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Am J Physiol Heart Circ Physiol 280: H2524-H2532, 2001;
0363-6135/01 $5.00
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Vol. 280, Issue 6, H2524-H2532, June 2001

Arterial baroreflex control of sympathetic nerve activity during acute hypotension: effect of fitness

P. J. Fadel1, M. Stromstad2, J. Hansen2, M. Sander2, K. Horn2, S. Ogoh1, M. L. Smith1, N. H. Secher2, and P. B. Raven1

1 Department of Integrative Physiology and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas 76107; and 2 Copenhagen Muscle Research Center, Department of Anesthesia, Rigshospitalet, University of Copenhagen, DK-2200 Copenhagen, Denmark


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We examined arterial baroreflex control of muscle sympathetic nerve activity (MSNA) during abrupt decreases in mean arterial pressure (MAP) and evaluated whether endurance training alters baroreflex function. Acute hypotension was induced nonpharmacologically in 14 healthy subjects, of which 7 were of high fitness (HF) and 7 were of average fitness (AF), by releasing a unilateral arterial thigh cuff after 9 min of resting ischemia under two conditions: control, which used aortic and carotid baroreflex (ABR and CBR, respectively) deactivation; and suction, which used ABR deactivation alone. The application of neck suction to counteract changes in carotid sinus transmural pressure during cuff release significantly attenuated the MSNA response (which increased 134 ± 32 U/14 s) compared with control (which increased 195 ± 43 U/14 s) and caused a greater decrease in MAP (19 ± 2 vs. 15 ± 2 mmHg; P < 0.05). Furthermore, during both trials, the HF subjects exhibited a greater decrease in MAP compared with AF subjects despite an augmented baroreflex control of MSNA. These data indicate that the CBR contributes importantly to the MSNA response during acute systemic hypotension. Additionally, we suggest that an impaired control of vascular reactivity hinders blood pressure regulation in HF subjects.

carotid baroreceptors; aortic baroreceptors; endurance training; neck suction


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

PREVIOUS INVESTIGATIONS that examined arterial baroreflex function in humans have primarily focused on baroreflex control of heart rate (HR) (8, 17, 29, 33). However, carotid and aortic baroreceptor control of muscle sympathetic nerve activity (MSNA) requires further definition. Human investigations of arterial baroreflex control of MSNA have been limited almost exclusively to the influence exerted by the carotid baroreflex (CBR) because there are few techniques that allow aortic baroreflex (ABR)-mediated changes in MSNA to be evaluated (7). Using the variable-pressure neck chamber, Wallin and Eckberg (38) reported that alterations in carotid sinus transmural pressure with neck pressure and neck suction (NS) caused profound and transitory changes in MSNA. Furthermore, because CBR activation with NS completely suppressed MSNA, these investigators suggested that afferent baroreceptor neurons (ABR and CBR) influence the same efferent postganglionic sympathetic motoneuron pool. However, the importance of the CBR to the integrated reflex MSNA response when both the CBR and ABR are deactivated together is unclear.

Sanders and colleagues (25, 26) used steady-state infusions of phenylephrine and nitroprusside alone (aortic and carotid baroreceptor activation and deactivation) and in combination with neck pressure and NS, respectively (aortic baroreceptor activation and deactivation) to evaluate the relative importance of the CBR versus the ABR for the control of MSNA. From these investigations it was concluded that the ABR dominates in the arterial baroreflex control of MSNA. However, there remains some question as to the specific interpretation of these data. In particular, questions have arisen about the use of 3-min periods to evaluate baroreflex function as baroreflex adaptation may have occurred (7). In addition, the steady-state infusions of vasoactive drugs caused sustained alterations in arterial blood pressure (ABP) despite the counteractive reflex responses. These continuous and constant changes in ABP may not represent the true physiological stimulus to the ABR and CBR during dynamic changes in ABP (i.e., standing), because, by maintaining a fixed pressure at the baroreceptors, the interaction between these two baroreceptor populations may have been altered. Therefore, one purpose of this investigation was to use a nonpharmacological method to induce acute hypotension to examine arterial baroreflex control of MSNA during a more transient and dynamic change in ABP.

Another purpose of the present investigation was to examine whether chronic endurance-exercise training alters arterial baroreflex function. Chronic endurance-exercise training has been reported to place the endurance-trained (ET) individual at risk for orthostatic intolerance (3, 12). One explanation for the increased prevalence of orthostatic intolerance in ET individuals appears to be an attenuation of the arterial baroreflex control of HR and vascular resistance (20). Several investigations have demonstrated that CBR control of HR was unaffected by endurance training; however, in these same investigations, it was reported that an attenuation of the ABR resulted in a diminished arterial baroreflex control of HR in ET individuals (28, 33). Although these investigations delineated an endurance training-induced functional difference in HR control between the CBR and ABR, limited information pertaining to alterations in arterial baroreflex control of MSNA due to training have been reported. Currently only two studies have examined the effect of endurance training on baroreflex control of MSNA in humans, and the results are equivocal and appear confounded by the subjects' relatively low maximal oxygen uptake (VO2 max) values even after the training periods (10, 27).

To address some of these issues pertaining to arterial baroreflex control and the effects of endurance training on baroreflex function, we used a nonpharmacological method to induce acute hypotension with and without NS to deactivate the aortic baroreceptors alone (suction) and in combination with the carotid baroreceptors (control). One goal was to examine arterial baroreflex control of MSNA during a dynamic and transient decrease in ABP and to determine the influence of the carotid baroreceptors in the reflex control of MSNA during acute systemic hypotension. We hypothesized that the dynamic nature of the ABP change would elucidate the discrete importance of the CBR in the reflex control of MSNA in response to acute hypotension. A second goal was to determine if long-term endurance-exercise training alters arterial baroreflex function. We hypothesized that chronic endurance-exercise training would attenuate arterial baroreflex control of MSNA.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects

Fourteen healthy men participated in the present study. The group means (±SE) for age, height, and weight were 25.5 ± 1.0 yr, 183.8 ± 1.7 cm, and 77.2 ± 1.9 kg, respectively. Each subject was advised of the testing protocols and provided written informed consent for this investigation. This study was approved by the Ethics Committee of Copenhagen. All subjects were free of any known cardiovascular disease and were not taking any medications. Subjects were administered an incremental exercise test on a cycle ergometer (Monark 818e) for the determination of VO2 max. The cycle work rate was set at 100 W and was increased 50 W every 2 min until the subject could no longer maintain a work rate at 60 rpm despite strong verbal encouragement. To assess fitness differences, subjects were divided into two groups. Subjects involved in competitive sports competition were considered to have a high fitness (HF) level (n = 7; group VO2 max = 67.8 ± 2.3 ml · kg-1 · min-1), and those not performing exercise training regularly were considered to be of average fitness (AF; n = 7; group VO2 max = 49.4 ± 2.1 ml · kg-1 · min-1). All of the HF subjects trained for >1 h/day and had been doing so for a minimum of 2 yr. The actual experimental protocol was scheduled on a separate day from the exercise test. Strenuous physical activity and alcohol consumption were prohibited 24 h before the experiment, and subjects were asked to abstain from caffeinated beverages for 12 h before testing. Each subject was familiarized with the equipment and procedures before the start of each experimental protocol.

Experimental Procedures

Measurements. The subjects were in the supine position for all testing and were instrumented with standard electrocardiogram (ECG) electrodes. HR measurements were processed by an ECG data computer (Dialogue 2000; IBC-Dancia) interfaced with a personal computer (PC). ABP was measured from the brachial artery of the nondominant arm using a 19-gauge (1 mm) Teflon catheter connected to a pressure transducer (PX-260; Baxter) and pressure monitoring system (Dialogue 2000) interfaced with the PC. Systolic and diastolic blood pressure (SBP and DBP, respectively) and mean arterial pressure (MAP) were calculated for each cardiac cycle using custom-made software. The catheter was kept patent by a continuous drip of heparinized saline (3 ml/h), and the transducer was zeroed to the midaxillary line of the subject. Central venous pressure (CVP) was measured by a sterile disposable pressure transducer (PX-260) interfaced with the aforementioned monitoring system via a single-lumen catheter. The central catheter was placed in the median antecubital vein of the left arm and advanced to an intrathoracic position. The reference point was zeroed at the midaxillary line, and patency was maintained by a continuous drip of heparinized saline.

Sympathetic nerve recordings. Postganglionic MSNA was recorded with standard microneurographic techniques as described previously (38). A tungsten microelectrode was inserted into the peroneal nerve near the fibular head of the noncuffed leg. The nerve signal was processed by a preamplifier and an amplifier (model 662C-3, Nerve Traffic Analyzer; University of Iowa Bioengineering, Iowa City, IA) with a total gain of 90,000. Amplified signals were band-pass filtered (700-2,000 Hz), rectified, and integrated by a resistance-capacitance circuit with a time constant of 0.1 s. MSNA recordings display a pulse-synchronous burst pattern and an increase in burst frequency with end-expiratory breath holds and Valsalva maneuvers. However, there is no response to arousal or skin stroking. These characteristics were used to discriminate between muscle and skin sympathetic nerve fibers. Sympathetic nerve activity was expressed as burst frequency and as total activity, which was calculated as the product of burst frequency and mean burst amplitude and expressed in arbitrary units.

Experimental protocol. After they were instrumented, the subjects rested quietly for ~10 min before any testing commenced. The arterial baroreflex, carotid sinus (CBR), and aortic arch (ABR) control of MSNA during acute hypotension were then assessed nonpharmacologically by releasing a unilateral arterial thigh cuff (300 Torr) after 9 min of resting-leg ischemia. Release of the thigh cuff produced a sudden drop in MAP that was reproducible within 1.7 ± 1.2 mmHg between trials during pilot studies (n = 9). A unilateral thigh cuff was used to limit the drop in CVP, as unloading of the cardiopulmonary baroreceptors alters MSNA (37). The protocol started with a 5-min baseline period and inflation of the thigh cuff for 9 min; after this the cuff was deflated and measurements were continued for an additional 4 min. Cuff deflation was initiated at a normal end expiration as observed from the subjects' diaphragm movement. This was to ensure that all subjects were at the same point in the breathing cycle to minimize the effects of respiration on the comparison of responses between cuff-release trials. The initial trial served as a control from which the nadir of the MAP response was calculated and used to determine the level of NS needed during the suction trial. We assumed that during this phase of testing both the CBR and ABR were deactivated by the acute drop in MAP, and therefore the response would characterize the arterial baroreflex control of MSNA and HR.

After ~25 min (to allow for all cardiovascular variables to return to basal levels) the protocol was repeated with the application of NS to the anterior two-thirds of the neck through a malleable lead collar (6). The NS was applied to the carotid sinus close to the nadir of the pressure change as estimated from the initial cuff-release trial. Suction was continued for 14 s after cuff release to counteract the changes in carotid sinus transmural pressure induced by the release of the arterial thigh cuff. This procedure enabled us to negate the cuff-release-induced alterations in MAP at the carotid sinus and therefore to functionally isolate the ABR (ABR deactivation alone). The amount of NS utilized was derived from the nadir of the MAP response during the control trial using a pressure-transmission value of 68% (NS = control Delta MAP/0.68). Incomplete transmission of neck pressure and suction to the carotid sinus region has been well documented (7, 16). Therefore, we felt it important to correct the NS if we were to successfully negate the fall in pressure at the carotid sinus and functionally isolate the ABR control of MSNA. The amount of NS used in this investigation ranged from -15 to -35 mmHg. To offset an effect of order on the MSNA responses, in three subjects the control condition was repeated after the suction and compared with the initial control trial. No significant differences were found in the changes in MSNA due to cuff release (P > 0.05). MSNA comparisons were made between equivalent time periods for baseline, cuff inflation (pre-cuff release), and cuff release (i.e., 14 s). To minimize any potential confounding effects of a shift in the nerve-recording site between the control and suction trials and to account for changes in MSNA from baseline to 9 min of cuff inflation (Table 1), changes in MSNA during cuff release were compared with the average 14-s MSNA value obtained between 8 and 9 min of cuff inflation.

                              
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  		Table 1.   Subjects' responses to 9 min of resting-leg ischemia

Data analyses. Control and suction cuff-release trials were matched according to the time NS was initiated and terminated and the period of the cardiac cycle at that time. Owing to the pulse synchronicity of MSNA bursts (38), we felt it important to start and end the data analysis periods at the same period of the cardiac cycle. MSNA was calculated as burst frequency and total activity for the 14 s of cuff release with and without NS and compared with the average 14-s MSNA value between 8 and 9 min of the cuff-inflation period. The MSNA responses are presented as changes from this pre-cuff-release period. Nadir and peak responses for MAP and HR, respectively, were calculated as 5-s averages for the time period at 6-10 s cuff release and were compared with the 60-s mean MAP and HR values at 8-9 min of cuff inflation. CVP was calculated in the same manner as MAP and HR, and all three variables are reported as changes from the pre-cuff-release period. The values are all presented as differences from pre-cuff release to account for any differences in trials and changes provoked by the 9 min of cuff inflation. Baroreflex responsiveness was assessed as a change in HR or MSNA per change in DBP and comparisons were made between HF and AF subjects over the 14 s of cuff release with and without NS. The Delta HR/Delta DBP response was used for comparisons between fitness groups for two reasons: 1) there were no significant differences between Delta HR/Delta MAP and Delta HR/Delta DBP, and 2) the changes in MSNA were related to the DBP. During baseline measurements, mean values for a 60-s MAP, HR, and CVP and a 14-s MSNA were calculated and compared with the values obtained at 8-9 min of cuff inflation.

Statistical analyses. Statistical comparisons of physiological variables (HR, MAP, MSNA, and CVP) between the control and suction trials were made utilizing a repeated-measures two-way ANOVA with a 2 × 2 design (condition × time). Comparisons of the changes in MSNA and nadir MAP responses between cuff release with NS (suction) and without NS (control) and the cardiovascular and MSNA variables between baseline and 8-9 min of cuff inflation were made by paired t-tests. The effect of fitness on the changes in MSNA, HR, MAP, CVP, and baroreflex responsiveness were made utilizing a repeated-measures two-way ANOVA with a 2 × 2 design (fitness group × condition). After ANOVA analyses, a Student-Newman-Keuls test was employed post hoc when interactions were significant. Statistical significance was set at P < 0.05. Results are presented as means ± SE.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Cuff inflation. The MSNA and cardiovascular responses to 9 min of complete vascular occlusion in one leg during control and suction trials are presented in Table 1. No significant differences were found between the trials at baseline or at 9 min of cuff inflation. However, during the resting-leg ischemia, MAP increased 4 ± 1 and 5 ± 1 mmHg (P < 0.05) from baseline to 9 min of cuff inflation during control and suction trials, respectively. This increase in MAP during control and suction corresponded to increases in MSNA of 27 ± 9 and 24 ± 7 units, respectively; P < 0.05. HR was not significantly altered during suction and increased 3 ± 1 beats/min in the control trial (P < 0.05). CVP decreased ~1 mmHg during both conditions (P < 0.05).

Cuff release. In all subjects, during the initial deflation of the thigh cuff, MAP rapidly decreased and reached a nadir of -18 ± 2 mmHg within 3 s during the control trial (ABR and CBR deactivation); see Fig. 1. The application of NS to offset changes in carotid sinus pressure during cuff release caused a greater decrease in MAP (-21 ± 2 mmHg; P < 0.05), which occurred at 5 s. This greater decrease in MAP persisted throughout the 14 s with the greatest difference between trials occurring over the 6- to 10-s time period (decrease of 15 ± 2 and 19 ± 2 mmHg during control and suction, respectively; P < 0.05). Estimated carotid sinus pressure (ECSP) values, which were calculated as MAP minus chamber pressure, indicated that we were successful in maintaining carotid sinus pressure fairly constant during the suction trials (see Fig. 1).


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  		Fig. 1.   Changes in mean arterial pressure (MAP) and estimated carotid sinus pressure (ECSP) during cuff release with neck suction [NS; aortic baroreflex (ABR) deactivation] and without NS [ABR and carotid baroreflex (CBR) deactivation]. ECSP was calculated as MAP minus chamber pressure and is not plotted for the control condition as it would be equal to MAP. Group means ± SE are presented as a change from the 60-s average recorded for 8-9 min of the cuff-inflation period. *Significant differences between control and suction, P < 0.05.

The larger fall in MAP during the suction trial corresponded to an attenuated reflex-mediated increase in MSNA from 195 ± 43 U/14 s (control) to 134 ± 32 U/14 s (suction) (P < 0.05; see Fig. 2). This decrease in MSNA was also evident by the significant reduction in burst frequency noted during the suction trial. In contrast, no significant differences in HR were noted between control and suction trials, and CVP was unaltered by cuff release (see Fig. 3).


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  		Fig. 2.   Muscle sympathetic nerve activity (MSNA) responses to cuff release with ABR deactivation alone (suction) and in combination with CBR deactivation (control). A: changes in MSNA from the average 14-s MSNA value for 8-9 min of the cuff-inflation period presented as averages over 0-5 s, 6-10 s, and 11-14 s; P < 0.015 indicates the overall effect of the application of NS during cuff release on the MSNA responses. B: MSNA assessed as burst frequency (Freq) and total activity (burst frequency × amplitude) for the initial 14 s of cuff release during control and suction trials and presented as a change from the average 14-s MSNA value for 8-9 min of cuff inflation. *Significant differences between control and suction, P < 0.05.



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  		Fig. 3.   Heart rate (HR) and central venous pressure (CVP) changes during cuff release with ABR deactivation alone (suction) and in combination with CBR deactivation (control). Group means ± SE are presented as changes from the 60-s averages obtained for 8-9 min of cuff inflation. CVP was not significantly different from 0 at any time point. No significant differences were found for HR and CVP between control and suction.

Fitness differences. During both cuff-release trials (control and suction), HF subjects exhibited a significantly larger drop in MAP compared with their AF counterparts (see Fig. 4). Under control conditions, when the ABR and CBR were deactivated, MAP decreased 19 ± 2 and 11 ± 2 mmHg in the HF and AF subjects, respectively. The application of NS during cuff release caused a greater decrease in MAP in both fitness groups with a decrease of 22 ± 3 mmHg in the HF group and 16 ± 1 mmHg in the AF group (P < 0.05). The larger decrease in MAP in HF subjects during both control and suction conditions was accompanied by a greater increase in MSNA compared with the AF subjects (P < 0.05; see Fig. 5). On the other hand, despite the larger fall in MAP, reflex-mediated increases in HR were not significantly different between the HF and AF subjects and even tended to be lower in the HF group during control conditions (see Fig. 4).


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  		Fig. 4.   Comparison of MAP and HR responses to cuff release with NS (suction) and without NS (control) in high-fitness (HF) and average-fitness (AF) subjects. Group means ± SE over 14-s of cuff release are presented as changes from the 60-s averages recorded between 8 and 9 min of cuff inflation. dagger Significant main effect for fitness in MAP responses, P < 0.05. *Significant main effect for condition in MAP responses (i.e., control vs. suction), P < 0.05.



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  		Fig. 5.   Comparison of MSNA responses to cuff release with ABR deactivation alone (suction) and in combination with CBR deactivation (control) in HF and AF subjects. dagger Significant main effect for fitness in MSNA responses, P < 0.05. *Significant main effect for condition in MSNA responses (i.e., control vs. suction), P < 0.05.

When both the aortic and carotid baroreceptors were deactivated together (control), both HF and AF subjects exhibited large increases in MSNA that were significantly attenuated when NS was used to counteract changes in carotid sinus transmural pressure (suction); see Fig. 5. In contrast, the application of NS during cuff release had no effect on the HR response in the HF and AF subjects (see Fig. 4).

Overall baroreflex responsiveness assessed during the cuff-release trials indicated fitness-related differences in the baroreflex control of MSNA (i.e., Delta MSNA/Delta DBP); see Table 2. During the acute decrease in MAP that was induced by cuff release, arterial baroreflex control of MSNA appeared to be augmented in the HF compared with the AF subjects as indicated by a significant main effect for fitness (P < 0.05). This occurred without any interaction with condition. In contrast, no significant differences in the baroreflex control of HR were noted between the HF and AF subjects.

                              
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  		Table 2.   Comparison of baroreflex responsiveness between high-fitness and average-fitness subjects


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The major findings of the present investigation were 1) the CBR contributed importantly to the MSNA response during acute systemic hypotension, 2) unilateral arterial cuff deflation provided a reproducible nonpharmacological method for evaluating arterial baroreflex function during acute hypotension that is independent of significant stimuli to the cardiopulmonary baroreceptors, and 3) arterial baroreflex control of MSNA appeared to be augmented in ET subjects.

CBR and ABR responses. The application of NS to negate the decrease in pressure at the carotid sinus caused a greater decrease in MAP in all subjects. Thus the attenuation of the CBR contribution to the arterial baroreflex-mediated response during acute hypotension allowed MAP to decline further, thereby signifying the importance of the CBR in the maintenance of ABP. This larger decrease in MAP was accompanied by an attenuated MSNA response compared with control conditions when both the CBR and ABR were deactivated. Considering that the reflex increases in HR were not significantly different between control (CBR and ABR deactivation) and suction (ABR deactivation alone), it is likely that the decreased MSNA response produced by eliminating the decrease in pressure at the carotid sinus accounted for the greater fall in MAP. This indicates the importance of the CBR in the reflex control of MSNA and subsequent correction of sudden decreases in MAP. These findings confirm previous reports that have indicated a profound ability of the CBR to effectively modulate sympathetic outflow during alterations in carotid sinus transmural pressure (9, 21, 38). Moreover, the present findings extend these reports by delineating the importance of the CBR to the integrated reflex MSNA response when both the CBR and ABR are deactivated.

In contrast, using a 3-min aortic isolation protocol, Sanders and colleagues (26) concluded that the aortic baroreceptors dominated the arterial baroreflex control of MSNA and that the CBR contributed minimally. We suggest that differences between the findings of the present investigation and those reported by Sanders and co-workers (26) were most likely due to differences in experimental methodologies. In the 3-min steady-state nitroprusside infusions, the vascular smooth muscle was continuously relaxed and resulted in a maintained decrease in MAP. In contrast, the present investigation used a unilateral arterial thigh-cuff occlusion-and-release method that allowed for more dynamic and transient decreases in ABP.

The rationale for developing a protocol that provided for a more dynamic and transient decrease in ABP than those induced by the use of steady-state nitroprusside infusions was based on the following: 1) a sustained drop in ABP (3 min) and subsequent application of NS for 3 min during nitroprusside infusions most likely caused both ABR and CBR adaptations to occur (7, 38); 2) a continuous and constant drop in ABP despite counteractive reflex responses is unphysiological and may have altered baroreflex function as well as the interaction between the ABR and CBR; 3) a central adaptation may have occurred, as investigations using anaesthetized dogs have shown that during sustained electrical carotid sinus nerve stimulation, central adaptation of sympathetic responses developed (22); and 4) the sustained drops in ABP may dampen any effects of the CBR on the control of MSNA, as it is the changes in afferent carotid baroreceptor activity that are important in determining the sympathetic outflow rather than the absolute arterial pressure (9, 38). Any or all of these factors may have contributed to the results and interpretation of the findings of previous work utilizing steady-state drug infusions (26, 28). We expected that by employing a method of using a more dynamic and transient decrease in ABP we would eliminate the concerns raised by the previously used techniques of aortic isolation (26, 28). In addition, the unilateral arterial thigh-cuff release did not alter CVP. Therefore, unlike in nitroprusside infusions, there was no need to counteract decreases in CVP with volume infusion (26) or lower-body positive pressure (28). Moreover, it was of particular importance to maintain CVP constant when examining arterial baroreflex control of MSNA, because unloading of the cardiopulmonary baroreceptors causes reflex-mediated increases in MSNA (37). In addition, Pawelczyk and Raven (19) have reported that reductions in CVP augmented CBR sensitivity. Thus we contend that unilateral cuff deflation provides a new and advantageous method for evaluating arterial baroreflex control of MSNA during an acute induction of hypotension.

In the present investigation, we demonstrated that the application of NS to attenuate the CBR caused a significant attenuation of arterial baroreflex-mediated MSNA responses. However, the overall MSNA response was still significant during the suction trials (ABR deactivation alone). Although it would be tempting to conclude that this substantial MSNA response indicated an apparent dominance of the ABR in the reflex control of MSNA, caution should be used when interpreting these findings due to the uncertainty of the interactive relationship between the ABR and CBR (7). Animal studies have indicated that whichever arterial baroreceptor population is denervated last appears to be the more powerful of the two (11). These findings suggest that when either baroreflex is eliminated the response of the other reflex is enhanced which suggests redundancy in central processing of arterial baroreceptor inputs. Thus it is likely that the ABR was enhanced when NS was used to attenuate the CBR, and this may therefore explain any apparent dominance of the ABR in the reflex control of MSNA. More importantly, these findings do not prove that the ABR predominates when both the aortic and carotid baroreceptor inputs are fully expressed. In fact, the relative importance of the ABR and CBR in humans may always remain speculative due to methodological considerations when removing input from one of the baroreceptor populations. However, experimental strategies employed in the present investigation were able to identify the importance of the CBR in the arterial baroreflex control of MSNA because even if the ABR response was enhanced during the suction period the overall MSNA response was still significantly attenuated from control in the absence of CBR input. Thus the CBR contributed importantly to the overall MSNA response to acute systemic hypotension.

Fitness differences. HF subjects demonstrated a greater fall in MAP compared with their AF counterparts. This occurred when both the CBR and ABR were deactivated together (control) as well as when the ABR was deactivated alone (suction). These findings are in agreement with numerous studies that have reported larger decreases in blood pressure during varying levels of lower-body negative pressure after endurance-exercise training (20, 30, 35, 36) and several cross-sectional studies that have noted a reduced orthostatic tolerance in HF subjects (14, 28, 30). Although these studies clearly link endurance training and orthostatic intolerance, the exact mechanism(s) responsible for the reduction in orthostatic tolerance remains unclear. However, several potential contributing factors have been identified including training-induced alterations in baroreceptor function (20), alpha -receptor sensitivity (4), vascular compliance (1), or myocardial compliance (15).

Interestingly, in the present investigation, the HF subjects appeared to exhibit an augmented baroreflex control of MSNA compared with the AF subjects. These findings were unexpected and were contrary to our hypothesis. However, further evidence suggesting an increased baroreflex control of MSNA with training has been reported by Grassi and colleagues (10). These investigators reported a potentiation of the baroreceptor-sympathetic reflex responses in a group of young subjects after they underwent a 10-wk running program. In contrast, Sheldahl and co-workers (27) have reported no changes in baroreflex control of MSNA after training in middle-aged men, and DiCarlo and Bishop (5) noted an attenuated baroreflex control of renal sympathetic nerve activity in conscious rabbits after 8 wk of endurance training. Thus the primary effect of endurance training on baroreflex control of sympathetic nerve activity is equivocal; however, differences in training status, age, and species may explain the disparities.

We suggest that potential reasons for a possible augmentation in the arterial baroreflex control of MSNA in HF subjects may be training-induced changes in central neural processing or an impaired control of vascular reactivity. Recently, Chen and colleagues (2) reported that exercise-trained rats exhibited a reduced central gain of the baroreflex regulation of HR that was attributed to an altered central processing of afferent signals without changes in the reactivity of afferent nerves. In addition, Moffitt and co-workers (18) have reported an attenuated baroreflex control of renal sympathetic nerve activity after deconditioning induced by hindlimb unloading in rats that was due to changes in central processing of baroreceptor afferent information. Thus if deconditioning can reduce baroreflex control of sympathetic nerve activity by altering central neural processing, then it is plausible that training can enhance baroreflex sympathetic responses through similar mechanisms. Collectively, these animal investigations indicate that alterations in central nervous system processing may play a role in modifying arterial baroreflex function after endurance-exercise training and that these alterations may affect HR and MSNA control differently. The apparent differential effects of endurance training on baroreflex function may be due to differences in sympathetic and vagal processing as sympathetic motoneurons have been reported to respond very differently than vagal cardiac motoneurons to manipulations of the baroreceptors (9). Furthermore, both neural networks respond differently to exercise training (31, 32). Taken together, these studies may explain the apparent augmentation in arterial baroreflex control of MSNA in the HF subjects in the present investigation without any significant alteration noted in baroreflex control of HR.

Another possible reason for an augmented arterial baroreflex-mediated Delta MSNA/Delta DBP in ET subjects may be related to a change in the control of vascular responsiveness. Previous investigations have reported an attenuated vasoconstrictor response and an increased capacity for vasodilation in ET individuals (14, 30, 34, 35). The reduced vasoconstrictor response may be due to an attenuated alpha -adrenergic receptor sensitivity; however, results from studies examining alterations in alpha -adrenergic receptors with training are equivocal in indicating a decrease (4), increase (13), or no change (30) in responsiveness. Alternatively, it may be that changes in local metabolites during cuff inflation interfered with or overrode the ability of the alpha -adrenergic receptors to vasoconstrict (4). In addition, structural changes (34) and increases in arterial compliance (1) may also contribute to an altered vasculature in HF subjects that leads to a greater pooling in the ischemic leg. Thus it can be reasoned that training-induced alterations in the vasculature leave the ET subject susceptible to decreases in ABP (i.e., orthostatic intolerance). Therefore, one could speculate that as a compensatory mechanism the arterial baroreflex adapts by increasing its control of MSNA to assist in the maintenance of blood pressure. However, despite the increased MSNA, ABP remains low because the MSNA cannot overcome the changes in vascular remodeling that occur with chronic endurance-exercise training. Further studies examining baroreflex-mediated changes in MSNA and subsequent alterations in vascular resistance in ET subjects are warranted.

Unilateral leg ischemia. During both the suction and control trials, the application of a unilateral arterial thigh cuff (300 Torr) for 9 min under resting conditions caused slight but significant increases in MSNA and MAP (Table 1). This finding was consistent for both HF and AF subjects. However, previous investigations have indicated that under resting conditions the cuff occlusion-induced ischemia does not induce a muscle metaboreflex-mediated increase in blood pressure (23). Thus the mechanism causing this increase in MSNA and MAP is unclear. However, it is possible that the slight increases observed were the result of cardiopulmonary baroreflex unloading. The decrease in CVP produced by the trapping of blood in the occluded leg may have deactivated the cardiopulmonary baroreflex and contributed to an increase in MSNA and subsequent increase in ABP. Alternatively, it may be that activation of nocioreceptors contributed to the observed increases in MSNA and MAP; however, the subjects did not report any pain during the occlusion period.

Potential limitations in the design and interpretation of the present investigation should be considered. First, estimations of carotid sinus pressure during the suction trial indicated that the technique was very successful in negating the change in pressure at the carotid sinus; however, some deactivation or activation of the CBR cannot be discounted despite our correcting for incomplete transmission. Second, given that an inhibitory interaction has been reported between the CBR and ABR in humans (33) and in several animal species (24), any quantitative analysis of the relative importance of these baroreceptor populations in the baroreflex control of MSNA cannot be made. It is highly likely that in the present investigation the ABR compensated for the attenuation of the CBR during the suction condition. Nevertheless, the MSNA response was significantly attenuated which indicated for the first time the importance of the CBR to the integrated reflex response of MSNA when both the CBR and ABR are deactivated.

In summary, the present findings demonstrate that the CBR contributes significantly to the MSNA response during acute systemic hypotension. More importantly, we were able to discern the importance of CBR control of MSNA to the integrated reflex response. Furthermore, unilateral arterial cuff deflation provides a reproducible nonpharmacological method for evaluating the reflex control of MSNA by the arterial baroreceptors during acute hypotension; moreover, it allows for a more dynamic and transient decrease in ABP, which presents a truer physiological stimulus to the arterial baroreceptors. In addition, CVP is unaltered during this protocol and therefore limits the confounding affect of deactivation of the cardiopulmonary baroreceptors.

Chronic endurance-exercise trained individuals exhibited a greater fall in MAP compared with their AF counterparts. In response to the greater decrease in MAP, arterial baroreflex control of MSNA appeared augmented. However, despite the greater increases in MSNA, HF subjects continued to have a greater fall in MAP. This suggests that, although the arterial baroreflex may increase the MSNA of the ET individual, the regulation of blood pressure during hypotension remains attenuated. We suggest that the more marked hypotension is a result of endurance-exercise training-mediated vascular adaptations.


    ACKNOWLEDGEMENTS

The authors thank all subjects for providing time and cooperation for this investigation. In addition, the authors especially thank Dr. Koshiro Ide for technical support and Lisa Marquez for secretarial support in preparation of the manuscript.


    FOOTNOTES

This study was supported in part by the Life Sciences Division of the National Aeronautics and Space Administration under NASA Grant NAG5-4668, National Heart, Lung, and Blood Institute Grant HL-45547, and Danish National Research Foundation Grant 504-14, Copenhagen, Denmark.

This research was submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy for P. J. Fadel.

Address for reprint requests and other correspondence: P. J. Fadel, Div. of Hypertension, Univ. of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-8586 (E-mail: paul.fadel{at}utsouthwestern.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 6 June 2000; accepted in final form 9 January 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Heart Circ Physiol 280(6):H2524-H2532
0363-6135/01 $5.00 Copyright © 2001 the American Physiological Society


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