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Am J Physiol Heart Circ Physiol 281: H2456-H2462, 2001;
0363-6135/01 $5.00
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Vol. 281, Issue 6, H2456-H2462, December 2001

Afferent baroreceptor discharge in pregnant rats

J. D. Laiprasert1, R. L. Hamlin1, and C. M. Heesch2

1 Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio 43210; and 2 Department of Veterinary Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211-3300


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
PERSPECTIVES
REFERENCES

The baroreflex function curve is shifted to lower operating pressures, efferent sympathoexcitatory responses are attenuated, and sympathoinhibitory responses are potentiated in pregnant compared with virgin rats. It has been proposed that during pregnancy, elevated levels of 3alpha -hydroxy-dihydroprogesterone (3alpha -OH-DHP), a major metabolite of progesterone, may contribute to this difference, because acute intravenous administration of 3alpha -OH-DHP to virgin female rats mimics the effects of pregnancy on the baroreflex. To determine whether changes in the afferent limb might contribute to these baroreflex responses, the effects of pregnancy and 3alpha -OH-DHP on aortic depressor nerve activity were assessed in the current study. Baroreceptor discharge curves were obtained in Inactin-anesthetized rats by recording aortic nerve activity during ramp increases and decreases in mean arterial pressure (MAP) [intravenous phenylephrine and nitroprusside infusion] before [(control, C) 15 min (E1), and 30 min (E2) after 3alpha -OH-DHP (220 µg/kg bolus + 22 µg · kg-1 · min-1 infusion iv)]. Baseline blood pressure was significantly lower in pregnant (109 ± 4.4 mmHg) compared with virgin (122 ± 2.8 mmHg) rats. The only significant difference in the baroreceptor discharge curves was a decrease in curve midpoint in pregnant rats (virgin = 140 ± 2.7 vs. pregnant = 124 ± 3.6 mmHg). 3alpha -OH-DHP had no effect on afferent baroreceptor discharge curves in either virgin or pregnant groups. These results suggest that pressure-dependent baroreceptor resetting may contribute to a shift in the baroreflex curve to lower operating pressures, but cannot completely explain differences in baroreflex function between virgin and pregnant animals.

aortic depressor nerve; 3alpha -hydroxy-dihydroprogesterone; neurosteroid; baroreflex; pregnancy


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
PERSPECTIVES
REFERENCES

PREGNANCY IS ASSOCIATED with many cardiovascular adaptations. For example, blood volume and cardiac output are increased, arterial pressure is decreased, and heart rate (HR) is elevated in pregnant compared with virgin animals (10, 11, 17, 21). Among the adaptations to pregnancy are changes in arterial baroreflex function. Sympathoexcitatory responses to decreases in arterial blood pressure are attenuated and sympathoinhibitory responses to increases in blood pressure are potentiated in pregnant animals (7, 15, 23). In addition, baseline arterial pressure is lower in pregnant animals and the baroreflex function curve is shifted to a lower operating pressure range (1, 7, 15, 23).

The presence of elevated levels of the primary metabolite of progesterone, 3alpha -hydroxy-dihydroprogesterone (3alpha -OH-DHP), may be one mechanism involved in producing the changes in baroreflex function during pregnancy. Previous studies in our laboratory have demonstrated that acute intravenous administration of 3alpha -OH-DHP to virgin female rats attenuates sympathoexcitatory responses to decreases in arterial blood pressure, a response also seen in pregnancy (7, 15, 23). The 3alpha -OH-DHP metabolite of progesterone belongs to a class of compounds known as neurosteroids that produce effects through an action on the central nervous system (CNS). It has been demonstrated that 3alpha -OH-DHP is the most potent endogenous positive modulator of CNS GABAA receptors (25, 26). The progesterone metabolites, 3alpha -OH-DHP (allopreganolone) and allotetrahydrodeoxycorticosterone, bind stereospecifically to a unique site on the GABAA receptor complex and positively modulate GABA action on GABAA receptors through an allosteric mechanism (6). Both plasma and CNS concentrations of these metabolites are increased in pregnancy (5). Previously (12) our laboratory demonstrated that 3alpha -OH-DHP potentiated binding of the GABAA receptor ligand flunitrazepam in brainstem nuclei involved in the arterial baroreflex, including the nucleus tractus solitarius, caudal ventrolateral medulla, and rostral ventrolateral medulla (RVLM). A subsequent study (8) revealed that after a hypotensive challenge, expression of the early gene, c-fos, was attenuated in the RVLM of pregnant compared with virgin female rats.

Changes in baroreflex function and brainstem c-fos expression observed during pregnancy are consistent with a potentiation of GABAA receptor function in the RVLM and preliminary experiments in our laboratory suggest that direct application of 3alpha -OH-DHP to the RVLM produces changes in baroreflex function similar to those observed after intravenous administration (13). These results indicate that CNS effects of 3alpha -OH-DHP likely contribute to the effects of pregnancy on arterial baroreflex function. However, others have demonstrated that circulating and locally released substances can modulate baroreceptor afferent activity (2, 3). Whether pregnancy or the primary progesterone metabolite 3alpha -OH-DHP have an effect on baroreceptor afferent discharge that could participate in baroreflex adaptations has not been addressed. Therefore, the current experiments were designed to evaluate the effects of pregnancy and of 3alpha -OH-DHP on the afferent limb of the baroreflex.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
PERSPECTIVES
REFERENCES

Experiments were performed in 51 female Sprague-Dawley rats (Harlan Sprague Dawley, Indianapolis, IN) at 3 to 5 mo of age. Before the experiment, daily vaginal smear cytology was used to determine the stage of the estrous cycle and each rat was followed through at least two full estrous cycles. Animals to be included in the pregnant groups (n = 26) were placed with a fertile male, and day 1 of pregnancy was determined when sperm were observed in vaginal smears. Experiments were then performed on pregnant rats on days 20-21. Experiments in rats included in the virgin groups (n = 25) were performed in animals in the estrus stage of the cycle, a time when ovarian hormone levels are low.

Surgical preparation

Rats were anesthetized with Inactin (100 mg/kg ip). The trachea was cannulated and the rat artificially ventilated with room air supplemented with oxygen (small animal ventilator, Harvard Apparatus; South Natick, MA). Body temperature was monitored and maintained at 37°C. The rat was then instrumented with a left femoral arterial and venous catheter to monitor arterial blood pressure and for intravenous administration of supplemental anesthetic (5 mg iv as needed), respectively. Three catheters were also implanted in the left jugular vein for intravenous drug infusion.

To verify the effect of pregnancy on efferent baroreflex function in Inactin-anesthetized rats, the left renal nerve was isolated retroperitoneally and placed on a bipolar platinum recording electrode in virgin (n = 13) and pregnant (n = 14) rats. The renal nerve was secured on the electrode with polyvinylsiloxane gel (Coltene President, Mahwah, NJ). A ground wire was sutured to muscle at the incision site and the wound was closed.

Afferent baroreceptor responses were evaluated in a separate set of experiments by recording from the aortic depressor nerve, which has been demonstrated to contain almost exclusively baroreceptor afferent fibers in the rat (24, 29). The aortic nerve in 12 virgin and 12 pregnant rats was isolated through a ventral approach. Once isolated, the nerve was placed on a bipolar platinum recording electrode and secured in place with polyvinylsiloxane gel. A ground wire was sutured to muscle at the incision site, and the wound was closed.

Drugs and Solution

The anesthetic Inactin was obtained from RBI (Natick, MA) and dissolved in sterile water. Phenylephrine (PE) and nitroprusside (NTP) were purchased from Sigma (St. Louis, MO) and diluted in isotonic saline. The primary metabolite of progesterone, 3alpha -OH-DHP, was also obtained from Sigma and was dissolved in 40% beta -cyclodextrin (RBI).

Experimental Protocol

Efferent nerve activity baroreflex experiments. While the effect of pregnancy on baroreflex function has been previously evaluated in our laboratory in both chloralose-anesthetized (7) and conscious (23) rats, the attenuation in sympathoexcitatory responses to low blood pressures in pregnant chloralose-anesthetized rats is relatively small compared with the conscious preparation. To evaluate whether this may be due to the type of anesthetic used, preliminary experiments using the long-lasting rodent anesthetic Inactin were performed in 13 virgin and 14 pregnant animals.

Similar to previous protocols (7, 23) baroreflex function was evaluated by recording renal sympathetic nerve activity (RSNA) responses to slow ramp (~2 mmHg/s) decreases and increases in mean arterial pressure (MAP) (intravenous NTP and PE infusion, respectively). Nerve activity responses were obtained as MAP was lowered to 50 mmHg and then raised to 200 mmHg from baseline. MAP and RSNA were allowed to recover between pressure ramps. Any nerve activity signal remaining for 30 min after an overdose of anesthetic was defined as electrical noise and subtracted from the nerve activity values.

Afferent nerve activity baroreceptor experiments. Changes in baroreceptor afferent nerve discharge were evaluated by recording aortic nerve activity (AoNA) responses to slow ramp decreases and increases in MAP (intravenous NTP and PE infusion, respectively). Baroreceptor discharge responses were obtained as MAP was lowered to 50 mmHg and raised to 200 mmHg from baseline. MAP and AoNA were allowed to recover between pressure ramps. Baroreceptor discharge curves were obtained before (control, C) 15 min after 3alpha -OH-DHP (E1, 220 µg/kg bolus + 22 µg · kg-1 · min-1 infusion iv), and again 15 min after a second dose of 3alpha -OH-DHP (E2, 220 µg/kg bolus + 22 µg · kg-1 · min-1 infusion iv). Previously, a similar treatment regimen was shown to attenuate baroreflex-mediated sympathoexcitatory responses (15, 23). The goal in these previous studies was to achieve low micromolar concentrations of 3alpha -OH-DHP (~2 µM) that would be immediately available to the CNS via the circulation, and would be within the feasible range for endogenous CNS concentrations (23). The same treatment regimen was used in the current experiments to determine whether doses of 3alpha -OH-DHP known to affect baroreflex control of sympathetic nerve activity, had an effect on afferent baroreceptor nerve activity. Because arterial baroreceptors are sensitive to the rate of change of pressure, care was taken to ensure that the rate of decreases and increases in MAP was consistent between curves. The animals were then killed at the end of the experiment via an overdose of anesthetic, and any nerve activity signal remaining after 30 min was defined as electrical noise. The pups of pregnant animals were counted and weighed to ensure that pup weight was normal for the day of pregnancy.

Data were collected using the Biopac data acquisition system. The neural signal was amplified 50,000-fold and recorded on a Dell Pentium II 333-MHz computer. The signal was simultaneously monitored on a loudspeaker and on the computer screen as data were collected. Collected data were analyzed using Acknowledge v3.0 software. Data points for MAP, HR, and nerve activity were obtained at a rate of 1 Hz. The Acknowledge system was used to limit the raw NA signal to activity that exceeded a selected voltage set above noise level.

Data Analysis

Because absolute multiunit nerve activity values are dependent on recording conditions, nerve activity was standardized as a percentage of the initial baseline of the control curve.

Data obtained in the efferent nerve activity baroreflex experiments were fitted to the following nonlinear logistic curve equation (19)
Y=A1/{1+exp[<IT>A</IT>2(<IT>X−A</IT>3)]}<IT>+A</IT>4
where Y = nerve activity (NA), X = MAP, A1 = NA range, A2 = slope coefficient, A3 = MAP at curve midpoint, and A4 = minimum NA. The maximum NA and maximum slope of each curve were then calculated using the following equations
Maximum<IT> NA=A</IT>1<IT>+A</IT>4

Maximum slope<IT>=−</IT>(<IT>A</IT>2<IT>·A</IT>1)<IT>/</IT>4
Data obtained in experiments evaluating the afferent limb of the baroreflex by measuring AoNA responses were also fitted to a nonlinear logistic curve equation
Y=−<IT>A</IT>1<IT>/</IT>{1<IT>+</IT>exp[<IT>A</IT>2(<IT>X−A</IT>3)]}<IT>+A</IT>4
where Y, X, and A1-A3 are the same as above and A4 = maximum NA. The minimum NA and maximum slope of each baroreceptor discharge curve were then calculated using the following two equations
Minimum<IT> NA=A</IT>4<IT>−A</IT>1

Maximum slope<IT>=</IT>−(<IT>A</IT>2<IT>·A</IT>1)<IT>/</IT>4
In all experiments, values for baseline MAP, HR, baseline raw NA, and maximum raw NA were also determined for each curve. Baroreflex HR responses are modest in anesthetized rats, and, therefore, only HR range was evaluated.

Linear regressions on the linear portion of the RSNA or AoNA discharge response to NTP and also to PE were performed to separately evaluate the sensitivity to hypotensive and hypertensive challenges.

Unpaired t-tests were used for comparisons of parameters between virgin and pregnant rats and one-way ANOVA with repeated measures, followed by Student-Newman-Keuls post hoc test was used to evaluate the response to 3alpha -OH-DHP for a given parameter within each group. Data are presented as means ± SE. P <=  0.05 was considered significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
PERSPECTIVES
REFERENCES

Effects of Pregnancy on RSNA Baroreflex Curves

Prior studies in our laboratory have evaluated the effects of pregnancy on baroreflex function in chloralose-anesthetized (7) and in conscious (23) rats. Whereas evidence for attenuated sympathoexcitatory responses was observed in pregnant chloralose-anesthetized rats, the sympathoexcitatory responses were relatively small in the anesthetized compared with the conscious preparation. Preliminary experiments using the anesthetic Inactin were performed in 13 virgin and 14 pregnant animals to evaluate whether this may be due to the type of anesthetic used. The results indicated that under Inactin anesthesia, responses similar to those obtained in chloralose-anesthetized animals were observed and at high MAP were more similar to responses in conscious animals (Fig. 1). In pregnant rats, the RSNA baroreflex function curve midpoint (A3) tended to be lower (pregnant = 118 ± 2.4, virgin = 126 ± 2.8 mmHg, P < 0.056) suggesting a shift in the curve to a lower operating pressure range. Consistent with this trend, baseline MAP was significantly lower in pregnant (104 ± 3.1 mmHg) compared with virgin (121 ± 3.3 mmHg) animals. Slope of the NTP portion of the curve tended (P < 0.08) to be decreased in pregnant (-1.9 ± 0.27) compared with virgin (-2.6 ± 0.32) rats, suggesting that during pregnancy, sympathoexcitatory responses to low MAP may be attenuated. Meanwhile, a significantly lower minimum NA (A4) in pregnant rats (pregnant = 11 ± 2.8, virgin = 22 ± 3.2% baseline) indicated that sympathoinhibitory responses were potentiated at high MAP. Thus although not as pronounced as in conscious rats, potentiated sympathoinhibition and a tendency for attenuated sympathoexcitation are evident in pregnant Inactin-anesthetized rats.


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  		Fig. 1.   Effect of pregnancy on renal sympathetic nerve activity (RSNA) baroreflex curves. Mean RSNA baroreflex curves in Inactin-anesthetized rats are shown. Pregnancy was associated with a decrease in baseline mean arterial pressure (MAP) (closed circles) and a decrease in the baroreflex curve midpoint (P < 0.056, arrow). Additionally, the sympathoinhibitory response to high MAP was potentiated (*) and sensitivity to decreases in MAP tended (P < 0.08) to be less in pregnant rats (EFFECTS OF PREGNANCY ON RSNA BAROREFLEX CURVES).

The effect of pregnancy on baseline HR and HR range in these Inactin-anesthetized rats was also evaluated in these experiments. HR data were obtained in 13 pregnant and 9 virgin animals. Baseline HR was significantly higher in pregnant compared with virgin animals (pregnant = 408 ± 8.0 beats/min, virgin = 359 ± 7.5 beats/min). However, no difference was observed in baroreflex HR range between pregnant and virgin groups (pregnant = 46 ± 7.4 beats/min, virgin = 53 ± 10.1 beats/min).

Effects of Pregnancy on Aortic Nerve Discharge Curves

The effect of pregnancy on aortic depressor nerve activity was evaluated in 12 virgin and 12 pregnant rats and the results are summarized in Table 1. Baseline MAP was significantly lower in pregnant compared with virgin rats. A significant decrease in the baroreceptor discharge curve midpoint (A3) was also observed indicating a leftward shift of the curve during pregnancy (Fig. 2). There were, however, no significant differences in any of the other curve coefficients (NA range, slope coefficient, or maximum NA). Similarly, the calculated parameters, minimum NA, and maximum slope were not significantly different between virgin and pregnant animals. Further comparison of the slopes of the baroreceptor response to NTP and PE were performed using linear regression analysis of the linear portion of the NTP and PE ends of the curve, and neither NTP nor PE slopes were found to be different between the two groups.

                              
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  		Table 1.   Effects of pregnancy on baroreceptor discharge function



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  		Fig. 2.   Effect of pregnancy on baroreceptor discharge curves. Mean baroreceptor discharge curves for 12 pregnant and 12 virgin rats are shown. Pregnancy was associated with a significant decrease in baseline MAP (closed circles) and a parallel leftward shift in the baroreceptor discharge curve (arrow). AoNA, aortic nerve activity.

The effect of pregnancy on baseline HR and baroreflex HR range was also evaluated. As expected, pregnancy was associated with a significantly higher baseline HR (pregnant = 431 ± 8.8 beats/min, virgin = 378 ± 7.1 beats/min). Baroreflex HR range, however, was not different between pregnant and virgin groups (pregnant = 59 ± 9.9 beats/min, virgin = 45 ± 7.4 beats/min). Because baroreflex-induced changes in HR were minimal in anesthetized rats, baroreflex HR responses were not evaluated further.

Effects of 3alpha -OH-DHP

The effect of exogenous administration of the primary metabolite of progesterone, 3alpha -OH-DHP, on baroreceptor discharge was evaluated in 12 virgin and 12 pregnant rats and the results are summarized in Tables 2 and 3.

                              
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  		Table 2.   Effect of 3alpha -OH-DHP on baroreceptor afferent nerve discharge in virgin rats


                              
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  		Table 3.   Effect of 3alpha -OH-DHP on baroreceptor afferent nerve discharge in pregnant rats

Intravenous administration of 3alpha -OH-DHP to virgin animals had no effect on baseline MAP or baseline raw NA compared with control. No significant effect on the baroreceptor discharge curve coefficients (A1-A4) was observed after administration of 3alpha -OH-DHP (Table 2, Fig. 3). Likewise, the calculated parameters (minimum NA and maximum slope) were not different from control. Analysis of the NTP and PE slopes showed that there was no effect of 3alpha -OH-DHP on sensitivities at either end of the curve (Table 2). Baseline HR and HR range were also unaffected by the administration of 3alpha -OH-DHP (not shown).


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  		Fig. 3.   Effect of 3alpha -hydroxy-dihydroprogesterone (3alpha -OH-DHP) on baroreceptor discharge curves in virgin rats. Mean baroreceptor discharge curves for 12 virgin rats are shown. Baroreceptor discharge curves in virgin rats at either 15 min (E1) or 30 min (E2) after the administration of 3alpha -OH-DHP were no different from the control curve (C). , Baseline MAP.

The effect of exogenous 3alpha -OH-DHP administration in pregnant animals was also evaluated. As in the virgin group, no effect of 3alpha -OH-DHP on baseline MAP or baseline raw NA was observed. Baroreceptor discharge curve coefficients (A1-A4) after the administration of 3alpha -OH-DHP, were not different from control (Table 3, Fig. 4). Similarly, minimum NA, maximum slope, and NTP and PE slopes were not different (Table 3). Baseline HR and HR range were also unaffected by 3alpha -OH-DHP in pregnant animals (not shown).


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  		Fig. 4.   Effect of 3alpha -OH-DHP on baroreceptor discharge curve in pregnant rats. Mean baroreceptor discharge curves for 12 pregnant rats are shown. Similar to results observed in virgin animals, there was no significant effect on the baroreceptor discharge curve in pregnant rats at either 15 min (E1) or 30 min (E2) after 3alpha -OH-DHP administration. , Baseline MAP.

These results indicate that unlike the baroreflex efferent nerve activity responses observed in previous studies in our laboratory (15, 23) 3alpha -OH-DHP has no effect on afferent discharge curves in either virgin or pregnant animals.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
PERSPECTIVES
REFERENCES

There are a number of cardiovascular adaptations associated with pregnancy including increases in blood volume, cardiac output, and HR and a decrease in arterial pressure (10, 11, 17, 21). Similar to other reports, a decrease in baseline arterial pressure and tachycardia were observed in the pregnant rats in the current study. Among the adaptations to pregnancy are changes in arterial baroreflex function. Previous studies in our laboratory have demonstrated that the lower baseline blood pressure during pregnancy is associated with a decrease in the midpoint of the baroreflex function curve to a lower operating pressure range. In addition, sympathoexcitatory responses to decreases in arterial blood pressure are attenuated, and an increased sympathoinhibition occurs at high blood pressures in pregnant compared with virgin rats (7, 15, 23). The effects of pregnancy on baroreflex control of efferent renal sympathetic nerve activity were verified in Inactin-anesthetized rats in the current study.

The changes in baroreflex function observed during pregnancy may be due, in part, to the presence of elevated levels of the primary metabolite of progesterone 3alpha -OH-DHP the most potent positive modulator of CNS GABAA receptors. In pregnant women, serum progesterone and 3alpha -OH-DHP levels increase significantly throughout gestation, with no major changes at normal delivery (22). In rats, plasma levels of progesterone and the major metabolites of progesterone peak around the day designated as day 16 of pregnancy in our study, and then fall rapidly during the last couple of days of gestation. However, cerebrocortical concentrations of 3alpha -OH-DHP do not peak until the day we designate as day 20 of pregnancy (5). Thus it is likely that CNS 3alpha -OH-DHP levels are elevated in the pregnant rats in this and previous studies from our laboratory (7, 15, 23).

Previous studies evaluating the effect of 3alpha -OH-DHP on baroreflex function have demonstrated that acute intravenous administration of 3alpha -OH-DHP to virgin female rats attenuates efferent baroreflex sympathoexcitatory responses (15, 23). This response mimics an effect of pregnancy on baroreflex function and is consistent with a CNS mechanism of action but could also be due to effects on afferent baroreceptor discharge. Thus the current experiments were designed to evaluate the effects of pregnancy and 3alpha -OH-DHP on the afferent limb of the baroreflex.

The effect of pregnancy on the afferent limb of the baroreflex was evaluated by recording aortic nerve activity responses to changes in pressure. A significant decrease in baseline MAP and a shift in the baroreceptor discharge curve midpoint to the left was observed in pregnant animals. However, the other curve parameters [baroreceptor discharge curve range (A1), slope coefficient (A2), maximum NA (A4), minimum NA] and responsiveness to hypotensive and hypertensive challenges (maximum slope, NTP slope, and PE slope) were not different. Others have demonstrated that exposure to chronic (18, 28) and acute (4, 3) hypotension results in a parallel shift of the baroreceptor discharge curve to lower operating pressures, with no change in sensitivity to increments in pressure. Thus the results from the current experiments are consistent with a pressure-dependent hypotensive resetting of the baroreceptors in pregnant rats. The baroreceptor function curve of pregnant rats exhibited a parallel shift in the direction of the prevailing pressure with no change in slope. Although responses to longer-term changes in arterial pressure differed, Hines (16) found that, similar to the current study, short-term changes in arterial pressure produced by bolus injections of PE and NTP, elicited equivalent changes in aortic depressor nerve activity in virgin and pregnant rats, suggesting no change in baroreceptor gain. The leftward shift of the baroreceptor afferent nerve discharge curve seen in the current experiments likely contributes to the leftward shift of the baroreflex curve that occurs in pregnancy (current Fig. 1, and Refs. 7, 23). However, pressure-dependent downward resetting of baroreceptors is characterized by a parallel leftward shift of the function curve along the pressure axis with no effect on sensitivity to increments in pressure (4, 14, 18). Thus mechanisms other than pressure-dependent baroreceptor resetting must account for the attenuated sympathoexcitatory and the potentiated sympathoinhibitory baroreflex responses seen in pregnant animals.

In contrast to the effects of 3alpha -OH-DHP to attenuate baroreflex sympathoexcitatory responses (15, 23), acute administration of 3alpha -OH-DHP to virgin rats did not have an effect on the baroreceptor afferent nerve discharge curve. HR was also unaffected by 3alpha -OH-DHP. Similarly, the administration of 3alpha -OH-DHP to pregnant rats did not affect either the baroreceptor afferent nerve discharge curve or HR range. The plasma concentrations of circulating 3alpha -OH-DHP achieved in the current experiments (~2 µM, Ref. 23), most likely exceed the maximum plasma concentrations present during pregnancy (~0.13 µM, Ref. 5). Although not specifically measured in brain regions involved in control of cardiovascular function, it has been reported that compared with plasma levels 3alpha -OH-DHP levels may be 10- to 100-fold higher in some brain regions (27). Thus a higher dose of 3alpha -OH-DHP was used in the previous experiments to achieve concentrations that would be immediately available to the CNS via the circulation and would be within a feasible range for physiological CNS concentrations. Because a similar treatment regimen resulted in attenuated baroreflex sympathoexcitation (15, 23) but had no effect on afferent aortic baroreceptor function in the current experiments, it appears that changes in afferent baroreceptor input do not contribute to the attenuated baroreflex sympathoexcitatory responses due to intravenous 3alpha -OH-DHP administration. Therefore, the effect of intravenous 3alpha -OH-DHP on baroreflex function most likely occurs at the level of the CNS.

The effect of 3alpha -OH-DHP to potentiate GABAergic inhibition within the CNS is well known (25, 26). GABA receptors are ubiquitous within the CNS and tonic GABAergic inhibition has been demonstrated in the major brainstem nuclei participating in the baroreflex pathway. GABA likely modulates, but does not initiate, baroreflex-induced changes in sympathetic outflow at the level of the nucleus tractus solitarius and the caudal ventrolateral medulla. In contrast, changes in GABA receptor activation within the RVLM are of primary importance in mediating baroreflex-induced changes in sympathetic efferent nerve activity in response to changes in arterial blood pressure (9). Previous experiments from our laboratory demonstrated that intravenous administration of 3alpha -OH-DHP altered sympathetic nerve activity responses to changes in arterial pressure that would be consistent with potentiated GABAergic inhibition in the RVLM, but not the nucleu tractus solitariuus or caudal ventrolateral medulla (15, 23). Thus additional experiments tested the possibility that 3alpha -OH-DHP potentiated inhibition within the RVLM. Extracellular recordings were made from presumed presympathetic, spinally projecting, baroreflex-sensitive neurons in the rostral ventrolateral medulla. Intravenous administration of 3alpha -OH-DHP decreased the arterial pressure threshold for inhibition of these neurons (20), which is consistent with the potentiated baroreflex sympathoinhibition seen in pregnancy (7, 15, 23). In addition, a preliminary report demonstrated that local microinjection of 3alpha -OH-DHP into the RVLM resulted in attenuated baroreflex sympathoexcitatory responses (13).


    PERSPECTIVES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
PERSPECTIVES
REFERENCES

Previous studies (7, 15, 23) in our laboratory have demonstrated that pregnancy is associated with a decreased MAP, a shift in the baroreflex function curve to a lower operating pressure range, potentiated baroreflex sympathoinhibition, and attenuated baroreflex sympathoexcitation. Acute intravenous administration of 3alpha -OH-DHP, the primary metabolite of progesterone and the most potent endogenous positive modulator of CNS GABAA receptor function (25, 26), attenuates efferent baroreflex sympathoexcitatory responses similar to the effect of pregnancy. These results are consistent with increased GABAergic influence in CNS sites controlling sympathetic outflow in pregnant animals. Recent studies evaluating the effect of 3alpha -OH-DHP on the rostral ventrolateral medulla, have demonstrated changes in neuronal discharge (20) and baroreflex function (13) consistent with effects observed during pregnancy (7, 15, 23). The current experiments were designed to evaluate the effects of pregnancy and 3alpha -OH-DHP on the afferent limb of the baroreflex. In this study, a significant parallel leftward shift of the baroreceptor discharge curve to a lower operating pressure in pregnant animals was observed, which is consistent with a pressure-dependent resetting. This downward resetting of the baroreceptor function curve likely contributes to the shift of the baroreflex curve to a lower operating pressure range in pregnant animals. The administration of 3alpha -OH-DHP, however, did not have an effect on the afferent nerve discharge in either virgin or pregnant animals. These results indicate that the previously observed effects of 3alpha -OH-DHP on the baroreflex are most likely due to a central mechanism of action and may contribute to the attenuated sympathoexcitation seen in pregnant compared with virgin animals.


    ACKNOWLEDGEMENTS

The authors thank Sarbani Ghosh, Jessica Lee, Tomohiro Nakayama, and Hitomi Nakayama for expert technical assistance and advice in performing these experiments.


    FOOTNOTES

This study was supported by National Heart, Lung, and Blood Institute Grant R01-HL-36245 (to C. M. Heesch).

Address for reprint requests and other correspondence: C. M. Heesch, Univ. of Missouri, Dalton Cardiovascular Research Center, Research Park, Columbia, MO 65211-3300 (E-mail: heeschc{at}missouri.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.

Received 13 April 2000; accepted in final form 1 August 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
PERSPECTIVES
REFERENCES

1.   Brooks, V, Quesnell R, Cumbee S, and Bishop V. Pregnancy attenuates activity of the baroreceptor reflex. Clin Exp Pharmacol Physiol 22: 152-156, 1995[ISI][Medline].

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Am J Physiol Heart Circ Physiol 281(6):H2456-H2462
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