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Am J Physiol Regul Integr Comp Physiol 283: R429-R440, 2002. First published March 22, 2002; doi:10.1152/ajpregu.00014.2002
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Vol. 283, Issue 2, R429-R440, August 2002

Pregnancy and acute baroreflex resetting in conscious rabbits

Virginia L. Brooks1, Kathy A. Clow1, and Kathleen P. O'Hagan2

1 Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97201; and 2 Department of Physiology, Midwestern University, Downers Grove, Illinois 60515


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

To test the hypothesis that acute resetting of baroreflex control of heart rate (HR) is enhanced during pregnancy, we determined whether the rightward shift in the baroreflex relationship between arterial pressure and HR after arterial pressure is raised [~25 mmHg for 30 min, due to infusion of phenylephrine (PE) or methoxamine (Meth)] is greater in late pregnant compared with nonpregnant conscious rabbits. Baroreflex function was assessed by monitoring HR responses to both stepwise steady-state changes (n = 14) and rapid ramp changes (n = 10) in arterial pressure. Pregnancy decreased reflex gain, increased reflex minimum HR, and shifted the curves to a lower pressure level, when either the steady-state or ramp method was used (all changes, P < 0.05). When PE was used to increase pressure, resetting of steady-state curves was observed both before and during pregnancy, but the magnitude of the resetting was less in the pregnant rabbits. Further inspection of the data revealed that the size of the shift in pregnant rabbits was inversely related to the dose of PE. Because the pressure rise was the same in all experiments, PE appears to nonspecifically counteract acute resetting. When Meth was used instead to increase pressure, resetting of steady-state curves was similar in pregnant and nonpregnant rabbits and was unrelated to dose. Similarly, when reflex curves were generated using the ramp method, and either Meth or low doses of PE were used to increase pressure, no differences in the degree of resetting were observed between pregnant and nonpregnant rabbits. In summary, high doses of PE counteract acute resetting of baroreflex control of HR. More importantly, while baroreflex function is depressed, the ability of the baroreflex to reset appears to be preserved during pregnancy.

heart rate; arterial pressure; phenylephrine; methoxamine


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE CARDIOVASCULAR SYSTEM undergoes remarkable changes in structure and function during pregnancy, presumably, at least in part, to meet the demands of the developing fetus (24, 27). However, one change is not beneficial to the mother, that is, function of the baroreceptor reflex becomes impaired (for reviews, see Refs. 6, 17). Specifically, numerous studies have documented that baroreflex gain is diminished, such that increases in heart rate (HR) and sympathetic activity in response to hypotension are attenuated in pregnant mammals. In addition, pregnant women exhibit blunted increases in HR and norepinephrine levels during orthostatic stress (3, 15, 29). It is likely that this impairment in baroreflex function contributes to the lesser ability of pregnant animals to maintain arterial pressure during hemorrhage (6). In addition, in pregnant rabbits (5, 32) and sheep (25), reflex bradycardia in response to acute hypertension is also reduced.

Thus both reflex increases and decreases in HR can be attenuated during pregnancy; however, the mechanism for this change is unclear. One potential explanation involves the phenomenon of baroreflex resetting. Resetting occurs when sustained changes in arterial pressure lead to a shift in the sigmoidal relationship between arterial pressure and sympathetic activity or HR in the direction of the pressure change (for reviews, see Refs. 2, 9, 22). The process of baroreflex resetting is generally considered to exhibit two loosely defined time frames. Acute resetting occurs within seconds to minutes, and it results in a shift in the curve of about 30-40% of the pressure change. In contrast, chronic resetting, which takes days to weeks, results in a relatively complete shift of the curve. In either case, with time the reflex shifts or resets to defend the new arterial pressure level.

During pregnancy, arterial pressure falls and reflex curves are shifted to the lower arterial pressure level due to chronic resetting. This phenomenon does not, however, contribute to reduced reflex gain or to the lesser ability of pregnant animals to defend acute arterial pressure challenges, but instead allows pregnant animals to better defend the new lower pressure level. In contrast, if during pregnancy acute resetting is enhanced, such that the baroreflex adapts or resets more rapidly or extensively to an acute but sustained change in pressure as during orthostasis or hemorrhage, then the signal from the baroreceptors would quickly wane, and reflex responses would be attenuated. The net result would be a decrease in reflex responses for any given change in arterial pressure, which would be manifested by a decrease in the slope of the linear portion of sigmoidal reflex curves or a decrease in reflex gain.

Hines (18) recently presented data to support this explanation and reported that the aortic baroreceptor afferents of pregnant anesthetized rats adapt to sustained hypotensive and hypertensive pressure stimuli, whereas the afferents of virgin animals do not. However, whether the reflex relationship between aortic depressor nerve activity and arterial pressure was reset differently at each pressure step was not evaluated. Moreover, because the experiments of Hines (18) were necessarily performed in intact anesthetized animals after acute surgical preparation and because anesthesia markedly attenuates baroreflex function (33, 39), it is not known whether adaptation or resetting of the efferent segment of the baroreceptor reflex is also altered during pregnancy. Therefore, the purpose of this study was to test the hypothesis that acute resetting of baroreflex control of HR is enhanced when conscious, unstressed rabbits are pregnant. To test this hypothesis, we determined whether the rightward shift in the baroreflex relationship between arterial pressure and HR after a 30-min increase in arterial pressure is greater when rabbits are studied in late pregnancy compared with the nonpregnant state.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Experiments were performed using 16 female New Zealand White rabbits, weighing 3.8 ± 0.1 kg in the nonpregnant state and 4.6 ± 0.1 kg (P < 0.0001) at the end of gestation. All studies were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the institutional animal care and use committee at Oregon Health and Science University.

Surgery

Surgery was performed to implant nonocclusive catheters in the abdominal aorta and vena cava as described previously (16). Briefly, the animals were initially anesthetized (1 ml/kg im) with a cocktail containing 5:2.5:1 of ketamine (100 mg/ml), xylazine (20 mg/ml), and acepromazine (10 mg/ml). A surgical plane of anesthesia was maintained with 1:10 ketamine/0.9% NaCl solution administered intravenously as needed. A midline abdominal incision was made, and indwelling polyethylene catheters with Silastic tips were implanted in the abdominal aorta (one) and vena cava (two). The catheters were tunneled from the abdominal cavity subcutaneously and were exteriorized at the nape of the neck. The rabbits were given penicillin G procaine (60,000 U im) just before and the day after surgery. Buprenex (0.09-0.15 mg im) was administered for analgesia 2-3 h after surgery and usually again the next day. Immediately after surgery and then three times weekly, catheters were flushed using sterile 0.9% NaCl and filled with heparin (1,000 U/ml) to maintain patency.

Animals were allowed at least 2 wk to recover from surgery. Usually beginning before surgery, and continuing into the recovery period, the diet of the rabbits was slowly changed from the normal high-fiber diet (Ralston Purina, 5326) to a high-protein diet (Ralston Purina, 5321), increasing 10% high protein/day for 10 days. The female rabbits were then maintained on 150 g/day of the high-protein diet (0.25% sodium and 16.2% protein) to enhance breeding efficiency. All animals were allowed free access to distilled water. During recovery, the rabbits were also trained to rest quietly in a specially designed opaque Plexiglas box that was used to restrain the rabbits during experiments. Room temperature was kept between 64 and 68°F, and a 16-h light cycle was maintained for optimum breeding.

Experimental Protocols

A key feature of this study is that each rabbit was studied in both the nonpregnant state and again after 28-30 days gestation (term is 31 days), so that potentially subtle effects of gestation could be detected. Many rabbits were used for more than one protocol; eight rabbits were used for one protocol, three for two protocols, and five for three protocols. In all but one rabbit, multiple experiments were first performed in virgin rabbits before pregnancy. The rabbits were then bred with proven male breeder rabbits, and this was considered day 1 of pregnancy. At most two experiments were performed at the end of the first pregnancy; then, usually the day after delivery, the rabbits were bred again, so that additional experiments could be performed at the end of the second pregnancy. For one protocol in one rabbit, the first experiment was performed during gestation, and the control experiment in the nonpregnant state was performed ~1 mo after delivery.

On the experimental day, the rabbits were placed in the Plexiglas box and allowed 30-45 min to settle. Arterial pressure and HR were measured continuously via the aortic catheter using a Statham pressure transducer, a Grass tachometer and a Grass polygraph.

Steady-state baroreflex curves. To determine the steady-state baroreflex relationship between arterial pressure and HR, arterial pressure was first lowered by intravenous infusion of increasing doses of nitroprusside (3, 6, 12, 24, 48 µg · kg-1 · min-1, nonpregnant; 1.5, 3, 6, 12, 24, 48 µg · kg-1 · min-1, pregnant; in 5% dextrose in water vehicle). Doses were increased by doubling the infusion rate, beginning with a flow rate of 0.04 ml/min. After a ~20-30 min rest period, arterial pressure was then raised by intravenous infusion of increasing doses of phenylephrine (0.5, 1, 2, 4, 8 µg · kg-1 · min-1; in 5% dextrose in water vehicle). Again, the doses were increased by increasing the flow rate, beginning with a flow rate of 0.04 ml/min. Most rabbits also received a higher dose of phenylephrine (~10.5 µg · kg-1 · min-1) and/or nitroprusside (~54 µg · kg-1 · min-1), to more accurately estimate maximum and minimum HRs. Each dose was infused until blood pressure and HR stabilized, ~2-8 min; usually about 5-10 ml of fluid were infused for each nitroprusside or phenylephrine segment of the reflex curve.

Ramp baroreflex curves. Because the determination of steady-state baroreflex curves takes several minutes, during which acute resetting can occur (2), baroreflex relationships were also defined using a ramp method of raising and lowering arterial pressure. Arterial pressure was lowered by initiating a nitroprusside infusion (3.2 µg · kg-1 · min-1, nonpregnant; 1.6 µg · kg-1 · min-1, pregnant) and doubling the dose every 15 s until a dose of 50.5 µg · kg-1 · min-1 was reached. Then the dose of nitroprusside was increased in 16 µg · kg-1 · min-1 increments until HR reached maximum values. This process took 140 ± 10 s (range 44-290 s). Arterial pressure was raised by infusing increasing doses of phenylephrine (0.5, 1, 2, 4, 8 µg · kg-1 · min-1), again increasing the dose every 15 s (therefore total time for curve generation is 95 s). Usually more than one nitroprusside and phenylephrine infusion was performed, and approximately 10-15 min were allowed between determinations to ensure that variables had returned to basal levels.

Protocol 1: baroreflex resetting of steady-state curves after phenylephrine infusion. The purpose of this experiment was to test the hypothesis that baroreflex resetting is greater during pregnancy. To test this hypothesis, control steady-state reflex curves were generated, and then infusion of phenylephrine was begun to raise pressure by ~25 mmHg. All nonpregnant rabbits (n = 8) received a dose of 4 µg · kg-1 · min-1 (infused at 0.04 ml/min). In pregnant rabbits, the dose of phenylephrine was adjusted by altering the infusion rate, so that the same increase in pressure was produced as in the nonpregnant state. Because pregnant animals become resistant to pressor agents, usually a higher dose of phenylephrine was required (5.4 ± 0.8 µg · kg-1 · min-1; range 3.4-9.9 µg · kg-1 · min-1). In three nonpregnant rabbits, an additional experiment using a higher dose of phenylephrine (8 µg · kg-1 · min-1) was also performed. In all experiments, baroreflex curve generation commenced ~30 min after beginning the phenylephrine infusion. While minor adjustments in the phenylephrine dose were sometimes made, arterial pressure and HR were stable at least 15 min before initiating reflex reassessment. During the construction of this second set of reflex curves, the phenylephrine infusion was continued (and therefore the hypertension was maintained).

Protocol 2: baroreflex resetting of steady-state curves after methoxamine infusion. This protocol is identical to protocol 1, except that methoxamine was used to produce sustained hypertension rather than phenylephrine. In this protocol (n = 7), after control steady-state reflex curves were produced, an infusion of methoxamine at 7.5 µg · kg-1 · min-1 was begun (infusion rate 0.04 ml/min), but then the dose was adjusted by altering the infusion rate so that the pressure rise was close to 25 mmHg above basal. In nonpregnant rabbits, the dose averaged 8.5 ± 0.7 µg · kg-1 · min-1; during pregnancy, the dose averaged 9.1 ± 0.7 µg · kg-1 · min-1. There was no difference in these doses or pressor responses (P > 0.2; n = 7). Three rabbits also received lower doses of methoxamine, which raised pressure by ~15 mmHg (nonpregnant, 6.8 ± 1.4 µg · kg-1 · min-1; pregnant, 7.2 ± 1.4 µg · kg-1 · min-1).

Protocol 3: baroreflex resetting of ramp curves after phenylephrine infusion. The purpose of this protocol was to determine if the magnitude of acute resetting after a sustained pressure rise is greater in pregnant rabbits in which baroreflex curves are rapidly generated, before significant acute resetting can take place. After obtaining control curves using the ramp method, an infusion of phenylephrine was begun to raise pressure by ~25 mmHg, and the curves were then regenerated beginning ~30 min later (n = 5). Before pregnancy, four rabbits received a phenylephrine dose of 4 µg · kg-1 · min-1 (0.04 ml/min), and the fifth received 5.9 µg · kg-1 · min-1. At the end of gestation, the same four rabbits received 4 µg · kg-1 · min-1, and the fifth received 6.7 µg · kg-1 · min-1. Therefore, as in protocol 1, some adjustments were made in the phenylephrine dose, but arterial pressure was stable at least 15 min before reflex responses were reassessed. In addition, the phenylephrine infusion and the hypertension were maintained during the generation of the second set of reflex curves.

Protocol 4: baroreflex resetting of ramp curves after methoxamine infusion. This protocol was identical to protocol 3, except that methoxamine was used to produce sustained hypertension. After obtaining control curves using the ramp method, methoxamine was infused and after 30 min the curves regenerated (n = 6). Before pregnancy, rabbits received doses of 10.3 ± 0.8 µg · kg-1 · min-1, and during pregnancy, rabbits received similar (P > 0.2) doses of methoxamine (10.1 ± 0.7 µg · kg-1 · min-1).

Data Analysis

For the steady-state curves, ~1-min averages of arterial pressure and HR were determined at the end of each dose of nitroprusside and phenylephrine. For the ramp curves, the data were collected at 200 Hz and processed using a Biopac (Santa Barbara, CA) MP100 data acquisition and analysis system. Raw data were grouped into 2-s bins from which mean values were obtained. For experiments in which more than one ramp curve was produced, the curves selected were free from movement artifact, exhibited similar basal arterial pressure levels between pressor and depressor segments, and/or exhibited the best sigmoidal fit. If basal arterial pressure before the pressor (phenylephrine) part of the reflex curve was different from the depressor (nitroprusside) part (but HRs were the same), then half of the pressure difference was added to all pressure values in the segment with the lower basal pressure and half the difference was subtracted from the pressures in the segment with the higher pressure, so that the two segments were aligned, as previously described (14).

The sigmoidal baroreflex relationships between arterial pressure and HR thus generated in each experiment were fitted and compared using the Boltzmann equation HR = (A1 - A2)/1 + exp[(MAP - x0)/dx], where MAP is mean arterial pressure, A1 is maximum HR, A2 is minimum HR, dx is width (a parameter used to calculate maximum reflex gain), and x0 is the MAP associated with the HR value midway between the maximal and minimal HRs (BP50; denotes the position of the curve on the x-axis)(21). Maximum gain was calculated as -x0 × (1/dx) × 1/4, and HR range as A1 - A2.

During the fitting procedure for some experiments, the maximum or minimum HR values were constrained to the value determined during the experiment (e.g., same HR at different pressures). In addition, as illustrated in representative curves from experiments using ramp changes in pressure (Fig. 1), when arterial pressure reached high levels, HR often exhibited a sharp decrease, as described previously (37). This second phase of bradycardia was eliminated from the sigmoidal fitting of the ramp data, by utilizing the HR and pressure values from only the initial 20-mmHg increase in pressure. Similarly, in experiments utilizing the steady-state technique, a sharp decrease in HR was occasionally observed when arterial pressure exceeded 100 mmHg, and these values were also eliminated from curve fitting.


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  		Fig. 1.   Representative baroreflex curves generated using the ramp method. Curves were produced in 1 rabbit in both the nonpregnant (A) and pregnant (B) state, before and after a 30-min infusion of methoxamine. bpm, Beats/min.

Baroreflex resetting was assessed in two ways. In the first, BP50 values from reflex curves generated before and after phenylephrine or methoxamine infusion were compared. Because the hypertensive stimulus often led to a decrease in reflex gain, which could influence the midpoint of the curve (BP50) independently of reflex resetting, the position of the sigmoidal curves along the x-axis was also determined using a different approach. In this second method, the BP values associated with the basal HR (before pressor infusions; BPHR) were interpolated off the fitted curves before and after phenylephrine or methoxamine infusion and compared. By definition, the BPHR for the control curve was very close to the actual blood pressure value. After the sustained pressure stimulus, however, the BPHR value was less than the actual pressure because HR was markedly depressed by the hypertension.

Curve fitting parameters were compared between groups using ANOVA for repeated measures and the post hoc Newman-Keuls test or the paired t-test (38). For the steady-state curves, the mean ± SE arterial pressure and HR values were plotted for each dose of nitroprusside or phenylephrine. For graphical purposes in the figures, sigmoidal curves were drawn through these points by constraining the parameters to the average values obtained from all experiments. For the ramp experiments, the sigmoidal curves derived from the averaged parameters are shown along with control points.

Differences between the pregnant and nonpregnant state in basal values and in logistical parameters were assessed using the paired t-test (38). The relationship between the dose of methoxamine infused to produce sustained hypertension and the reflex shifts was assessed using linear regression analysis, and differences in the dose responses between groups were assessed using analysis of covariance (ANCOVA) (38).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Effect of Pregnancy on Baroreflex Control of HR

Steady-state curves (n = 14). At rest, arterial pressure was lower (65.0 ± 0.8 mmHg, nonpregnant; 57.9 ± 1.3 mmHg, pregnant; P < 0.001) and HR was higher (158 ± 4 beats/min, nonpregnant; 184 ± 4 beats/min, pregnant; P < 0.05) when the rabbits were pregnant. Pregnancy also produced three major changes in baroreflex control of HR (Fig. 2, Table 1): minimum reflex HR was higher, maximum reflex gain was lower, and the curve was shifted to the lower basal arterial pressure level (BP50 was lower). In addition, the width, which is inversely related to the slope of the linear part of the curve, was increased.


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  		Fig. 2.   Effect of pregnancy on baroreflex control of heart rate (HR), assessed using the steady-state (A; n = 14) and the ramp (B; n = 10) methods. Basal values ± SE of arterial pressure and HR are indicated by shaded triangles (A) or by circles (B).


                              
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  		Table 1.   Effect of pregnancy on baroreflex control of heart rate

Ramp curves (n = 10). In this group of animals, again, pregnancy was associated with lower arterial pressure levels (66.7 ± 1.5 mmHg, nonpregnant; 57.2 ± 1.7 mmHg, pregnant; P < 0.001) and higher HRs (168 ± 2 beats/min, nonpregnant; 190 ± 7 beats/min, pregnant; P < 0.05). Pregnancy-induced changes in the reflex were similar to that observed using the steady-state method (Fig. 2, Table 1): minimum HR was elevated, gain was reduced, and the curve was shifted to the lower arterial pressure level.

Baroreflex Resetting After Phenylephrine Infusion: Steady-State Curves (Protocol 1)

When the rabbits were studied before pregnancy, the 30-min phenylephrine infusion increased arterial pressure by 25 ± 1 mmHg (range 22-30 mmHg) to 91 ± 1 mmHg and decreased HR to 104 ± 6 beats/min (P < 0.05). In addition, the reflex curve was shifted to a higher arterial pressure level (Fig. 3), as indicated by increases in the BP50 and BPHR (Table 2). During pregnancy, 30 min of phenylephrine infusion increased arterial pressure by 24 ± 1 mmHg (range 20-29 mmHg) to 83 ± 2 mmHg and decreased HR to 144 ± 5 beats/min (P < 0.05). The curve was again shifted to a higher pressure level (Fig. 3 and Table 2); however, if anything, the increment in the BP50, or the resetting shift, was less during pregnancy (6.0 ± 1.6 mmHg) compared with before pregnancy (9.1 ± 0.7 mmHg; P = 0.08). Similarly, the rightward shift in the BPHR was significantly less when the rabbits were pregnant (4.8 ± 1.7 mmHg) compared with the nonpregnant state (9.6 ± 0.8 mmHg; P < 0.05). In addition, in the pregnant rabbits, both the maximum and minimum HR were reduced after phenylephrine infusion (Table 2).


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  		Fig. 3.   Baroreflex resetting after a 30-min infusion of phenylephrine in conscious rabbits (n = 8) before pregnancy (A) and at the end of gestation (B). Baroreflex curves were generated using the steady-state method (see METHODS for details). Three rabbits were studied in their 1st pregnancy; five rabbits were studied in their 2nd pregnancy. Differences in the resetting observed in these 2 groups are illustrated in Fig. 4. Shaded triangles indicate means ± SE of basal values of arterial pressure and HR.


                              
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  		Table 2.   Baroreflex resetting after phenylephrine infusion

What is not evident from these averaged data is that the degree of resetting observed in the pregnant rabbits was quite variable, ranging from a rightward shift of the BP50 of 10.9 mmHg to a small leftward shift of 1.2 mmHg (range of shift in BPHR was 12.0 to -1.9 mmHg). Further inspection of the data revealed that those rabbits studied during their second pregnancy exhibited smaller shifts in the BP50 (10.2 ± 0.4 mmHg, first pregnancy; 3.9 ± 1.2 mmHg, second pregnancy; P < 0.01) and also that these animals required higher doses of phenylephrine to sufficiently elevate arterial pressure. Figure 4 illustrates the negative correlation between the dose of phenylephrine infused during pregnancy and the difference in the BP50 shifts between the pregnant and nonpregnant rabbits. Positive numbers indicate that the shift was greater during pregnancy, while negative numbers indicate that the shift was less during pregnancy. Because the increase in pressure in all experiments was the same, this result suggests that phenylephrine counteracts acute resetting by an action other than by increasing pressure. Before pregnancy, all rabbits received the same dose of phenylephrine. Therefore, to determine if larger doses of phenylephrine counteract resetting in nonpregnant animals as well, three rabbits received 8 µg · kg-1 · min-1, instead of the usual 4 µg · kg-1 · min-1. The higher dose increased arterial pressure by 49 ± 4 mmHg and shifted the curve by 3.3 ± 1.8 mmHg (increase in the BP50). This shift (7.3 ± 4.2% of the pressure rise) was significantly smaller (P = 0.001) than the shifts observed using the lower dose of phenylephrine (36.3 ± 3.6% of the pressure rise). These data suggest that phenylephrine dose dependently, via a mechanism unrelated to the pressure increase, counteracts resetting in both pregnant and nonpregnant rabbits.


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  		Fig. 4.   Relationship between dose of phenylephrine infused during pregnancy and the difference in shifts of the sigmoidal position parameter, BP50, obtained before and at the end of gestation in each rabbit. The BP50 shift is the difference in the BP50 values of baroreflex curves generated before and after a 30-min infusion of phenylephrine. All rabbits received the same dose of phenylephrine (4 µg · kg-1 · min-1) in the nonpregnant state. , Results from rabbits studied during their 1st pregnancy; open circle , rabbits studied during the 2nd pregnancy.

Baroreflex Resetting After Methoxamine Infusion: Steady-State Curves (Protocol 2)

Because the results of protocol 1 suggested that phenylephrine may nonspecifically counteract acute resetting, another set of experiments was performed using methoxamine instead to increase arterial pressure. Before pregnancy, methoxamine increased arterial pressure from 63.9 ± 1.2 to 87.9 ± 1.1 mmHg (pressure increase, 24 ± 1 mmHg; range, 22-26 mmHg) and decreased HR from 165 ± 3 to 136 ± 5 beats/min (P < 0.01). The baroreflex curve was shifted to a higher pressure (Fig. 5) as indicated by the increase in BP50 and BPHR (Table 3). When the rabbits were pregnant, methoxamine infusion increased arterial pressure from 59.1 ± 1.5 to 84.9 ± 1.8 mmHg (pressure increase, 26 ± 1 mmHg; range, 21-29 mmHg), decreased HR from 180 ± 6 to 155 ± 10 beats/min (P < 0.01), and again shifted the curve to a higher pressure (Fig. 5, Table 3). However, there was no difference (P > 0.2) in the shifts between groups; the BP50 shift was 11.0 ± 1.1 mmHg (or 46.3 ± 5.1% of the pressure rise) before pregnancy and 9.7 ± 2.0 mmHg (or 38.6 ± 8.4% of the pressure rise) during pregnancy. Similarly, the shifts in the BPHR were not different (P > 0.2) between pregnant (10.8 ± 1.9 mmHg) and nonpregnant (13.8 ± 1.4 mmHg) rabbits.


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  		Fig. 5.   Baroreflex resetting after a 30-min infusion of methoxamine in conscious rabbits (n = 7) before pregnancy (A) and at end of gestation (B). Baroreflex curves were generated using the steady-state method (see METHODS for details). Two rabbits were studied during their 1st pregnancy and five during their 2nd pregnancy; there was no difference in the resetting shift between these 2 groups. Shaded triangles indicate means ± SE of basal values of arterial pressure and HR.


                              
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  		Table 3.   Baroreflex resetting after methoxamine infusion

A previous study indicated that a severalfold higher dose of methoxamine can prevent or counteract acute resetting of renal sympathetic nerve activity in rabbits (13). Therefore, we did a another set of experiments, using a lower dose, to determine if a nonspecific effect of methoxamine could be masking an effect of pregnancy to enhance resetting. The rationale was that if methoxamine dose dependently counteracts acute resetting, as does phenylephrine, then resetting should be greater in animals given a lower dose. At this dose, methoxamine infusion increased arterial pressure by 16 ± 1 mmHg to 79.7 ± 0.7 mmHg before pregnancy and by 16 ± 1 mmHg to 71.0 ± 3.5 mmHg at the end of gestation. As summarized in Table 3, while resetting was again observed in rabbits given the lower dose of methoxamine, there was no difference between pregnant and nonpregnant rabbits as indicated by similar increases in the BP50 and BPHR. The results of all the methoxamine experiments were then combined to determine if there was a significant relationship between the dose of methoxamine infused vs. the resulting increase in BP50, or reflex shift, as a percentage of the pressure rise. In neither pregnant nor nonpregnant rabbits was there a relationship between the dose of methoxamine (dose range 5.2-11.8 µg · kg-1 · min-1) and the magnitude of the shift (P > 0.10). More importantly, again greater resetting was not evident during pregnancy (ANCOVA, P > 0.2). Thus these data suggest that acute reflex resetting is unaltered by pregnancy.

Baroreflex Resetting After Phenylephrine Infusion: Ramp Curves (Protocol 3)

Acute baroreflex resetting can occur very rapidly, within seconds to minutes (2, 9). Therefore, the possibility was considered that resetting is greater during pregnancy but that this action is reversed during construction of steady-state reflex curves, which takes several minutes to be completed. To test this possibility, curves were generated rapidly using the ramp method, before and after infusion of phenylephrine. It is important to emphasize that generally low doses of phenylephrine were used to produce sustained hypertension in this experiment. Before pregnancy, blood pressure increased by 22 ± 1 mmHg (range 20-25 mmHg) to 89.0 ± 2.0 mmHg, and during pregnancy blood pressure increased by 24 ± 1 mmHg (range 20-26 mmHg) to 81.0 ± 2.2 mmHg. As summarized in Fig. 6 and Table 2, resetting (increases in BP50 and BPHR) was observed in both reproductive states. However, the size of the BP50 shift was not different (P > 0.2) between nonpregnant (15.3 ± 0.8 mmHg) and pregnant (14.0 ± 3.1 mmHg) rabbits. Similarly, the BPHR shifts were also not different between groups (14.2 ± 1.2 mmHg, nonpregnant; 9.7 ± 3.1 mmHg, pregnant; P > 0.10). These data again indicate that acute baroreflex resetting is unaltered by pregnancy.


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  		Fig. 6.   Baroreflex resetting after a 30-min infusion of phenylephrine in conscious rabbits (n = 5) before pregnancy (A) and at end of gestation (B). Baroreflex curves were generated using the ramp method (see METHODS for details). Two rabbits were studied during their 1st pregnancy and three during their 2nd pregnancy; there was no difference in the resetting shift between these 2 groups. Circles indicate means ± SE of basal values of arterial pressure and HR.

Baroreflex Resetting After Methoxamine Infusion: Ramp Curves (Protocol 4)

Because the results of protocol 2 suggested that methoxamine at the doses used in the present study does not counteract acute resetting, protocol 3 was repeated using methoxamine to confirm that the failure to observe enhanced resetting during pregnancy in protocol 3 is not because phenylephrine is counteracting resetting. Methoxamine infusion increased arterial pressure by 24 ± 1 mmHg (range 21-28 mmHg) to 90.0 ± 2.1 mmHg (nonpregnant) and by 24 ± 1 mmHg (range 21-29 mmHg) to 81.0 ± 3.0 mmHg (pregnant). Again, resetting was documented in both groups (Fig. 7, Table 3). However, the magnitudes of the shifts were not different: the BP50 shift was 8.9 ± 1.0 mmHg (37.6 ± 5.5% of pressure rise) before pregnancy and 7.8 ± 2.8 mmHg (32.1 ± 12.5% of pressure rise) at the end of gestation (P > 0.2). The BPHR shift was 12.5 ± 2.3 mmHg (nonpregnant) and 14.1 ± 2.5 mmHg (pregnant; P > 0.2). Moreover, these shifts were not different from the shifts observed using the steady-state method of baroreflex curve construction.


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  		Fig. 7.   Baroreflex resetting after a 30-min infusion of methoxamine in conscious rabbits (n = 6) before pregnancy (A) and at end of gestation (B). Baroreflex curves were generated using the ramp method (see METHODS for details). All rabbits were studied during their 1st pregnancy. Circles indicate means ± SE of basal values of arterial pressure and HR.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The present study confirms (5, 32) that baroreflex control of HR, assessed using the steady-state method, is modified by pregnancy in conscious rabbits. In particular, maximum baroreflex gain is reduced, minimum reflex HR is elevated, and the curve is shifted to the lower basal arterial pressure level observed during pregnancy. The results further show that a similar pregnancy-induced change in reflex function is observed when the ramp method of reflex curve generation is used. Other major new findings are that 1) acute resetting of baroreflex control of HR is observed after a 30-min hypertensive stimulus in both pregnant and nonpregnant conscious rabbits; 2) the magnitude of the resetting is similar in both groups and this similarity was noted when baroreflex function was assessed using either steady-state or ramp changes in arterial pressure; 3) phenylephrine dose dependently counteracts resetting of baroreflex control of HR in both pregnant and nonpregnant rabbits; and 4) methoxamine, at doses used in the present study, does not appear to counteract reflex resetting. Therefore, while these data indicate that baroreflex function is depressed in late pregnancy, acute resetting of baroreflex control of HR is unaltered by pregnancy in conscious rabbits. Thus it is likely that the change in the baroreflex induced by pregnancy is not mediated by a change in acute resetting of the baroreflex.

One method used to study resetting in the present study was to determine the shift in the baroreflex curve after an infusion of phenylephrine to raise arterial pressure for 30 min. Previously published time control experiments indicate that two steady-state reflex curves generated 30 min apart can be superimposed in both pregnant and nonpregnant rabbits (7). Therefore, the curve shifts produced after sustained hypertension in the present study are not secondary to time or order of curve generation and therefore indicate acute reflex resetting. However, the magnitude of the shift in the baroreflex curve was not different between pregnant and nonpregnant rabbits. Interestingly, in some pregnant rabbits the shift was minimal, and further inspection of the data revealed that in this group the degree of resetting was inversely related to the dose of phenylephrine infused. Infusion of a higher dose of phenylephrine in nonpregnant rabbits also produced less resetting, when the shift was expressed as a function of the pressure rise. In addition, minimum and maximum HR were also suppressed after phenylephrine infusion in the pregnant animals. Thus it appears that phenylephrine dose dependently counteracts resetting of baroreflex control of HR by lowering HR at any given arterial pressure level.

Phenylephrine and norepinephrine have been previously shown to inhibit renal nerve activity in rabbits via a pressure-independent mechanism (1, 20, 35), but to our knowledge, this is the first study demonstrating a similar effect of phenylephrine on HR. As in previous studies of the renal nerve (20, 35), the effect of phenylephrine in the present study to counteract resetting was dose dependent. In addition, the effect was independent of the increase in arterial pressure, because in the pregnant animals, phenylephrine produced a dose-dependent inhibition of resetting despite the fact that the same level of hypertension was produced in each experiment. That this action is independent of the hypertension is consistent with previous studies showing that the inhibition of renal nerve activity does not correlate with activity of baroreceptor afferents (20) and that it can be produced even if hypertension is prevented by controlled hemorrhage (1). Previous studies have also shown that the inhibitory action of phenylephrine on renal nerve activity is not only dose- but also time dependent (20, 35). In addition, although the action is independent of the magnitude of the pressure rise, it requires baroreceptor input because the inhibition is abolished after baroreceptor denervation (20, 35). Although the site of action of phenylephrine to produce these effects is not specifically known, previous studies suggest that the drug may be acting either centrally (20) or at peripheral C-fibers (1). Nevertheless, whatever the mechanism, these data suggest that the use of phenylephrine for construction of the pressor portion of baroreflex function curves should be restricted to low doses (e.g., below ~4 µg · kg-1 · min-1), at least in rabbits.

Because phenylephrine was found to counteract resetting, a second series of experiments was performed using methoxamine to increase pressure for 30 min. The fact that the degree of resetting (as a function of the pressure rise) did not vary inversely with the dose of methoxamine suggests that methoxamine does not counteract resetting, at least at the doses used in the present study. Dorward et al. (13) previously reported that methoxamine infusion does inhibit resetting of baroreflex control of renal sympathetic nerve activity, to a small degree by activation of cardiac afferents but also by an unknown mechanism. However, much higher doses of methoxamine (100-400 µg · kg-1 · min-1) were used in that study (13). Thus it appears that methoxamine is also capable of nonspecifically reducing sympathetic outflow in rabbits, but the doses required are much higher than the doses at which phenylephrine is effective.

A second finding from the experiments utilizing methoxamine (protocol 2) was that resetting of baroreflex control of HR was similar in pregnant and nonpregnant rabbits. Again, the failure to detect a greater shift does not appear to be due to an action of methoxamine to counteract resetting, in particular in pregnant animals. Nevertheless, we next considered the possibility that resetting actually was enhanced in the pregnant animals but that the enhancement was obscured by another mechanism. More specifically, because the steady-state method of baroreflex curve construction requires that pressure be held for 2-8 min at each pressure level to reach stable values, it seemed possible that any enhanced resetting could be reversed as pressure was slowly lowered during the generation of the hypotensive part of the curve with nitroprusside infusion. If resetting was greater during pregnancy, the curve would reset back toward control curves more in the pregnant rabbits, thereby diminishing the difference in the magnitude of the resetting. To test this possibility, protocols 1 and 2 were repeated, but instead reflex curves were generated very quickly, in about 1-2 min for each pressure limb. This method of generating reflex curves is short enough to minimize acute resetting (8, 28). However, as in protocol 2, resetting was not different between reproductive states, when either methoxamine (protocol 4) or low doses of phenylephrine (protocol 3) were used to increase arterial pressure, and baroreflex curves were rapidly generated using the ramp method. Thus collectively these data indicate that the magnitude of acute resetting of baroreflex control of HR in response to a hypertensive challenge is not modified during pregnancy in conscious rabbits. Because acute resetting after hypertensive and hypotensive stimuli is quantitatively similar (2, 8, 12, 28), it is likely that resetting to sustained hypotension is also unaltered by pregnancy in conscious rabbits.

Hines (18) reported that baroreceptor afferents rapidly adapt to a sustained pressure stimulus in anesthetized pregnant, but not virgin, rats, a finding that appears to conflict with the present results documenting similar baroreflex resetting in each group. Many potential explanations exist for this apparent dichotomy. First, several differences in the experimental preparation could provide an explanation, including the presence or absence of anesthesia, species, level of stress, and method of analysis of resetting. However, it is noteworthy that considerable previous work indicates that the magnitude of acute resetting quantitatively does not vary among animals in numerous pathophysiological states exhibiting marked differences in arterial pressure or distensibility (for review, see Ref. 2). Thus, in this context, the preservation of acute reflex resetting during pregnancy is not surprising. Another possibility is that some aspect of pregnancy allows for faster resetting, but not greater resetting. Hines (18) observed greater adaptation of aortic baroreceptor afferents from pregnant rats 10 min after a step change in pressure, but not 1 min after. In contrast, in the present study, pressure was maintained at an elevated level for 30 min before reflex curve generation. Thus it is possible that 10 min after the pressure change, baroreflex resetting would have been greater in the pregnant rabbits, but at 30 min the resetting would be the same between reproductive states. However, the literature suggests that acute resetting of baroreceptor afferents is nearly complete in nonpregnant rats after ~5 min (28) and in rabbits after ~30 s (8) after a step change in pressure, suggesting that in both groups resetting after 10 min should be complete.

Finally, it is possible that the baroreceptor afferents do reset more rapidly, but that central processing of afferent activity counteracts this change. Hironaga et al. (19) showed that nitric oxide counteracts acute resetting by a central site of action. Because pregnancy is associated with increased nitric oxide production (for reviews, see Refs. 26, 34, 36), it is possible that any enhanced resetting of baroreceptor afferents is negated by parallel increases in the activity of nitric oxide in the brain to counteract resetting.

In summary, we show for the first time that acute baroreflex resetting is observed in conscious rabbits in both the pregnant and nonpregnant states and that the magnitude of the resetting is similar between groups. Thus, while baroreflex function is depressed, the ability of the baroreflex to reset appears to be preserved during pregnancy, suggesting that depressed reflex responses are not due to enhanced acute resetting. In addition, the data indicate that higher doses of phenylephrine counteract resetting of baroreflex control of HR in rabbits, by decreasing HR via a mechanism independent of the pressor effect. As a result, the use of phenylephrine for the generation of baroreflex curves should be restricted to low doses, at least in rabbits.

Perspectives

One maladaptive consequence of pregnancy is the lesser ability to maintain arterial pressure during hemorrhage and, in women, a greater susceptibility to orthostatic hypotension (3, 6, 15, 17, 29). Because hemorrhage accompanies even normal delivery, it is important to understand the mechanism for this change. Pregnancy also decreases baroreflex gain, which in particular causes an attenuation in reflex responses to hypotension; therefore, the change in baroreflex function has been suggested to mediate the decreased ability to maintain pressure during hypotensive challenges. The mechanism by which baroreflex gain decreases is incompletely understood, but the possibility that the change originates in the baroreceptor afferents can be considered. Recent studies demonstrate that responses of the aortic depressor nerve to rapid changes in arterial pressure are equivalent in virgin and pregnant rats (18, 23), indicating that the blunted reflex gain is not due to a decrease in gain or responsiveness of the afferents to the initial change in arterial pressure. On the other hand, Hines (18) has suggested that a more rapid adaptation of baroreceptor afferents to a sustained pressure stimulus during pregnancy contributes significantly to impaired reflex gain. More specifically, with sustained incremental changes in arterial pressure, the activity of the afferents would wane at each pressure level, thereby leading to a decrease in the slope or gain of the linear segment of the baroreflex relationship. The present results would appear to conflict with this suggestion, as resetting of baroreflex efferents (e.g., HR) was unaltered by pregnancy. In addition, if the decreased maximum gain observed during pregnancy is due to enhanced resetting, then greater decreases in gain would be expected in the reflex curves generated using the steady-state method compared with the ramp method. Instead, however, in the present study the changes in the curves induced by pregnancy were remarkably similar between the two methods (Fig. 2). Similarly, O'Hagan and colleagues (30, 31), who used pressure ramps of 2-3 mmHg/s in conscious pregnant and nonpregnant rabbits, have also observed decreases in maximum gain of baroreflex control of renal sympathetic nerve activity. Other investigators have reported decreases in reflex gain in pregnant individuals using rapid changes (4, 10), as well as steady-state changes (25), in arterial pressure for baroreflex curve generation, again suggesting that reflex resetting does not importantly contribute.

With the sigmoidal curve-fitting model that we are using for assessment of the baroreflex, maximum reflex gain is a function not only of the slope of the linear part of the reflex curve but also of the reflex range. In the present study, we dissected these two components of maximum gain. When all animals were included in the analysis of the steady-state results (Fig. 2, Table 1), it was clear that the reduced maximal gain was due to both a decrease in slope (increase in width) and a decrease in range, caused primarily by the increased minimum HR. For the ramp curves, however, the decreased maximum gain was due mainly to a decrease in the range component (Fig. 2, Table 1); an increase in width (e.g., as in the animal in Fig. 1) was not consistently observed. These results could suggest that detection of a decrease in slope requires steady-state curve generation. However, the combined results of two studies from the O'Hagan laboratory (Refs. 30, 31; Table 4) using the ramp method indicate that the decreased gain of baroreflex control of renal sympathetic nerve activity is primarily due to a decrease in the slope parameter. Similarly, Crandall and Heesch (10) report decreased slope of the hypotensive part of the curve with rapidly generated curves. Thus, collectively, the results from several labs indicate that a decrease in maximum reflex gain can be due to a decrease in the slope parameter (and/or a decrease in reflex range), regardless of whether curves are generated rapidly or slowly, and again suggest that reflex resetting is not a major contributor to decreases in reflex gain. Instead, the present results and the study of Curtis et al. (11) indirectly support the hypothesis that a change in central control of autonomic outflow underlies the decreased reflex gain observed in pregnant animals.

                              
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  		Table 4.   Effect of pregnancy on baroreflex control of RSNA


    ACKNOWLEDGEMENTS

The authors are grateful for the assistance of D. Daubert and for suggestions made by Drs. G. Head and M. Andresen during preparation of the manuscript.


    FOOTNOTES

This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-39923 and HL-35872.

Address for reprint requests and other correspondence: V. L. Brooks, Dept. of Physiology and Pharmacology, L-334, Oregon Health & Science Univ., Portland, OR 97201 (E-mail: brooksv{at}ohsu.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.

March 22, 2002;10.1152/ajpregu.00014.2002

Received 11 January 2002; accepted in final form 20 March 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Regul Integr Comp Physiol 283(2):R429-R440
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