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Am J Physiol Heart Circ Physiol 284: H1751-H1761, 2003. First published January 16, 2003; doi:10.1152/ajpheart.01033.2002
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Vol. 284, Issue 5, H1751-H1761, May 2003

Glucocorticoids reduce responses to AMPA receptor activation and blockade in nucleus tractus solitarius

Sylvan S. Shank and Deborah A. Scheuer

Department of Pharmacology, The University of Missouri, Kansas City, Missouri 64108


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We tested the hypothesis that glucocorticoids attenuate changes in arterial pressure and renal sympathetic nerve activity (RSNA) in response to activation and blockade of alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors within the nucleus of the solitary tract (NTS). Experiments were performed in Inactin-anesthetized male Sprague-Dawley rats treated for 7 ± 1 days with a subcutaneous corticosterone (Cort) pellet or in control rats. Baseline mean arterial pressure (MAP) was significantly higher in Cort-treated rats (109 ± 2 mmHg, n = 39) than in control rats (101 ± 1 mmHg, n = 48, P < 0.05). In control rats, microinjection of AMPA (0.03, 0.1, and 0.3 pmol/100 nl) into the NTS significantly decreased MAP at all doses and decreased RSNA at 0.1 and 0.3 pmol/100 nl. Responses to AMPA in Cort-treated rats were attenuated at all doses of AMPA (P < 0.05). Responses to the AMPA-kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) were also significantly reduced in Cort-treated rats relative to control rats. Blockade of glucocorticoid type II receptors with mifepristone significantly enhanced responses to CNQX in both control and Cort rats. We conclude that glucocorticoids attenuate MAP and RSNA responses to activation and blockade of AMPA receptors in the NTS.

hypertension; corticosterone; baroreceptor reflex; glutamate


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

SEVERAL LINES OF EVIDENCE demonstrate that glucocorticoids are important for the regulation of arterial pressure. Adrenalectomy, adrenal insufficiency, or blockade of glucocorticoid type II receptors can produce a reduction in arterial pressure (16, 20, 49). The effects of adrenalectomy on arterial pressure can be reversed by glucocorticoid, but not mineralocorticoid, replacement (49). Conversely, prolonged elevations in glucocorticoids produce a dose-dependent increase in arterial pressure (47). Increases in plasma glucocorticoids due to endogenous overproduction or exogenous administration can produce frank hypertension in humans (25, 58).

There is also evidence that prolonged mild elevations in glucocorticoids or increased sensitivity to the actions of glucocorticoids can play a permissive role in the development and maintenance of hypertension. In the spontaneously hypertensive rat (SHR), basal plasma glucocorticoid concentrations are doubled compared with control Wistar-Kyoto rats (23, 26). Doubling plasma glucocorticoid concentration, by itself, produces no increase or only a small (5-10 mmHg) increase in arterial pressure (36, 37). However, adrenalectomy prevents the development of hypertension or partially reverses established hypertension in the SHR (23, 26, 42, 43). This effect of adrenalectomy is prevented by glucocorticoid replacement. Obese Zucker rats exhibit mild abnormalities in glucocorticoid regulation, and the glucocorticoid receptor antagonist mifepristone can reduce arterial pressure in these rats (10, 33). In a model of social isolation stress-induced hypertension in rats, adrenalectomy eliminated the increase in arterial pressure, and glucocorticoid replacement reversed the effect of adrenalectomy (24). In humans, some studies (31, 41, 56, 59) have reported mild elevations in plasma and/or urinary glucocorticoids in essential hypertension. Analysis of polymorphism of the glucocorticoid receptor gene reveals an association of genotype with increased blood pressure and elevated basal glucocorticoid concentration (35, 56). Altered glucocorticoid metabolism that can lead to increased tissue exposure to glucocorticoids has also been reported in essential hypertension (11, 41, 54, 59).

The mechanisms of glucocorticoid-mediated control of arterial pressure have been investigated in previous experiments but remain poorly understood. Most work has focused on actions of glucocorticoids in the peripheral circulation (8, 50). These studies demonstrate that glucocorticoids can increase vascular reactivity to norepinephrine and angiotensin and can downregulate local vasodilators such as nitric oxide. However, it is not clear that these vascular changes alone can account for the hypertensive effects of glucocorticoids. Fewer studies have explored the effect of elevated glucocorticoids on central mechanisms involved in the neural control of the circulation, and the results have been ambiguous (17, 28, 34, 45, 48, 52). Recently, we reported (36, 39) that mild elevations in glucocorticoids decrease the slope and increase the midpoint of arterial baroreflex control of both renal sympathetic nerve activity (RSNA) and heart rate. The changes in baroreflex function were not dependent on the effects of glucocorticoids to increase arterial pressure. These results provide clear evidence that glucocorticoids attenuate the ability of the baroreceptor reflex to buffer changes in arterial pressure, which could promote the development of hypertension.

Baroreceptor afferents terminate in the NTS where the information regarding prevailing arterial pressure is processed and integrated with information from other sensory afferents and central projections (13). Efferent projections from the NTS mediate reflex control of the sympathetic nerve activity to the vasculature as well as sympathetic and vagal control of heart rate (5). Thus the NTS is critical for baroreceptor control of both heart rate and RSNA. Within the NTS, glutamate is the primary neurotransmitter of baroreceptor afferents (27, 46). There are three classes of ionotropic glutamate receptors: AMPA, kainate, and N-methyl-D-aspartic (NMDA). Although all three classes can influence baroreceptor reflex function, current evidence suggests that within the NTS, AMPA receptors have a dominant influence on baseline arterial pressure and on arterial baroreflex function (6, 19, 29, 60-62). Microinjection of AMPA into the NTS to activate neurons in the baroreceptor reflex pathway produces a reduction in arterial pressure (14, 19). Conversely, microinjection of an AMPA-kainate receptor antagonist blocks or attenuates baroreflex function (19, 29). Because the NTS exerts a tonic inhibitory influence on sympathetic outflow from the rostral ventral lateral medulla (RVLM) (44), microinjection of an AMPA-kainate receptor antagonist into the NTS also increases baseline arterial pressure and sympathetic nerve activity.

The NTS contains a high density of glucocorticoid type II receptors (1, 15). Attenuation of NTS AMPA receptor function by glucocorticoids could result in the reductions in baroreflex function we have observed (36, 39). Therefore, we tested the hypothesis that glucocorticoids attenuate blood pressure and RSNA responses to activation and blockade of NTS AMPA receptors. Experiments were performed in Inactin-anesthetized male Sprague-Dawley rats treated for 7 ± 1 (mean ± SE, range 5-9) days with subcutaneous corticosterone (Cort) pellets or in control rats. Microinjection of AMPA and the AMPA-kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) were used activate and block NTS AMPA receptors, respectively.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

General. Experiments were performed using 87 male Sprague-Dawley rats purchased from Charles River Laboratories. All animals were housed in the animal care facility at the University of Missouri (Kansas City, MO) in a room with a 12:12-h light-dark cycle. Animals were provided food and water ad libitum (sodium content of 0.17 mmol/g). The facility is accredited by the US Department of Agriculture and the American Association for the Accreditation of Laboratory Animal Care, and all experimental protocols and procedures were approved by the Institutional Animal Care and Use Committee.

Cort treatment. Increases in plasma Cort concentration were produced (n = 39) by subcutaneous implantation of a Cort pellet weighing ~100 mg. Pellets were made using an established technique (3, 36-39). Briefly, Cort was liquefied and pipetted into a mold designed specifically for manufacturing the pellets (Ted Pella; Redding CA). Surgery for implantation of the pellets was performed using aseptic techniques under isoflurane anesthesia. The depth of anesthesia was maintained to eliminate the withdrawal reflex to pinch of the hind paw. A small skin incision was made in the dorsal lumbar region, and the pellet was inserted subcutaneously. A small number (7 of 48) of control animals underwent the same surgical procedure but no pellet was implanted. The incision was sutured closed, and the rat was placed in a clean recovery cage.

We have previously reported that the dose of Cort used in these experiments increases the midmorning plasma Cort concentration in conscious rats from 3 µg/dl in control rats to 7 µg/dl in Cort-treated rats (36, 37). We have also previously shown that the Cort treatment used in these experiments decreases the thymus and adrenal weight, indicating the physiological effectiveness of the Cort (3, 36-39). To confirm the physiological efficacy of the Cort used in these experiments, the thymus and adrenal glands were removed at the end of the experiment, patted dry, and weighed. For data analysis, thymus and adrenal weights were normalized to body weight.

Drugs used for microinjection. All drugs administered by microinjection were dissolved in 100 µl of artificial cerebrospinal fluid (in mM: 128 NaCl, 2.6 KCl, 1.3 CaCl2, 0.9 MgCl2, 20 NaHCO3, and 1.3 Na2HPO4; pH 7.4). AMPA receptors were activated by using AMPA at 0.03, 0.1, and 0.3 pmol/100 nl (0.3, 1.0, and 3 µM). AMPA receptors were blocked by using the AMPA-kainate receptor antagonist CNQX (250 pmol/100 nl, 2.5 mM). To determine whether the effects of Cort on the response to CNQX were selective for blockade of AMPA-kainate receptors, control experiments were performed in which the arterial pressure response to NMDA blockade were tested using the NMDA-selective receptor antagonist 2-amino-5-phospho-novalerate (AP5, 1 nmol/100 nl, 10 mM). In separate experiments, NMDA (5 pmol/100 nl, 0.05 mM) was used to test the selectivity of CNQX for AMPA-kainate receptors.

Surgical preparation. Experiments were performed 7 ± 1 (range 5-9) days after sham surgery or subcutaneous Cort pellet implantation or in naive rats that had been in the laboratory animal facility for a minimum of 1 wk. Naive rats and rats that underwent sham surgery were combined into a single control group for data analysis and presentation. Body weight averaged 377 ± 5 g for control rats and 373 ± 11 g for Cort-treated rats. Rats were anesthetized with the long-acting rodent anesthetic thiobarbital sodium (Inactin; Sigma) at an initial dose of 110 mg/kg ip. Supplemental anesthetic was given by an intraperitoneal or intravenous injection as required to maintain a surgical plane of anesthesia. Adequate depth of anesthesia was determined by observing an absence of withdrawal to the pinch of the hind paw and no evidence of fluctuations in blood pressure in response to surgical manipulation or pinch of the hind paw. Body temperature was maintained at 36-38°C by using a ventral heating pad and, when necessary, an infrared lamp. The animal was intubated through a tracheotomy and ventilated with oxygen-supplemented room air. A catheter made of Tygon tubing with a 28-gauge Teflon tubing tip was inserted into the abdominal aorta via the femoral artery and was used for the measurement of arterial pressure. A venous catheter of polyethylene-50 tubing was inserted into the abdominal vena cava via the femoral vein for the infusion of drugs. Gallamine triethiodide was given intravenously at an initial dose of 25 mg and was followed with a maintenance dose of 10 mg every hour. After administration of the gallamine, depth of anesthesia was monitored by assuring that there were no fluctuations in arterial pressure in response to surgical manipulation or pinch of the hind paw. The rat was placed into a stereotaxic head frame, the head was ventroflexed at a 60° angle, and a medial incision was made to expose the surface of the hind brain.

During the microinjection of drugs, the meniscus in the electrode was always observed by using a surgical microscope with a calibrated reticle to assure correct injection volume. Thus bilateral microinjections could not be given simultaneously. Maximum changes in mean arterial pressure (MAP) and RSNA in response to AMPA were observed within 30 s of microinjection, whereas maximum responses to CNQX or AP5 required several minutes. Therefore, microinjection of CNQX or AP5 was made bilaterally, with the two injections separated by a maximum of 1 min, whereas AMPA was given unilaterally. Preliminary experiments indicated that unilateral injections of lower doses of AMPA (0.03 or 0.1 pmol) produced inconsistent changes in arterial pressure, presumably due to the buffering reflex effects mediated by the contralateral NTS. Thus experiments requiring microinjection of AMPA were performed following a lesion of the contralateral NTS. To perform the lesion, a stainless steel microelectrode with a tip diameter of 25 µm (Fredrick Haer; Bowdoinham, ME) was inserted into the right NTS at 0.3 mm rostral and 0.4 mm lateral relative to the obex, and at a depth of 0.5 mm. The obex was defined, according to Paxinose and Watson, Fig. 77 (32), as the caudal-most tip of visible area postrema. A lesion was produced by application of an 800-µA current to the electrode for a period of 10 s. Completeness of the lesion was verified by the absence of a change in arterial pressure in response to the microinjection of AMPA (0.3 pmol) into the site of the lesion. Initial testing demonstrated that this high dose of AMPA always produced a reduction in arterial pressure when injected unilaterally into the NTS before the lesion or in nonlesioned rats.

For recording RSNA, a left flank incision was made to expose the renal nerves within the retroperitoneal space. Bipolar electrodes made of Teflon-coated, platinum-iridium wires, with the Teflon stripped from the ends, were placed around a bundle of renal nerves. The electrodes were secured in place using a silicone elastomer (Kwik-Cast, WPI). After several minutes, the cavity was filled with a 1:1 mineral oil-petroleum jelly mixture. RSNA was not successfully recorded in all experiments, and the number of animals in each group from which RSNA data were obtained is provided in Table 1. RSNA data are not reported for the AP5 microinjection experiments because of an insufficient number of animals with successful RSNA recording.

                              
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  		Table 1.   Baseline MAP and HR in control and Cort-treated rats

Microinjection protocols. The experimental protocol was initiated at least 30 min after the completion of the surgical procedures. Microinjections were usually made at 0.3 mm rostral and 0.4 mm lateral to the obex, at a depth of 0.5 mm. These coordinates were adjusted slightly for body weight of the rat; all coordinates were always within the range of 0.3-0.5 mm. Drugs were injected through glass micropipettes (1.2 mm diameter, 20- to 30-µm tips) attached to a Neurophore pressure injection module (Medical Systems). AMPA, CNQX, and AP5 were microinjected in separate experiments except in four animals in which the efficacy and selectivity of CNQX to block AMPA was determined. In those experiments, AMPA (0.3 pmol/100 nl) and NMDA (5 pmol/100 nl) were microinjected before and during blockade of AMPA-kainate receptors with CNQX. A minimum of 30 min was allowed between doses of AMPA.

The increases in arterial pressure produced by elevated glucocorticoids require several days to reach a plateau (unpublished observations and Ref. 21). However, we have observed that effects of Cort to attenuate baroreflex function can be reversed within 2-3 h by blocking glucocorticoid type II receptors with mifepristone (Mif) (36, 39). To determine whether Mif could also reverse the effects of Cort treatment on the responses to blockade of AMPA-kainate receptors, additional rats were given a subcutaneous injection of the glucocorticoid type II receptor antagonist Mif (30 mg/kg) in oil 2.5 h before microinjection of CNQX. Mif also antagonizes actions of progesterone, but we have previously demonstrated the selectivity of the drug in our model by showing that the antagonist has no effect in the absence of glucocorticoids (36). At the end of the experiment, all animals were euthanized without regaining consciousness with an overdose of Inactin (500 mg/kg) or pentobarbital sodium (200 mg/kg).

Data acquisition and analysis. Pulsatile arterial pressure was measured from the arterial catheter using a pressure transducer (Maxxim Medical) connected to a bridge amplifier (World Precision Instruments; Sarasota, FL). The output from the bridge amplifier was fed into a MacLab (ADIntruments) analog-to-digital processor connected to a Macintosh computer. RSNA was recorded in its raw form and amplified (10,000-100,000 times) with band-pass filters set at 10 and 3,000 Hz. The raw signal was monitored on an oscilloscope. For quantification purposes, the signal was rectified and integrated by using 20- and 600-ms time constants. The 20-ms time constant was used to determine the electrical noise level either during maximal reductions in nerve activity in response to microinjection of a large dose of AMPA (1.0 pmol/100 nl) or after death. The 600-ms time constant was used for data analysis. Noise was subtracted from baseline RSNA before microinjection of the drug or vehicle to determine 100% RSNA. RSNA had to be normalized to 100% because absolute values for RSNA are dependent on electrode placement and cannot be compared between animals. MAP and heart rate were also determined during the baseline period, and the results were analyzed by ANOVA. Changes in MAP, heart rate, and percent RSNA from baseline in response to AMPA were averaged into 1-s bins for both graphical presentation and statistical analysis. Responses to CNQX or AP5 were averaged into 30-s bins for graphical presentation and statistical analysis. Repeated measures ANOVA was used for analysis of time as a factor, and between-subjects ANOVA was used to compare groups. Results from control and Cort-treated rats given CNQX with or without pretreatment with Mif were analyzed together in a single ANOVA with all four groups included in the between-subjects factor. Values for percent RSNA were transformed by natural log before ANOVA to correct for the inherent nonnormal distribution of percentage values. For post hoc analysis, the Duncan new multiple-range test for between-subject variables and least-square means for repeated-measures variables were used as needed to determine significance. Regression analysis was performed on baseline MAP versus the peak MAP response in experiments with CNQX to determine whether baseline MAP influenced the responses. Significance was accepted at P < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

General. On the day of the experiment, body weight was not different (P = 0.72) between control (377 ± 5 g) and Cort-treated rats (373 ± 11 g). Baseline values for arterial pressure and heart rate are provided in Table 1. To determine whether Cort had any overall affect on these variables, values for all control versus all Cort-treated rats were compared, excluding the rats pretreated with Mif, because Mif can affect baseline arterial pressure (21, 36, 39). Overall, Cort treatment significantly increased baseline arterial pressure from 101 ± 1 mmHg in control rats to 109 ± 2 mmHg in Cort-treated rats (P < 0.01). The effect of Cort on baseline arterial pressure was also analyzed separately in rats used for each protocol, with values for each dose of AMPA considered individually because not all rats received all doses of AMPA. Only rats pretreated with Mif were excluded. Analyzed separately by experimental group, average values were not significantly different between control and Cort-treated rats (Table 1). Thus the action of Cort to increase baseline arterial pressure only reached statistical significance when a large number of animals were included in the analysis. Cort treatment had no effect on baseline heart rate (329 ± 5 vs. 323 ± 6 beats/min in control vs. Cort-treated rats, P = 0.45). Cort treatment significantly reduced thymus weight normalized to body weight from 1,213 ± 67 mg/kg in control rats (n = 20) to 431 ± 39 mg/kg in Cort-treated rats (P < 0.01). Similarly, adrenal weight normalized to body weight was decreased in Cort-treated rats (92 ± 5 mg/kg) relative to control rats (164 ± 5 mg/kg, P < 0.01). The reductions in thymus and adrenal weight are similar to what we have previously observed and clearly demonstrate the functional efficacy of the prolonged Cort treatment (2, 36-39).

Effect of Cort treatment on responses to AMPA. The effect of vehicle on MAP, RSNA, and heart rate for the first 30 s following microinjection was determined by within-subject ANOVA on the absolute data. Microinjection of the vehicle (100 nl artificial cerebrospinal fluid, n = 10) had a small (<3 mmHg), but significant (P < 0.01), effect to increase baseline MAP. Also, there was an immediate decrease in RSNA from 100% to 85 ± 5% (P = 0.038) that lasted <2 s. Microinjection of the vehicle had no significant effect on heart rate.

AMPA was microinjected at 0.03, 0.1, and 0.3 pmol/100 nl. An example of the response to AMPA (0.3 pmol/100 nl) is provided in Fig. 1. Microinjection of AMPA (0.03 pmol/100 nl) significantly reduced MAP in control rats by a maximum of 5 ± 2 mmHg, whereas there was no decrease in MAP in response to 0.03 pmol AMPA in Cort-treated rats (Fig. 2, top). There were no differences in RSNA in response to 0.03 pmol of AMPA between control and Cort-treated rats (Fig. 2, bottom). Heart rate did not change significantly in response to 0.03 pmol of AMPA in either control or Cort-treated rats.


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  		Fig. 1.   Example experimental record of effect of microinjection of alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA, 0.3 pmol) into the nucleus of solitary tract (NTS). Top trace, pulsatile arterial pressure (AP). The Event trace shows output from neurophore, marking the time of microinjection. Bottom 3 traces are renal sympathetic nerve activity (RSNA) in the following order: rectified and integrated at a 20-ms time constant, rectified and integrated at a 600-ms time constant, and raw nerve activity signal directly recorded from the output of the amplifier.



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  		Fig. 2.   Change in mean arterial pressure (MAP, top) and RSNA (bottom) in response to microinjection of AMPA (0.03 pmol) into the NTS in control (squares) and corticosterone (Cort)-treated (triangles) rats. Cort treatment significantly attenuated the reduction in MAP in response to AMPA. *P < 0.05 for comparison between control and Cort-treated rats.

Microinjection of 0.1 pmol of AMPA reduced MAP in control rats by a maximum of -16 ± 2 mmHg, whereas the maximum reduction in MAP in Cort-treated rats was only -5 ± 1 mmHg (Fig. 3, top). Cort treatment also attenuated the reduction in RSNA in response to 0.1 pmol of AMPA (Fig. 3, bottom). RSNA fell to a minimum of 37 ± 6% of baseline in control rats compared with 70 ± 7% in Cort-treated rats. This dose of AMPA produced a small reduction in heart rate (-9 ± 3 beats/min at 10 s after AMPA) in control rats, which was attenuated in Cort-treated rats (-2 ± 1 beats/min, P = 0.03).


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  		Fig. 3.   Change in MAP (top) and RSNA (bottom) in response to microinjection of AMPA (0.1 pmol) into the NTS in control (squares) and Cort-treated (triangles) rats. Cort treatment significantly attenuated the reduction in MAP and RSNA in response to AMPA. *P < 0.05 for comparison between control and Cort-treated rats for time points indicated by the solid lines.

Treatment with Cort also significantly attenuated the reductions in MAP and RSNA in response to microinjection of AMPA at 0.3 pmol (Fig. 4). The reduction in heart rate in response to AMPA was not different between control (-23 ± 4 beats/min) and Cort-treated rats (-22 ± 5 beats/min).


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  		Fig. 4.   Change in MAP (top) and RSNA (bottom) in response to microinjection of AMPA (0.3 pmol) into the NTS in control (squares) and Cort-treated (triangles) rats. Cort treatment significantly attenuated the reduction in MAP and RSNA in response to AMPA. *P < 0.05 for comparison between control and Cort-treated rats for time points indicated by the solid lines.

Effect of Cort treatment on responses to CNQX. Projections from the NTS tonically inhibit sympathetic outflow from the RVLM by a multisynaptic pathway (44). Blockade of AMPA-kainate receptors removes at least a portion of the tonic inhibition and baseline arterial pressure increases (19, 29). A reduction in AMPA receptor function within the NTS would be predicted to reduce the AMPA-mediated portion of the tonic inhibition, leading to a smaller increase in arterial pressure during NTS AMPA receptor blockade. In the present experiment, microinjection of CNQX in control rats produced a significant increase in MAP that peaked at 31 ± 3 mmHg (Fig. 5, top, solid squares). The increase in MAP was significantly less in Cort-treated rats peaking at 20 ± 2 mmHg, a 30% reduction relative to the control response (Fig. 5, top, solid triangles). There was no correlation between baseline MAP and peak increase in MAP in either control (r2 < 0.1, P = 0.14) or Cort-treated (r2 < 0.1, P = 0.74) rats. The increase in RSNA in response to CNQX was also significantly less in Cort-treated compared with control rats (Fig. 5, bottom, solid symbols). In fact, in Cort-treated rats, RSNA never increased significantly above the initial baseline in response to CNQX.


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  		Fig. 5.   Change in MAP (top) and RSNA (bottom) in response to bilateral microinjection of the AMPA-kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) into the NTS in control (squares) and Cort-treated (triangles) rats. Experiments were performed without (solid symbols) or with (open symbols) pretreatment with the glucocorticoid type II receptor antagonist mifepristone (Mif). CNQX was microinjected into the first side at time 0. Cort treatment reduced both the MAP and RSNA responses to CNQX. *P < 0.05 for comparison between control and Cort-treated rats for time points indicated by the solid line. Mif significantly enhanced the MAP and RSNA responses in both control and Cort-treated rats. dagger P < 0.05 for comparison between control and control + Mif rats. dagger dagger P < 0.05 for comparison between Cort and Cort + Mif rats. There were no significant differences between the MAP responses to CNQX in control + Mif versus Cort + Mif groups; however, percent RSNA was significantly different (**P < 0.05) between these groups.

Effect of Mif on responses to CNQX. Experiments were performed in an additional eight control and five Cort-treated rats that were pretreated 2.5 h before the CNQX microinjection with the glucocorticoid type II receptor antagonist Mif. There was no significant effect of Mif on baseline arterial pressure in either control or Cort-treated rats. In both control (Fig. 5, top, open squares) and Cort-treated rats (Fig. 5, top, open triangles), Mif significantly enhanced the increase in MAP after microinjection of CNQX. In rats pretreated with Mif, the increases in MAP in control versus Cort-treated rats were not statistically different. Mif also enhanced the increase in RSNA response to CNQX in both control and Cort-treated rats (Fig. 5, bottom, open symbols).

Selectivity and efficacy of CNQX. The selectivity and efficacy of CNQX were tested in four separate control rats, with RSNA recorded in three of those rats. AMPA (0.3 pmol, n = 3) and NMDA (5 pmol, n = 4) were microinjected before and during AMPA-kainate receptor blockade with CNQX. The response to AMPA was also determined 15 min following CNQX. Microinjection of AMPA in the baseline period reduced MAP by an average of -35 ± 3 mmHg and reduced RSNA to 3 ± 2% of baseline (100%). Five minutes after microinjection of CNQX, there was no significant change in MAP (-4 ± 5 mmHg) or in RSNA (100 ± 2% of baseline) in response to AMPA. Fifteen minutes after CNQX, the response to AMPA had returned to control (-39 ± 5 mmHg and 10 ± 4% of baseline RSNA). The responses to NMDA were unaffected by CNQX. In response to NMDA MAP fell by -22 ± 7 mmHg in the baseline period and by -35 ± 7 mmHg during CNQX. RSNA was reduced from 100% to 45 ± 24% in the baseline period and to 16 ± 9% during CNQX. Therefore, the dose of CNQX used in these experiments provided complete blockade of AMPA receptors without attenuating NMDA receptor function.

Effect of Cort treatment on responses to blockade of NMDA receptors by AP5. The focus of this study was to determine the effect of Cort treatment on responses to AMPA receptor activation and blockade within the NTS. However, it was important to determine whether Cort attenuated the actions of endogenous glutamate at all ionotropic glutamate receptors or whether the effect was selective for the AMPA-kainate receptors. Therefore, the effect of Cort treatment on the response to NMDA receptor blockade was determined by bilateral microinjection of AP5 into five control and seven Cort-treated rats. AP5 produced an increase in MAP that peaked at 17 ± 1 mmHg in control rats and at 24 ± 2 mmHg in Cort-treated rats (P = 0.037 for control vs. Cort, Fig. 6). Therefore, Cort treatment had an opposite effect on the arterial pressure response to the blockade of NMDA receptors compared with the blockade of AMPA-kainate receptors.


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  		Fig. 6.   Change in MAP in response to bilateral microinjection of the N-methyl-D-aspartate receptor antagonist 2-amino-5-phospho-novaleate (AP-5) in control (squares) and Cort-treated (triangles) rats. Cort significantly enhanced the MAP response to AP5 (*P < 0.05 for time points indicated by the solid line).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Summary and conclusions. The results demonstrate that glucocorticoid treatment attenuated the reductions in arterial pressure and RSNA in response to microinjection of AMPA. Glucocorticoid treatment also attenuated the increase in MAP in response to the AMPA-kainate receptor blockade with CNQX and eliminated the CNQX-evoked increase in RSNA. Therefore, we conclude that prolonged treatment with Cort attenuates arterial pressure and RSNA responses to both activation and blockade of AMPA receptors in the NTS. The relative role of AMPA versus kainate receptor blockade in the response to CNQX cannot be determined from these experiments. An important role for AMPA receptor blockade in the differential response to CNQX is suggested by the data demonstrating that Cort attenuates responses to selective activation of AMPA receptors.

Site of action of Cort. The attenuation of responses to both AMPA and CNQX by prolonged Cort treatment suggests that there is reduced tonic inhibition of the RVLM in Cort-treated rats. The NTS, by way of the caudal ventral lateral medulla, tonically inhibits RVLM neurons that send excitatory projections to the spinal cord preganglionic sympathetic neurons controlling RSNA (44). Blockade of NTS AMPA receptors removes this tonic inhibitory influence on RVLM neurons, and arterial pressure and nerve activity increase (19, 29). A glucocorticoid-mediated reduction in AMPA receptor function within the NTS could lead to decreased tonic inhibitory input into the RVLM, resulting in an attenuated response to CNQX, as was observed in this study. However, the results could also be explained by an effect of Cort to modulate the pathway at a site other than the NTS. For example, Cort-induced attenuation of inhibitory mechanisms within the rostral ventral lateral medulla could also produce a reduction in responses to NTS microinjection of AMPA and CNQX. If Cort was attenuating baroreflex function at a site distal to the NTS, responses to blockade of NTS NMDA receptors should also be attenuated in Cort-treated rats because NMDA receptors within the NTS can modulate baroreceptor-related neuronal activity and baroreceptor reflex function (4, 6, 19, 29, 61, 62). However, we observed that prolonged treatment with Cort enhanced the arterial pressure response to AP5, supporting a selective effect of Cort on AMPA-kainate receptors within the NTS. We also observed that Cort did not attenuate the responses to all doses of AMPA equally. Whereas the effect of Cort treatment to attenuate responses to AMPA was robust at the two lower doses of AMPA, the ability of Cort to attenuate the responses to the highest dose of AMPA was much smaller. This observation that a high dose of AMPA could overcome the attenuating effect of Cort is consistent with an effect of Cort to depress AMPA receptor function within the NTS. We have additional preliminary data (not shown) suggesting that prolonged local treatment of the NTS region with Cort can increase arterial pressure and modulate baroreflex function, and it is known that the NTS contains a high density of glucocorticoid type II receptors (1, 15). We also have preliminary results indicating that Cort increases expression of the GluR2 subunit of the AMPA receptor in the NTS. An increase in GluR2 would decrease calcium permeability of the AMPA receptor, resulting in decreased receptor function (30). Thus the data presented here, combined with other results, suggest the possibility that Cort can modulate NTS AMPA receptor function. Additional studies are required to demonstrate that there is a direct effect of Cort to attenuate AMPA receptor function in the NTS.

Efficacy of prolonged Cort treatment. Cort treatment was achieved by implantation of a subcutaneous Cort pellet. In awake rats, this dose of Cort increases midmorning plasma Cort concentration from 3 µg/dl in control rats to 7 µg/dl in Cort-treated rats (36, 37). In the present experiments we chose not to measure plasma Cort in the conscious animals for several reasons. Most importantly, the samples would have been obtained by nicking the tail vein of a restrained animal, and we did not want to confound the study by exposing the rats to this stress. Alternatively, we did not want to instrument the rats with chronic indwelling arterial catheters to obtain the blood samples, because leakage of heparin from the catheter would have increased bleeding during surgery. We have previously published studies (36-39) using this dose and method of prolonged Cort treatment, and in all cases we have measured elevated plasma Cort in the Cort-treated rats. In this study, the physiological efficacy of the Cort treatment was confirmed by the observed reduction in both thymus and adrenal weights in Cort-treated rats. This is an established and reliable effect of prolonged elevations in plasma glucocorticoids (3, 36-39).

Effect of Cort on baseline MAP. In previous studies, animals treated with this dose of Cort do not consistently have an elevated baseline MAP (36-39), whereas animals treated with twice this dose consistently have arterial pressures 15-20 mmHg above normal (unpublished observations). Thus the dose used in this study appears to be a borderline dose for increasing MAP. In our previous studies, Mif significantly decreased baseline arterial pressure in Cort-treated rats but only if the Cort treatment significantly elevated arterial pressure. In the present study, overall MAP was significantly increased in Cort-treated rats, but the effect was variable such that there were no significant Cort-induced increases in MAP within individual groups of rats (Table 1). Mif treatment significantly enhanced the MAP and RSNA responses to CNQX within 2.5 h but did not significantly reduce arterial pressure in either control or Cort-treated rats. This is consistent with previous results showing that Mif did not decrease baseline MAP in normotensive Cort-treated rats. (36).

The effect of Cort to attenuate responses to AMPA receptor activation in the NTS would be expected to produce an increase in baseline arterial pressure larger and more consistent than was observed in this study. It is possible that other actions of Cort, including the apparent enhancement of NMDA receptor-mediated modulation of baseline arterial pressure within the NTS (Fig. 6), might counteract the AMPA receptor-mediated effects under some conditions. Weiland et al. (57) demonstrated that 10 days of glucocorticoid treatment increased the expression of selective NMDA receptor subunits in the rat hippocampus. A similar increase in the present study could explain the observed enhanced response to AP5. NMDA receptors within the NTS influence multiple reflex pathways (9, 22, 29). Thus the effect of Cort to attenuated both the baroreceptor reflex and the responses to AMPA receptor activation in the NTS may have an influence on baseline arterial pressure that is dependent, among other things, on the prevailing relative influence of NMDA and AMPA receptors on NTS neuronal activity.

Effects of acute versus prolonged increases in Cort. Glucocorticoids act through both classical genomic and more recently appreciated nongenomic mechanisms (7). In the present study, we administered Mif 2.5 h before microinjection of CNQX, a time frame sufficient to permit for either nongenomic or rapid genomic effects. Anesthesia and surgery acutely increase plasma glucocorticoid concentration, allowing the possibility that some of the effects we observed were due to the acute, rather than prolonged, elevations in Cort. In possible support of rapid actions of Cort are the data in Fig. 5 demonstrating that blockade of glucocorticoid type II receptors for 2.5 h enhanced arterial pressure and RSNA responses to CNQX in both control and Cort-treated rats. However, we have previously shown that the Cort-induced alterations in baroreflex function can be reversed within 3 h of Mif treatment even in awake rats without acute increases in basal plasma glucocorticoids (36). Blockade of glucocorticoid receptors also reduced arterial pressure within 3 h in awake Cort-treated rats with elevated arterial pressure but not in Cort-treated normotensive animals. Those results indicate that the acute blockade of glucocorticoid receptors can reverse effects of prolonged (days) increases in Cort. Furthermore, there is evidence that the effect of Cort to increase arterial pressure takes several days to develop. We have administered a large dose of Cort acutely and observed no increase in baseline arterial pressure several hours later (38). It has been previously reported that it requires several days to reach a plateau arterial pressure with glucocorticoid administration (55). We have made similar (unpublished) observations when we measured arterial pressure in Cort-treated rats using radiotelemetry. Therefore, data suggest that acute increases in Cort do not elevate baseline arterial pressure, but that the effects of prolonged Cort exposure can be rapidly reversed by blockade of glucocorticoid type II receptors. Several possible mechanisms could account for these observations. The rapid reversal of Cort effects can be explained by inhibition of a protein with a rapid turnover, such as AMPA receptor subunits (30). The longer onset latency for the Cort-induced increase in pressure could be due to the involvement of an additional required protein with a longer turnover time. It is interesting that Mif had a similar effect in both control and Cort-treated rats to enhance responses to CNQX. This suggests the possibility that even in control rats Cort influences either AMPA receptor function in the NTS or some other neural component along the pathway of the response. This is in agreement with a report that baroreceptor reflex resetting was absent in adrenalectomized rats (16). The fact that prolonged increases in Cort attenuated responses to CNQX relative to control rats while blockade of glucocorticoid type II receptors enhanced responses to CNQX strongly supports the conclusion that prolonged Cort administration attenuates responses to CNQX.

Measurement of RSNA. RSNA was measured between subjects in these experiments and quantified as a percentage of baseline. Thus baseline RSNA could not be compared between control and Cort-treated rats. In response to CNQX, RSNA increased to >150% of baseline in control rats, whereas RSNA did not significantly increase in Cort-treated rats. Therefore, Cort treatment significantly reduced the RSNA response to CNQX regardless of the absolute level of RSNA during the baseline period. However, the difference in the percent RSNA response to CNQX in control and Cort rats pretreated with Mif could have been due to differences in absolute levels of baseline RSNA.

The changes in RSNA we observed did not always correlate with changes in MAP. At the lowest dose of AMPA, there was a small (5 mmHg) reduction in arterial pressure in control rats, but there was no detectable change in RSNA. This suggests that a decrease in nerve activity to some other vascular bed, such as the hindlimb or mesenteric circulation, produced the small reduction in pressure. At higher doses of AMPA, the maximum reductions in RSNA preceded the reductions in MAP, as would be expected. With the microinjection of CNQX, RSNA did not increase in Cort-treated rats, even though MAP increased by 20 mmHg. This implies that nerve activity increased to some other vascular bed(s) or possibly that CNQX stimulates the release of vasopressin. In control rats, RNSA was maintained at an elevated level after MAP had already begun to decline from its peak value. These results similarly suggest that sympathetic nerve activity to vascular beds other than the kidney contribute to the increase in arterial pressure observed during blockade of AMPA-kainate receptors in the NTS. Other investigators have reported differences between changes in arterial pressure and RNSA following activation of baroreceptor afferents. Undesser et al. (51) observed that following pressure increases produced by the infusion of phenylephrine, blood pressure returned to control values well before RSNA did. Drummond and Seagard (12) demonstrated that RNSA reset to a greater degree than did either arterial pressure or lumbar sympathetic nerve activity when carotid sinus pressure was selectively altered. The neural mechanisms accounting for the observed differences in the control of arterial pressure and RSNA are not known.

Effect of Cort on baroreflex function. The hypothesis for the present study was derived in part from our previous observation that Cort attenuates arterial baroreceptor reflex function (36, 39). Baroreceptor afferents terminate in the NTS where the information regarding prevailing pressure is relayed, processed, and integrated (13). The technique of microinjection was used in these studies to simultaneously activate or inhibit a sufficient number of NTS neurons to produce "reflex" changes in arterial pressure and RSNA, with the observed changes in MAP and RSNA presumably due in part to activation of the baroreceptor reflex pathway. However, many NTS neurons are not involved in baroreflex function. The effects of Cort on AMPA receptors located on these other neurons could have influenced the experimental results. Importantly, the attenuation of responses to AMPA receptor activation and blockade are consistent with an effect of Cort to attenuate baroreflex function. The effect of Cort to enhance the response to activation of NMDA receptors is not consistent with the observed effect of Cort on baroreflex function. However, because in the NTS the role of NMDA receptors in baroreflex control is less dominant than that of AMPA receptors, this opposing effect of Cort on NMDA versus AMPA receptor effects could still result in an attenuation of baroreflex function. (6, 19, 29, 61, 62). Because glutamate receptors are also important for baroreceptor reflex function in other brain nuclei (18), it will be important in the future to determine the effects of Cort on glutamate receptor function in these individual brain areas.

Perspectives. Understanding glucocorticoid effects on the neural control of the circulation is of significant clinical importance. It is known that Cort is elevated in the SHR and that removal of glucocorticoids eliminates the development of hypertension in this model (23, 26, 42, 43). There is growing evidence that elevated glucocorticoids contribute to the pathogenesis of essential hypertension in humans (11, 31, 35, 41, 53, 54, 56, 59). It is now apparent that prenatal exposure to elevated glucocorticoids increases both glucocorticoid levels and the risk of hypertension in adulthood (40). Glucocorticoids are also elevated in other clinical conditions associated with changes in reflex control of the circulation such as heart failure and pregnancy. Yet only a few studies have investigated the effects of glucocorticoids on the neural control of the circulation. We (36, 39) have recently reported that elevated glucocorticoids decrease the gain and increase the midpoint of the baroreceptor reflex. The present study extends those results by demonstrating that prolonged moderate elevations in Cort attenuate MAP and RSNA responses to activation and blockade of AMPA receptors within the NTS. The present study combined with future investigations will improve our understanding of the role of increased glucocorticoid activity in hypertension and other clinical conditions.


    ACKNOWLEDGEMENTS

This work was supported by National Heart, Lung, and Blood Institute Grant HL-56112, the Heartland Affiliate of the American Heart Association, and the University of Missouri Research Board.


    FOOTNOTES

Address for reprint requests and other correspondence: D. A. Scheuer, Dept. of Pharmacology, The Univ. of Missouri, 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.

First published January 16, 2003;10.1152/ajpheart.01033.2002

Received 2 December 2002; accepted in final form 8 January 2003.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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