mif also produced a transient decrease in HR in these animals. In experiments with baroreflex testing, no effects of Mif on baseline MAP or HR in control rats were observed. These results suggest that low resting levels of plasma glucocorticoids acting at the type II receptor do not modulate baroreflex control of HR and have a minimal effect on baseline MAP and HR. It is possible that blockade of glucocorticoid type I receptors for >3 h would alter baroreflex function in control rats. Also, these experiments were performed when plasma Cort was in the trough of the diurnal rhythm in control rats. Plasma glucocorticoids exhibit a diurnal rhythm with a peak just before the onset of the active period and a nadir associated with the beginning of the inactive period (4). In the present experiments, an average baseline plasma Cort of 2.9 ± 0.5 µg/dl was measured between 9:00 AM and noon. The peak concentration, at the start of the active period (lights off in rats), is 15-20 µg/dl. Therefore, it is possible that normal peak levels of plasma Cort in control rats could influence baroreflex control of HR. In a previous study from this laboratory performed in anesthetized rats, Mif significantly decreased the midpoint of the baroreflex function curve for renal sympathetic nerve activity in anesthetized control rats, but had no effect on the slope (18). Baseline Cort in these rats was elevated due to the acute anesthesia and surgery, suggesting that just a few hours of elevated Cort can increase the midpoint of the baroreceptor reflex. Different mechanisms probably contribute to the effects of acute vs. subacute elevations in Cort on reflex function, because the acute increase in Cort did not alter the slope of the baroreflex function curve.Effect of Cort Treatment on Baseline HR
Resetting of the baroreceptor reflex to a higher arterial pressure midpoint without a change in baseline pressure should theoretically lead to an increase in baseline HR. In experiments in which the baroreceptor reflex function was determined (protocol 1), baseline MAP was essentially identical in control and Cort-treated rats. Baseline HR tended to be higher in Cort-treated rats (Fig. 1), although the difference was not significant. The lack of a significant elevation in baseline HR in these animals is probably due to the fact that HR can be influenced by many parameters in addition to those of the baroreflex function. Administration of Mif to these animals significantly decreased baseline HR, indicating that the baroreceptor reflex component of HR control was producing a significant increase in baseline HR in Cort-treated rats.Effect of Duration of Cort Treatment on Arterial Pressure and HR
This laboratory previously reported that this dose of Cort elevates arterial pressure in both conscious (16) and anesthetized (17, 18) rats. In the present study, rats treated for just 4-6 days (short duration) were not hypertensive relative to controls, and Mif did not reduce arterial pressure in these rats in either protocol 1 or 2. Rats treated for a longer duration (as in previous studies) were hypertensive and Mif decreased arterial pressure in these animals. All animals in protocol 1 (baroreflex testing) were treated for a short duration. Those animals were not hypertensive, and Mif significantly reduced HR but not arterial pressure. Mif did not significantly (P = 0.09) reduce HR in rats with short-term Cort treatment in protocol 2, probably due to the small number of animals (n = 3). The data suggest that Mif may have a direct effect to decrease HR in Cort-treated rats, but this can be masked by reflex-mediated elevations in HR when there is a simultaneous reduction in arterial pressure. Baroreflex modulation by Cort was evident after just 4-6 days of treatment, at a time when arterial pressure was not yet significantly elevated. This is consistent with the hypothesis that active (pressure independent) baroreflex resetting by Cort contributes to the development of hypertension.Selectivity of Mif
Mif acts as a competitive antagonist by binding to the glucocorticoid type II receptor (7). It also acts as an antagonist at progesterone receptors. In male rats, progesterone is synthesized in the testis and adrenal, whereas Cort is secreted only from the adrenal. In these experiments, Mif had no effect on arterial pressure and HR in adrenalectomized rats, suggesting that the effect of Mif to modulate resting arterial pressure and HR and the baroreflex control of HR was due to blockade of actions of Cort rather than progesterone.Comparison of Present Results to Previous Studies
A handful of previous studies have investigated the effect of glucocorticoids or glucocorticoid deficiency on baroreflex control of HR (5, 8, 20, 24, 26). None of the studies is directly comparable to the present one because of differences in experimental methods and/or analysis. Szemeredi et al. (24) reported no significant effect of cortisol on baroreflex control of HR, although the slope of the reflex during increases in arterial pressure tended to be reduced. Segar et al. (20) reported that maternal administration of dexamethasone 24 and 48 h before delivery decreased the slope of baroreflex control of HR during increases in arterial pressure both before and after birth. Tam et al. (26) reported an increase in the slope (by linear regression analysis) of the relationship between pressure and HR during increases in arterial pressure in cortisol-treated humans; however, no individual or group curves were shown and only systolic pressure was measured. Thus some previous studies have supported the hypothesis that glucocorticoids can decrease the slope of baroreceptor reflex control of HR; however, no previous studies have determined the effect of elevated glucocorticoids on the midpoint of the baroreceptor reflex control of HR. The present study is the first to determine the effect of elevated glucocorticoids on both the slope and midpoint of arterial baroreceptor reflex control of HR. The results demonstrate that Cort can cause a pressure-independent decrease in slope and increase in midpoint of arterial baroreceptor reflex control of HR. Gardiner and Bennett (8) reported that adrenalectomy significantly reduced arterial pressure yet had no effect on the slope of the baroreceptor reflex function or on its position along the y-axis. Therefore, in these adrenalectomized rats, the baroreceptor reflex did not reset to the lower baseline MAP. These results suggest the possibility that the presence of glucocorticoids is required for pressure-dependent baroreceptor reflex resetting.Possible Mechanisms
A reduced slope and increased midpoint of the baroreceptor reflex has also been observed with angiotensin II treatment (14). Interestingly, Cort also enhances central actions of angiotensin II to increase arterial pressure (16). Whether elevations in central components of the renin-angiotensin system mediate the effects of Cort on baroreceptor reflex function remains to be determined. The fact that Cort has similar actions on baroreflex control of renal sympathetic nerve activity and HR suggests a role for altered function at an early point in the reflex loop, such as in the nucleus of the solitary tract (12). An effect on the baroreceptor afferents themselves cannot be ruled out at this time.Perspectives
The arterial baroreceptor reflex plays an important role in both short- and long-term arterial pressure homeostasis (21, 23, 27). Some functional adaptation of the baroreceptor reflex, such as an increase in midpoint or decrease in slope, must occur in sustained hypertension, otherwise, the reflex would effectively buffer the increase in arterial pressure (23). Such modulation of the baroreceptor reflex has been observed in hypertension (21, 23). There is increasing evidence that overactivity in the hypothalamic-pituitary-adrenal axis participates in the pathogenesis of human hypertension (2, 22, 28-30). In addition, it was recently recognized that prenatal exposure to excess glucocorticoids leads to both elevated glucocorticoids and an increased risk for hypertension in adulthood (19). The present study combined with a recent study from this laboratory (18) demonstrates that mild elevations in glucocorticoids can cause pressure-independent modulation of the arterial baroreceptor reflex that could maintain or exacerbate various forms of hypertension.| |
ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-56112.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. A. Scheuer, Dept. of Pharmacology, The Univ. of Missouri-Kansas City, 2411 Holmes St. Rm. MG 111, Kansas City, MO 64108 (E-mail: scheuerd{at}umkc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00300.2001
Received 23 May 2001; accepted in final form 25 October 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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) and corticosterone (Cort)-treated (
)
rats. 
, Average baseline resting values for mean
arterial pressure (MAP) and heart rate (HR; ±SE). The midpoint of the
curve (P3) was significantly greater in Cort-treated than in control
rats, whereas the slope was significantly reduced in Cort-treated rats.
bpm, Beats/min.
) vehicle
(A) or mifepristone (Mif; B). There were no
significant effects of either vehicle or Mif on baroreflex function
curve parameters in these rats. Resting MAP and HR were not affected by
vehicle or Mif. Values for resting MAP were 108 ± 2 mmHg before
vehicle vs. 105 ± 2 mmHg 3 h after vehicle and 107 ± 3 mmHg before Mif vs. 107 ± 1.2 mmHg 3 h after Mif. Values for
resting HR were 330 ± 10 beats/min before vehicle vs. 327 ± 11 beats/min 3 h after vehicle and 336 ± 8 beats/min before
Mif vs. 333 ± 9 beats/min 3 h after Mif.
) and 3 h after (
) Cort treatment.
*P < 0.05 relative to baseline value in that group.
Baseline MAP and HR were significantly higher in long-duration than in
short-duration Cort-treated rats receiving Mif (119 ± 4 vs.
103 ± 2 mmHg and 390 ± 22 vs. 308 ± 13 beats/min,
respectively).