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J Appl Physiol 101: 68-75, 2006. First published March 30, 2006; doi:10.1152/japplphysiol.01452.2005
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Effects of changes in central blood volume on carotid-vasomotor baroreflex sensitivity at rest and during exercise

Shigehiko Ogoh, R. Matthew Brothers, Quinton Barnes, Wendy L. Eubank, Megan N. Hawkins, Sushmita Purkayastha, Albert O-Yurvati, and Peter B. Raven

Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth, Texas

Submitted 16 November 2005 ; accepted in final form 21 March 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The purpose of this investigation was to examine whether the effect of changes in central blood volume on carotid-vasomotor baroreflex sensitivity at rest was the same during exercise. Eight men (means ± SE: age 26 ± 1 yr; height 180 ± 3 cm; weight 86 ± 6 kg) participated in the present study. Sixteen Torr of lower body negative pressure (LBNP) were applied to decrease central venous pressure (CVP) at rest and during steady-state leg cycling at 50% peak O2 uptake (104 ± 20 W). Subsequently, infusions of 25% human serum albumin solution were administered to increase CVP at rest and during exercise. During all protocols, heart rate, arterial blood pressure, and CVP were recorded continuously. At each stage of LBNP or albumin infusion, the maximal gain (Gmax) of the carotid-vasomotor baroreflex function curve was measured using the neck pressure and neck suction technique. LBNP reduced CVP and increased the Gmax of the carotid-vasomotor baroreflex function curve at rest (+63 ± 25%, P = 0.006) and during exercise (+69 ± 19%, P = 0.002). In contrast to the LBNP, increases in CVP resulted in the Gmax of the carotid-vasomotor baroreflex function curve being decreased at rest –8 ± 4% and during exercise –18 ± 5% (P > 0.05). These findings indicate that the relationship between CVP and carotid-vasomotor baroreflex sensitivity was nonlinear at rest and during exercise and suggests a saturation load of the cardiopulmonary baroreceptors at which carotid-vasomotor baroreflex sensitivity remains unchanged.

cardiopulmonary baroreceptors; arterial blood pressure; central venous pressure

MEASUREMENTS OF BEAT-TO-BEAT changes in heart rate (HR), stroke volume (SV) using two-dimensional echocardiography, pulse Doppler ultrasound or Modelflow, and arterial blood pressure (ABP) enables the calculation of systemic vascular conductance responses to neck pressure (NP) and neck suction (NS) at rest and during exercise (26, 27). When these responses are combined with NP- and NS-induced changes in muscle sympathetic nerve activity (MSNA), the specific contribution of the carotid-cardiac and the carotid-vasomotor baroreflexes in the regulation of ABP can be estimated (26, 27). Using these proportional calculations in comparing carotid baroreflex (CBR) control of blood pressure at rest and during exercise, it was found that the carotid-vasomotor arm of the reflex predominated (6, 26, 27). The importance of CBR control of the vasculature during exercise has been confirmed in both the dog (6) and human (26, 27). In a series of investigations (11, 17, 18, 41), the simultaneous entrainment of CBR changes in MSNA, femoral blood velocity, and tissue oxygenation was demonstrated, further identifying the sequential cascade of responses associated with CBR regulation of the vasculature in the baroreflex regulation of blood pressure.

In addition to the autonomic nervous system, central blood volume (CBV) is important for regulation of blood pressure, because CBV is related to preload and SV. Indeed, the larger the SV, the less the required change in HR or vascular resistance in regulating blood pressure (21). Interestingly, a change in CBV has been found to influence arterial baroreflex function (4, 7, 8, 29, 30, 35, 39). At rest, the maximal gain (Gmax), or sensitivity, of the carotid-vasomotor baroreflex increases during reductions in CBV induced by lower body negative pressure (LBNP) or head-up tilt (7, 8, 29, 30, 39). This enhanced autonomic control may be a compensatory mechanism ensuring maintenance of blood pressure in the face of a reduced CBV during orthostasis. In contrast, increases in CBV attenuate the Gmax of the carotid-vasomotor baroreflex (35) and reduce the sensitivity of the arterial baroreflex control of MSNA (4). Clinically, the increase in CBV associated with heart failure also reduces the sensitivity of arterial baroreflex control of blood pressure (10, 16). However, the physiological significance of these responses remains unclear. In contrast, during exercise, the increase in CBV resets the operating point of the cardiopulmonary baroreflex control of the forearm vasculature without a change in sensitivity (24). This finding provides an explanation as to why the exercise-induced increases in CBV did not reduce the Gmax of the carotid-vasomotor baroreflex (23, 27, 32, 33), in contrast to the reduction in the Gmax that occurs with an increased CBV at rest. However, whether increases or decreases in CBV imposed on the reset operational point of the cardiopulmonary baroreflex that occurs during exercise attenuates or augments, respectively, the Gmax of the carotid-vasomotor baroreflex remains a question. We hypothesized that, during exercise, an increase in CBV would reduce the Gmax of the carotid-vasomotor baroreflex, whereas a decrease in CBV would augment the Gmax of the carotid-vasomotor baroreflex, similar to the changes observed at rest.

We addressed this question using LBNP to decrease CBV, and infusions of human serum albumin to increase CBV in human subjects at rest and during steady-state exercise. CBR function curves were constructed using the variable-pressure neck collar technique, and the obtained baroreflex function parameters were compared across changes in CBV at rest and during exercise.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The present report represents additional data from the same experimental designed investigations that were published previously (24, 25). Therefore, the experimental subjects, protocols, and interventions were the same as in previous reports (24, 25). The use of the same experimental design was based on the concept of reducing the cumulative risk exposure of a total of 8 subjects, compared with the 24 subjects undergoing the same invasive protocols who would be required to answer the three questions separately. Eight men (means ± SE: age 26 ± 1 yr; height 180 ± 3 cm; weight 86 ± 6 kg) were recruited for voluntary participation in the present study. All subjects were free of any known cardiovascular and pulmonary disorders and were not using prescribed or over-the-counter medications. Each subject provided written, informed consent, which conformed to the Declaration of Helsinki and was approved by The University of North Texas Health Science Center Institutional Review Board (IRB Protocol no. 22-168). The subjects were requested to abstain from caffeinated beverages for 12 h and strenuous physical activity and alcohol intake for at least 1 day before testing. Before any experiments were performed, each subject visited the laboratory for familiarization with the techniques and procedures to be used in the experimental protocols. All experiments were conducted at a constant room temperature (25.2 ± 0.3°C).

Maximal exercise stress test.   On experimental day 1, each subject performed a maximal incremental workload test to volitional fatigue in a 70° back-supported semirecumbent position by cycling on an electronically braked cycle ergometer placed within the LBNP box. This test served as the initial screening and provided evidence of suitability for the study. Before the exercise test, the subject's resting blood pressure and 12-lead electrocardiogram were recorded at seated and standing positions. The initial cycle workload was set at 50 W for 2 min and was increased 30 W each minute. The criteria for attainment of peak oxygen uptake (VO2 peak) included the inability to maintain a cycling cadence of 60 rpm, accompanied by a respiratory quotient exceeding 1.10 or a documented plateau of oxygen uptake. Subjects respired through a mouthpiece attached to a low-resistance turbine volume transducer (model VMM E-2A, Sensor Medics, Anaheim, CA) and mass spectrometry (model MGA1100B, Perkin-Elmer, St. Louis, MO) for determination of oxygen uptake. The actual experimental protocol was scheduled on a separate day from the maximal exercise stress test.

Experimental protocol.   A schematic description of the experimental protocol is presented in Fig. 1. On experimental day 2, after instrumentation, the subjects were positioned in the 70° back-supported semirecumbent position with the lower body in the LBNP box. The subject was sealed in the LNBP box at the level of the iliac crest with a flexible rubber dam. The electrically braked cycle ergometer placed in the LBNP box was adjusted to each subject's leg length. During exercise, full extension of the leg was >20° above the horizontal plane of the hip.


Figure 1
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  		Fig. 1. Experimental protocol illustrating timing of lower body negative pressure (LBNP), human serum albumin infusion (INF), exercise, and neck pressure and neck suction (NP/NS). A: protocol 1, resting LBNP protocol; B: protocol 2, exercising LBNP protocol; C: protocol 3, resting and exercising INF protocol. Note that NP and NS protocol was applied at baseline and during LBNP of 16 Torr (LB16) and second albumin infusion (INF2) conditions, only to reduce the protocol time because the NP and NS technique would extend each condition's time for approximately an additional 20 min. VO2 peak, peak O2 uptake.

 
After the subjects rested for 30 min in the 70° back-supported semirecumbent position, beat-to-beat hemodynamic recordings of HR, central venous pressure (CVP), and ABP were recorded for 6 min (Fig. 1). Following the 6 min of recording baseline hemodynamic variables, CBR function was measured by using random-ordered 5-s pulses of NP and NS presented at +40, +20, 0, –20, –40, –60, and –80 Torr during a 10- to 15-s breath hold at end-expiration (32). Four to five pulses of NP and NS were performed at each pressure and separated by >45 s. Following the acquisition of the resting data, LBNP of 8 Torr (LB8) was applied for 2 min before another 6 min of hemodynamic recordings, and LBNP of 16 Torr (LB16) was applied for 20 min. During minutes 2–20 of LB16 condition, another 6 min of HR, CVP, and ABP recordings and measures of CBR function were obtained (Fig. 1, protocol 1). After completion of the resting LBNP protocol and a further 5 min of rest, the subject began cycling at 50 W for 2 min; thereafter, the workload was increased 20 W each minute until each subject's 50% VO2 peak was attained. Following ~6–8 min of attaining the 50% VO2 peak workload, the same hemodynamic and CBR function measurements were made. During exercise, NP and NS were applied without a breath hold. Only two to three 5-s pulses of NP and NS at each pressure were performed during exercise, as the time was limited to 12–14 min. Subsequently, 40 min of rest after the control exercise bout, the subjects repeated the 50% VO2 peak exercise workload. Additionally, 2 min before the beginning of this second bout of exercise, LB8 was applied. After 6 min of exercise in the LB8 condition, the same measurements were obtained. The exercise during LB8 condition was performed for ~15 min and was followed by another 40-min rest before the LB16 exercise condition. Two minutes before the beginning of this third bout of exercise, LB16 was applied. After 6 min of exercise at the LBNP condition, the same hemodynamic and CBR function measurements were obtained (Fig. 1, protocol 2). Following another 40 min of rest, 50 ml of human serum albumin were infused via the antecubital vein catheter. The infusions of 25% human serum albumin were administered slowly (1–3 ml/min) to prevent any adverse effects. After waiting for a period of 15 min and assessing the subject's reaction to the human serum albumin (none of the subjects reported any discomfort nor had symptomatic evidence associated with an allergic reaction), a further 50 ml of human serum albumin were infused until at least a 1-mmHg increase in CVP occurred [infusion 1 (INF1)]. Following the completion of INF1, both the resting and exercise protocols, described above, were repeated, along with the same hemodynamic measurement protocol. Subsequently, after another 40-min rest, the rest and exercise protocol, along with the same hemodynamic and CBR function measurements, were repeated after an additional 150-ml infusion of human serum albumin to a minimum increase in CVP of 2 mmHg [infusion 2 (INF2)]. During the course of the experiments, the subjects were constantly questioned about their comfort (Fig. 1, protocol 3). One subject did not complete the entire experiment because of the physical discomfort associated with the 70° back-supported semirecumbent position, especially during the exercise infusion experiments. The infusion volume of 25% albumin was 1.20 ± 0.06 ml/kg (INF1), and the additional volume was 1.60 ± 0.06 ml/kg for INF2. During the resting and exercise experiments, HR, ABP, and CVP were recorded continuously. NP and NS protocol was applied to measure the CBR function at rest and during exercise at baseline and during LB16 and INF2 conditions only (Fig. 1).

Measurements.   The HR was monitored with a standard lead II electrocardiogram (model 78342A, Hewlett Packard). The ABP and CVP were measured directly by a cannula (1.1 mm ID, 20 gauge) placed in the brachial artery for measurement of the ABP and another cannula (17-gauge, 65-cm radiopaque catheter) introduced into the superior vena cava via the basilica vein for measurement of CVP. Each pressure was recorded with a disposable pressure transducer (Maxxim Medical, Athens, TX) positioned at the level of the right atrium in the midaxillary line. In addition, the catheters had extension tubes connected to a slow drip of heparinized normal saline (2 U/ml). A venous catheter (1.2 mm ID, 18 gauge) was inserted into the median antecubital vein for CBV expansion by infusing 25% human serum albumin solution. Arterial blood samples were obtained at each condition and stored in ice water until analyzed for hematocrit and potassium concentrations (model no. 1735, Instrumentation Laboratory, Lexington, MA).

CBR function.   The carotid-cardiac (carotid-HR) and carotid-vasomotor [carotid-mean arterial pressure (MAP)] responses were evaluated by plotting the peak changes in HR and MAP, respectively, against the estimated carotid sinus pressure (ECSP), which was calculated as MAP minus neck chamber pressure. Seven points of the CBR stimulus-response data were fitted to the logistic model described by Kent et al. (19). In many of our laboratory's previous investigations (23, 27, 28, 31, 32) in which we addressed the question of CBR resetting, the responses to NP and NS were not fit to the linear-model because the linear model did not provide estimates of threshold (THR), saturation (SAT), and Gmax, and, even though the linear model was highly significant, it underestimated the Gmax of CBR function and provided no insight into whether resetting had occurred (28). Hence the individual responses to the NP and NS stimuli were fit to the logistic function curve, variables were calculated, and the group data were averaged for assessment of CBR function during each condition. This function incorporates the following equation:

Formula
where HR or MAP is the dependent variable, A1 is the range of response of the dependent variable (maximum – minimum), A2 is the gain coefficient (i.e., slope), A3 is the carotid sinus pressure required to elicit equal pressor and depressor responses (centering point), and A4 is the minimum response of HR. The data were fit to this model by nonlinear least squares regression (using a Marquardt-Levenberg algorithm), which minimized the sum of squares error term to predict a curve of "best fit" for each set of raw data. The coefficient of variation for the overall fit of this model to the individual responses was 18% (32). The gain was calculated from the first derivative of the logistic function, and the Gmax was applied as the index of CBR responsiveness. THR, the point at which no further increase in the dependent variable occurred, despite reductions in ECSP, and SAT, the point at which no further decrease in the dependent variable occurred, despite increases in ECSP, were calculated as the maximum and minimum second derivatives, respectively, of the logistic function curve. For calculation of THR and SAT, we applied equations described by Chen and Chang (5): THR = –2.0/A2 + A3 and SAT = 2.0/A2 + A3. These calculations of THR and SAT are the carotid sinus pressure at which HR is within 5% of their maximal or minimal responses (32). The maximal and operating point gain were calculated as follows: Gmax = –A1·A2/4, where Gmax is that of the CBR function curve.

Statistics.   Statistical comparisons of physiological variables were made utilizing a repeated-measures two-way ANOVA with a 5 x 2 design for data presented in Tables 1 and 2 and a 3 x 2 design (condition x exercise) for analysis of CBR function across conditions of cardiopulmonary load. A Student-Newman-Keuls test was employed post hoc when interactions were significant. Statistical significance was set at P < 0.05, and results were presented as means ± SE. Analyses were conducted using SigmaStat (Jandel Scientific Software, SPSS, Chicago, IL).


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  		Table 1. Hemodynamic response to lower body negative pressure and the infusion of albumin at rest and during exercise

 

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  		Table 2. Response of blood values to lower body negative pressure and the infusion of albumin at rest and during exercise

 

   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
This study involved two protocols that manipulated the loading status of the cardiopulmonary baroreceptors during which CBR function was assessed. One protocol used LBNP to unload the cardiopulmonary baroreceptors, and the second protocol used human serum albumin infusion to load the cardiopulmonary baroreceptors at rest and during exercise. In response to LB16, the reduction in CVP was 2.6 ± 0.5 mmHg at rest and 3.0 ± 0.4 mmHg during exercise. In response to INF2, the increase in CVP was 2.4 ± 0.4 mmHg at rest and 4.6 ± 0.9 mmHg during exercise, respectively.

Comparisons between rest and exercise identified increases in HR, MAP, systolic and diastolic blood pressure, and pulse pressure (PP) (Table 1). Accordingly, carotid-HR and carotid-MAP baroreflex function curves were reset rightward and upward during exercise at each CVP associated with LB16 and INF2 without a change in Gmax (Figs. 2, 3, and 4). During LB16, an increase in HR was observed at rest (+7 ± 2 beats/min, P < 0.05) and during exercise (+14 ± 4 beats/min, P < 0.05). In addition, HR gradually increased with the INF2 at rest (+16 ± 4 beats/min, P < 0.05) and during exercise (+17 ± 4 beats/min, P < 0.05).


Figure 2
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  		Fig. 2. Carotid-heart rate (HR) baroreflex function curves at rest and during exercise (EX). Shown are carotid-HR (cardiac) stimulus-response curves at rest and during exercise under control (A and B; thin line), LB16 (A; thick line), and INF2 (B; thick line) conditions. Symbols denote actual group data for all subjects (means ± SE). {blacktriangleup}, Prestimulus operating point; {triangleup}, centering point; {circ}, carotid sinus threshold pressure; {square}, carotid sinus saturation pressure. ECSP, estimated carotid sinus pressure; bpm, beats/min. Lines represent mean data fitted to the logistic function model.

 

Figure 3
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  		Fig. 3. Carotid-mean arterial pressure (MAP) baroreflex function curves at rest and during exercise. Shown are carotid-MAP (vasomotor) stimulus-response curves at rest and during exercise under control (A and B; thin line), LB16 (A; thick line), and INF2 (B; thick line) conditions. Symbols denote actual group data for all subjects (means ± SE) and are as defined in Fig. 2 legend. Lines represent mean data fitted to the logistic function model.

 

Figure 4
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  		Fig. 4. Averaged maximal gain (Gmax) for the carotid-HR and -MAP baroreflex function curves. Shown are Gmax of carotid-HR (A; cardiac) and carotid-MAP (B; vasomotor) baroreflexes at rest and during exercise under control (con), LB16, and INF2 conditions. Bars represent the average Gmax of the logistic function model for all subjects (means ± SE). *Different from control, P < 0.05; #different from INF, P < 0.05.

 
Comparisons of the data of all subjects between the nonlinear analysis (Kent model) and the linear analysis identified a significant increase in the curve fit for the nonlinear compared with the linear, i.e., nonlinear vs. linear at control condition (carotid-HR; r = 0.989 ± 0.003 vs. 0.966 ± 0.007). The difference in the r values of nonlinear vs. linear was significant (P = 0.009) (carotid-MAP; r = 0.984 ± 0.005 vs. 0.944 ± 0.007). The difference in the r values of nonlinear vs. linear was significant (P = 0.001). In addition, by using our NP and NS technique, we employ a wide range of carotid sinus pressures (~120 mmHg), enabling us to identify the SAT and THR pressures of the baroreflex function curve. Thus linear regression analysis of the NP and NS technique responses would include these parameters in the calculation of the slope of the regression and, thereby, underestimates the sensitivity, or the Gmax, of the CBR. Indeed, the gains of the linear fit were one-half of those of the Kent model in the present study, i.e., nonlinear vs. linear at control condition (carotid-HR: –0.422 ± 0.057 vs. –0.221 ± 0.032 beats·min–1·mmHg–1, P = 0.002; carotid-MAP: –0.401 ± 0.034 vs. –0.201 ± 0.017 beats·min–1·mmHg–1, P < 0.001). During both LB16 and INF2 conditions, the carotid-HR baroreflex function curve was reset upward and rightward at rest and during exercise (Fig. 2). Additionally, the Gmax of carotid-HR baroreflex function curve was nonsignificantly increased in the LB16 condition at rest and during exercise (Fig. 4). Furthermore, INF2 did not significantly influence Gmax of carotid-HR baroreflex function curve at rest and during exercise.

The MAP during LB16 condition was not altered at rest or during exercise (P > 0.05). However, the Gmax of carotid-MAP baroreflex function curve during LB16 condition was increased at rest (+63 ± 25%) and during exercise (+69 ± 19%) (Figs. 3 and 4). During INF2 condition, MAP was unchanged at rest and during exercise (P > 0.05). However, the carotid-MAP baroreflex function curves were insignificantly reset downward and leftward at rest and during exercise (Fig. 3). In contrast to the LB16 condition, the Gmax of the carotid-MAP baroreflex function curve during the INF2 condition was decreased at rest (–8 ± 4%) and during exercise (–18 ± 5%) (P > 0.05). Because the effect of increasing CVP on CBR sensitivity was very small compared with the CBR sensitivity that occurred during the reductions in CVP, the relationship between CVP and Gmax of carotid-MAP baroreflex was nonlinear (Fig. 5).


Figure 5
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  		Fig. 5. Summary of the relationships between central venous pressure (CVP) and Gmax of carotid-HR (A; cardiac) or carotid-MAP (B; vasomotor) baroreflexes. Symbols denote actual group data for all subjects (means ± SE).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The findings of the present investigation provide new information regarding the interaction between CBV and its consequent load on the cardiopulmonary baroreceptors and the Gmax of the carotid-vasomotor baroreflex, both at rest and during submaximal exercise. In particular, the decreases in CBV induced by 16-Torr LBNP resulted in a marked increase in Gmax of the carotid-vasomotor baroreflex at rest and during exercise, whereas increases in CBV resulting from the infusion of human serum albumin had only a slight reduction in the Gmax of the carotid-vasomotor baroreflex at rest and during exercise. These findings indicate the presence of a possible SAT CBV, or cardiopulmonary baroreceptor load, at which the inhibitory interaction between CBV and carotid-vasomotor baroreflex sensitivity that occurs within the central nervous system (2, 13, 14, 34) has been maximized. The recognition that infusions of human serum albumin resulted in a Bainbridge reflex-mediated tachycardia (1), along with 16-Torr LBNP arterial baroreflex-mediated tachycardia at rest and during exercise, negated our ability to interpret the interaction between CBV and the carotid-cardiac baroreflex.

The CBR regulation of ABP during upright seating and dynamic exercise has been found to operate primarily via the carotid-vasomotor baroreflex (26, 27). The augmentation of the carotid-vasomotor baroreflex sensitivity during decreases in cardiopulmonary baroreceptor load have been reported at rest using LBNP (7, 30, 39) and head-up tilt (8, 29) and are supported by the findings of the present investigation. However, during exercise, a nonsignificant increase in operating gain of the cardiopulmonary baroreflex control of forearm vascular resistance (22) and Gmax of the carotid-vasomotor baroreflex (31) with reductions in CBV are in contrast to the marked and significant increases in Gmax of the carotid-vasomotor baroreflex of the present investigation. The differences in the increase in Gmax between the present investigation and the previous investigation using LBNP during exercise (31) performed in the same laboratory may be reflective of the differences in workload-induced changes in end-diastolic volumes (EDV) and subsequent resetting of the operating point of the cardiopulmonary baroreceptors (24). The previous investigation used workloads of 25% VO2 peak and HR of 84 beats/min (31), whereas the current investigation used workloads of 50% VO2 peak and 114 beats/min. The marked differences in the augmentation of Gmax of the carotid-vasomotor baroreflex as a result of the reduction in CBV in the two studies may reflect that the exercise-induced increase in CBV of the present investigation resulted in the cardiopulmonary baroreceptors being reset to a higher EDV and resulted in a greater afferent nerve traffic to the nucleus tractus solitarii (NTS). The greater CBV of the present investigation results in a greater inhibition of the sympathetic neural outflow from NTS than at the lower EDV (14) of the previous investigation (31). Subsequently, the LBNP reduction in CBV during the greater intensity exercise results in a greater removal of inhibitory afferent nerve traffic, emanating from the heart, arriving at the NTS.

In human subjects at rest, reductions in CBV result in cardiopulmonary baroreflex-mediated vasoconstriction (15, 42) and a facilitatory interaction between the CBR (30, 39). In patients with postural syncope, the facilitatory interaction between orthostatically mediated decreases in CBV and CBR sensitivity is absent (8). In conditions of heat stress, the resultant reduction in CBV attenuated the carotid-vasomotor baroreflex sensitivity (9). During prolonged exercise resulting in an ~1°C rise in core temperature and progressive reductions in CBV, the carotid-vasomotor response to NP was increased (23). The presence of a body temperature modulation of the interaction that exists between CBV and arterial baroreflex regulation of the vasculature further supports the existence of a central nervous system mechanism.

In contrast to hypovolemia, it has been reported that loading cardiopulmonary baroreceptors diminished arterial baroreflex responsiveness at rest in animals (37) and humans (4, 35, 36). When lower body positive pressure (LBPP) between 0 and 30 Torr was used to load the cardiopulmonary baroreceptors, the Gmax of carotid-HR and -MAP reflexes were negatively related to LBPP (36). However, LBPP stimulates muscle mechanoreceptors to increase ABP (12); thus the calculation of Gmax included the effect of activation of muscle mechanoreceptors. When cardiopulmonary load was increased by venous infusions of dextran, a significant attenuation of the CBR sensitivity was observed (35). In addition, Charkoudian et al. (4) demonstrated that small increases in CVP resulted in a decrease in the sensitivity of integrated baroreflex control of sympathetic nerve activity. In the present study, Gmax of carotid-MAP baroreflex function curve decreased at rest (–8 ± 4%) and during exercise (–18 ± 5%). However, these changes were not statistically significant. Importantly, the interaction between cardiopulmonary baroreceptor and carotid-MAP baroreflex function during central hypervolemia was much smaller than that observed during central hypovolemia at rest and during exercise, suggesting that the relationship between CBV and CBR sensitivity was nonlinear (Fig. 5). In addition, this relationship was not altered by exercise.

Potential limitations.   In unanesthetized humans and animals, the selective disengagement of the cardiopulmonary baroreceptors has proven to be difficult to achieve without some suspected stimulation of the arterial baroreceptors (33). For example, imaging data of the aortic arch's surface area during LBNP (38) or diameter determinations of the carotid artery during LBNP or head-up tilt (20) have identified reductions in surface area or diameter length, respectively. However, below LBNP of –20 Torr or head-up tilt of 60°, no efferent reflex responses in HR were observed (20, 38). In the present investigation, LBNP of –16 Torr resulted in +7 beats/min tachycardia at rest and a +14 beats/min tachycardia during exercise, indicating arterial baroreflex disengagement without significant decreases in MAP and PP. In addition, infusion of human serum albumin resulted in a Bainbridge reflex-mediated tachycardia, both at rest and during exercise. Collectively, these confounding large HR responses, especially during albumin infusion, compromised our ability to interpret the results regarding the carotid-cardiac baroreflex. Moreover, there was the possibility that disengagement of the arterial baroreceptors during LBNP selectively influenced the HR response and, along with an unrecognized effect of albumin infusion, influenced the carotid-vasomotor baroreflex function. However, as a tachycardia was present without changes in MAP and PP, its influence on carotid-vasomotor reflex function was thought to be minimal. In addition, we have documented the carotid-vasomotor reflex to be identified by changes in MAP independent of changes in HR (26, 27). By measuring CBR function during the steady-state hemodynamics of each condition of cardiopulmonary loading, we suggest that we have accounted for any changes in carotid-cardiac baroreflex activity on the vasculature.

During prolonged exercise at >50% maximum O2 uptake, increases in body temperature have been found to alter arterial baroreflex control of the vasculature (23, 40). In the present investigation, we did not measure core temperature, but, as the exercise was performed at 50% VO2 peak for <25 min in an ambient environment of 25 ± 1°C with the subject being cooled by airflow across the thorax, we contend that the heat build-up was minimal.

Another possible limitation to our interpretation of the results involves possible changes in osmolality that occur as a result of the infusion of human serum albumin. It has recently been shown that increases in CVP induced by head-down tilt and saline infusion decreased the operating point gain of the arterial-MSNA reflex without a change in plasma osmolality (4). In another study when plasma osmolality was changed from 287 to 290 mosmol/kg, arterial MSNA operating point gain was enhanced; however, when plasma osmolality was increased a further 1 mosmol/kg, arterial MSNA operating point gain was reduced to control values (3). Although we did not measure plasma osmolality, our hematocrit changes following INF2 (Table 2) indicate a relative increase in plasma osmolality, which may have been involved in the nonsignificant reduction in Gmax of carotid-vasomotor reflex. However, data reporting increases in osmolality, independent of increases in cardiopulmonary loading, appear to suggest that it is cardiopulmonary load that predominates in reducing arterial MSNA operating point gain (4). Therefore, we conclude that the influence of the increased plasma osmolality on changes in carotid-vasomotor baroreflex function in the present study is minimal.

In summary, the data of the present investigation provide evidence of a nonlinear interaction between carotid-vasomotor baroreflex function and CBV at rest and during exercise. The presence of this interaction at rest and during exercise supports the concept of an acute resetting of the cardiopulmonary baroreflex to enable regulation of cardiac filling, especially during central hypovolemia.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This study was supported in part by American Heart Association Grant 0465104Y and National Heart, Lung, and Blood Institute Grant 045547.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors appreciate the time and effort expended by all of the volunteer subjects. We thank Jill Kurschner and Joseph Raven for expert technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: S. Ogoh, Dept. of Integrative Physiology, Univ. of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107 (e-mail: sogoh{at}hsc.unt.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.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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