| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Noll Physiological Research Center, The Pennsylvania State University, University Park, Pennsylvania 16802; and 2 Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center and Presbyterian Hospital of Dallas, Dallas, Texas 75231
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
METHODS AND PROCEDURES
RESULTS
DISCUSSION
REFERENCES
|
|---|
Cardiovascular deconditioning reduces
orthostatic tolerance. To determine whether changes in autonomic
function might produce this effect, we developed stimulus-response
curves relating limb vascular resistance, muscle sympathetic nerve
activity (MSNA), and pulmonary capillary wedge pressure (PCWP) with
seven subjects before and after 18 days of 
6° head-down bed rest.
Both lower body negative pressure (LBNP; 15 and 30 mmHg) and rapid
saline infusion (15 and 30 ml/kg body wt) were used to produce a wide variation in PCWP. Orthostatic tolerance was assessed with graded LBNP
to presyncope. Bed rest reduced LBNP tolerance from 23.9 ± 2.1 to
21.2 ± 1.5 min, respectively (means ± SE, P = 0.02). The MSNA-PCWP relationship was unchanged after bed rest,
though at any stage of the LBNP protocol PCWP was lower, and MSNA was greater. Thus bed rest deconditioning produced hypovolemia, causing a
shift in operating point on the stimulus-response curve. The relationship between limb vascular resistance and MSNA was not significantly altered after bed rest. We conclude that bed rest deconditioning does not alter reflex control of MSNA, but may produce
orthostatic intolerance through a combination of hypovolemia and
cardiac atrophy.
vasoconstriction; adrenergic nervous system; sympathetic reflex
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS AND PROCEDURES
RESULTS
DISCUSSION
REFERENCES
|
|---|
ORTHOSTATIC INTOLERANCE OCCURS after prolonged hypodynamic periods with reduced gravitational gradients, such as bed rest deconditioning and spaceflight (5, 27). These stresses lead to changes throughout the cardiovascular system, including hypovolemia (16), reductions in carotid-cardiac baroreflex responsiveness (7, 8, 11, 17, 19), and increased venous pooling (9). An equally attractive hypothesis is that adrenergically mediated vascular control changes in a way that diminishes vasoconstriction. Several reports suggest that sympathetic nervous system responsiveness may be attenuated after spaceflight in astronauts prone to orthostatic intolerance, evidenced by smaller increases in plasma levels of norepinephrine (18) and systemic vascular resistance (5) on standing after spaceflight compared with those without orthostatic intolerance. These changes are thought to result from diminished release of norepinephrine from sympathetic nerve terminals rather than changes in norepinephrine clearance (21, 33, 39). However, the mechanisms underlying these adaptations are not fully defined.
Recently, we (27) demonstrated that 18 days of bed rest
deconditioning with 6° head-down tilt bed rest (HDBR) resulted in
cardiac atrophy associated with reduced orthostatic tolerance, as
indicated by 1) an increase in the slope of the Starling
curves that relate stroke volume (SV) to left ventricular end-diastolic pressure and 2) a reduction in the zero pressure intercept
of the left ventricular diastolic pressure-volume relationship. These findings reveal that nonneural mechanisms can contribute to orthostatic intolerance in otherwise healthy individuals. However, others (37) have shown that resting muscle sympathetic nerve
activity (MSNA) increases in individuals who become susceptible to
orthostatic intolerance after HDBR, whereas the change in MSNA
associated with head-up tilt becomes blunted. Thus changes in neural
control of vascular resistance, in addition to nonneural mechanisms,
may contribute to orthostatic intolerance after HDBR.
Two possibilities could explain the diminished MSNA response to head-up tilt. First, the increase in resting MSNA observed in orthostatically intolerant individuals, in combination with cardiac atrophy, could predispose subjects to the hyperadrenergic variant of vasodepressor syncope. Alternatively, HDBR could attenuate MSNA and vasoconstriction during orthostatism by decreasing baroreflex responsiveness. Accordingly, we examined the changes in baroreflex control of sympathetic activity and regional vascular tone by studying the responses of MSNA, limb vascular resistance, and hemodynamic parameters during an 18-day period of HDBR to mimic comparable periods of space flight.
We hypothesized that HDBR would reduce the slope of baroreflex-mediated stimulus-response relationships, which were characterized as changes in MSNA and vascular resistance in response to decreases and increases in left ventricular end-diastolic pressure produced by graded lower body negative pressure (LBNP) and rapid infusion of saline, respectively. This paradigm produces physiological changes in filling pressure, heart rate (HR), and SV that elicit reflex increases and decreases in MSNA from the combined effect of cardiopulmonary and carotid baroreceptors (26, 45). Our results reveal that sympathetic nervous system responsiveness (slope of the MSNA stimulus-response curve) does not change after HDBR. Rather, the operating point on the stimulus-response relationship is shifted to lower cardiac filling pressures.
| |
METHODS AND PROCEDURES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS AND PROCEDURES
RESULTS
DISCUSSION
REFERENCES
|
|---|
Subjects
Twelve healthy subjects (11 men, 1 woman) were studied before and after HDBR deconditioning. The physical characteristics included a mean age of 24 ± 2 (range 18-35), height of 185 ± 23 cm, and weight of 79 ± 3 kg. No subject smoked, used recreational drugs, or had significant chronic medical problems. The subjects were excluded if they were endurance athletes (25) or exercised for more than 30 min/day, 3 times/wk with either dynamic or static exercise. The subjects were screened for medical history and with a physical examination, resting electrocardiogram (ECG), and resting echocardiogram, and were excluded if high-quality two-dimensional echocardiographic images could not be obtained. Body composition was obtained by densitometry with the use of underwater weighing (1). All of the subjects provided voluntary informed consent; protocols were approved by the Institutional Review Boards of both the University of Texas Southwestern Medical Center and the Presbyterian Hospital of Dallas.Measurements
Hemodynamics. A 6-Fr, balloon-tipped, flow-directed pulmonary arterial catheter (Swan-Ganz, Baxter) was placed under fluoroscopic guidance through an antecubital vein into the pulmonary artery. With the balloon inflated, the catheter was advanced into the pulmonary capillary wedge (PCW) position, which was confirmed both fluoroscopically and by the presence of characteristic pressure waveforms. Intracardiac pressures were referenced to atmospheric pressure, with the pressure transducer zero set at 5 cm below the sternal angle in the supine position. Pressure waveforms were amplified (model 78534A, Hewlett-Packard; and model ASC909, Astromed), transduced (Transpac IV, Abbott), and displayed on a strip-chart recorder (model MT95000, Astromed) with ±0.5 mmHg resolution. The mean PCW pressure (PCWP) was determined visually at end expiration and was used as an index of left ventricular end-diastolic pressure.
HR was monitored from lead II of the ECG. Arterial pressure was monitored by optoplethysmography of the middle digit (Finapres, Ohmeda). The arterial pressure waveform was integrated in real time at a rate of 200 Hz and stored with the instantaneous HR for every beat throughout the study. Mean HR and blood pressure (BP) were calculated from the time-weighted average of these data. Blood pressure was also measured in the arm intermittently by electrosphygmomanometry (model 4240, Suntech) with a microphone placed over the brachial artery and the Korotkoff sounds gated to the ECG. Limb blood flow was determined by venous occlusion plethysmography. During LBNP trials, measurements were made by using the forearm to avoid interference with the legs. During volume infusion, measurements were made by using the calf because saline was being infused through the pulmonary artery catheter and a catheter placed in the antecubital vein of the contralateral arm. The use of different limbs was justified on the basis of previous reports (32, 34) demonstrating little difference in neural control of arm and leg blood flow. Changes in limb volume were transduced with the use of dual-strand mercury-in-Silastic strain gauges (22), amplified (model EC-4; Hokansen), and displayed on a strip-chart recorder for post hoc analysis. Venous occlusion pressures of 50 mmHg were employed, and foot or hand blood flow was excluded from the measurement with an arresting cuff placed around the ankle or wrist inflated to 250 mmHg. Limb vascular resistance was calculated as the quotient of mean arterial pressure and limb blood flow. Arm and leg data were combined by normalizing responses to the resting blood flow of the respective limb. Cardiac output (
c) was measured by foreign gas
rebreathing, using acetylene as the soluble and helium as the insoluble
gas (44). Pulmonary blood flow was calculated from the
disappearance rate of acetylene in expired air, measured with a mass
spectrometer (model MGA1100; Marquette), after adequate mixing was
confirmed by a stable helium concentration. This method has been
validated in our laboratory against standard invasive techniques,
including thermodilution and direct Fick, over a range of cardiac
outputs from 2.75 to 27.00 l/min, with an r2 of
0.91 and standard error of estimate of 1.1 l/min
(30). SV was calculated as the quotient of
c and the HR measured during rebreathing. Total
peripheral resistance (TPR) was calculated as the quotient of the
auscultatory blood pressure and c.
Muscle sympathetic nerve activity.
Multiunit postganglionic recordings of MSNA were made using
200-µm-diameter stainless steel microelectrodes of 2-3 M
impedance (Frederick Haer) inserted percutaneously into muscle nerve
fascicles of the peroneal nerve. A recording electrode was placed in
the peroneal nerve at the fibular head or the popliteal fossa, and a
reference electrode was placed subcutaneously 2-3 cm from the recording electrode. The nerve signal was amplified (total
amplification 40,000-80,000), band-pass filtered (high pass of
0.3-0.7 kHz and low pass of 2-3 kHz), and then full-wave
rectified and smoothed with a resistance-capacitance circuit (time
constant, 0.1 s) to produce a recording of "integrated" MSNA.
Procedures
Protocol.
All of the experiments were performed in the morning, at least 2 h
after a light breakfast, and more than 12 h after the last caffeinated or alcoholic beverage, in a quiet, environmentally controlled laboratory, with an ambient temperature of 25 ± 1°C. After at least 30 min of quiet rest in the supine position, plasma volume was measured by using Evans blue dye (15). To
decrease and increase ventricular filling, we used a sequence of LBNP
and rapid saline infusion as previously reported (26). The
supine position was maintained throughout the experiment. LBNP was
performed by placing the subject in a Plexiglas box, sealed at the
level of the iliac crests. Suction was provided by a vacuum pump
controlled with a variable autotransformer. Limb blood flow, HR, BP,
and MSNA were recorded at baseline and then after 3 min each of LBNP at
15 and 30 mmHg.
c and PCWP immediately followed the
beat-to-beat recordings. The LBNP was then released. After baseline measurements were repeated to confirm return to hemodynamic
steady-state (usually 20-30 min), warm, isotonic saline (37°C)
was infused rapidly at a rate of 100 ml/min. Measurements were repeated
after 15 ml/kg and 30 ml/kg had been infused.
Seventy-two hours after this session, maximal orthostatic tolerance was
measured using a standardized, graded LBNP test. No invasive
measurements were made during this protocol. A cumulative stress index
(CSI) was calculated for this specific protocol by summing the product
of negative pressure and duration at each level of LBNP. Both CSI and
the time achieved with the LBNP protocol were used as continuous
measures of orthostatic tolerance. LBNP was begun at 15 mmHg for 5 min (CSI = 75 mmHg · min) and then increased to 30 and
40 mmHg for 5 min each (CSI = 225 and 445 mmHg · min,
respectively), followed by an increase in LBNP by 10 mmHg every 3 min
until signs or symptoms of presyncope were achieved. Presyncope was
defined as one of the following: 1) a decrease in systolic
blood pressure (SBP) below 80 mmHg; 2) a decrease in SBP
below 90 mmHg associated with symptoms of light headedness, nausea, or
diaphoresis; or 3) progressive symptoms of lipothymia
accompanied by subject request to discontinue the test. For the 24 tests, a true hemodynamic endpoint was reached in the majority of
circumstances (95%).
Microgravity simulation with HDBR.
After the initial series of experiments, head-to-foot gravitational
gradients were reduced by placing the subjects at complete bed rest,
with 6° head-down tilt. The subjects were allowed to elevate on one
elbow for meals, but otherwise were restricted to the head-down
position at all times. Subjects were housed in the General Clinical
Research Center at University of Texas Southwestern Medical Center and
given a standard diet, which consisted of 2,827 ± 609 cal/day,
including 5.2 ± 1.2 g/day of sodium. Fluids were allowed ad
libitum, but all fluid intake and urine output were carefully recorded.
The same series of experiments were repeated after 2 wk of HDBR. The
head-down tilt was maintained during the 72 h between the
measurement of MSNA and the orthostatic tolerance test, for a total of
18 days.
Statistical Analyses
Resting variables were compared by using paired Student's t-tests. Nonlinear regression was used to model the relationship between limb vascular resistance and MSNA as a first-order exponential (SigmaPlot, version 2.1, Jandel Scientific). Data collected during the infusion/LBNP protocol were compared by using two-factor (filling pressure × deconditioning) repeated-measures analysis of variance. Significant differences were probed post hoc by using t-tests with the Bonferroni correction for multiple comparisons. In all cases, the probability of rejecting the null hypothesis (no difference with changes in filling pressure or after deconditioning) was set at 5%.| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS AND PROCEDURES
RESULTS
DISCUSSION
REFERENCES
|
|---|
Figure 1 illustrates the dramatic
changes in MSNA that could be obtained from the use of volume infusion
and LBNP to alter cardiac filling. In some cases, spontaneous
MSNA was virtually abolished during volume infusion, but could still be
elicited with breath holding or a Valsalva maneuver. Unfortunately,
complete recordings for all segments of the protocol (i.e., baseline,
LBNP, and saline infusion) could not be obtained for two subjects
before HDBR and three other subjects after HDBR because of shifts in electrode position or failure to meet signal-to-noise criteria. As a
result, only seven complete sets of paired data were available for
analysis. Thus results are reported only for this subpopulation of
subjects; the hemodynamic data for the complete set of subjects are
summarized in our related work (27). A practical result of
the missing MSNA data was that the critical difference in MSNA that
could be identified (assuming a statistical power of 0.8) increased
from 7 to 10 bursts/min. This compares favorably with other published
reports (36).
|
Hemodynamics and Orthostatic Tolerance
Resting hemodynamic data are reported in Table 1. Eighteen days of bed rest resulted in a significant decrease in LBNP tolerance, expressed as CSI (P < 0.001). Although individual LBNP tolerance was variable, ranging from 492 to 1,775 mmHg · min before HDBR and 467 to 1,318 mmHg · min after HDBR, the two levels of LBNP used for hemodynamic comparisons (corresponding to CSI of 75 and 225 mmHg · min, respectively) were well tolerated with no evidence of hemodynamic instability or presyncope. The decrease in LBNP tolerance was associated with a 10% decrease in plasma volume (P = 0.06), and a decrease in resting PCW pressure (P < 0.05). SV was lower at baseline in the supine position (P < 0.001).
|
Changes in response to perturbations in cardiac filling are shown
graphically in Fig. 2. SV decreased
significantly at both levels of LBNP (P < 0.05 for
each comparison) and fell to a greater extent after HDBR
(P < 0.01). HR was unchanged at baseline but tended to
increase at low-level LBNP and was significantly increased at 30 mmHg
LBNP. After HDBR, HR tended to be higher than before HDBR at 15 mmHg,
(P = 0.07), and was elevated significantly more at 30
mmHg (P = 0.006). Cardiac output was thereby well
maintained at rest and mild LBNP, although cardiac output was lower at
LBNP 30 mmHg after bed rest (P < 0.05). Of note, HR
also increased during saline infusion, both before and after bed rest,
consistent with an active Bainbridge reflex in humans, as we previously
reported (29). After bed rest, this response was
significantly greater at the higher level of volume infusion
(P < 0.05).
|
LBNP produced significant reductions in SBP (P < 0.001) and pulse pressure (PP; P < 0.001) without a change in diastolic blood pressure, whereas both SBP and PP increased during volume infusion (P < 0.001). However, neither systolic, diastolic, pulse, nor mean blood pressure responses to LBNP and volume infusion were different after HDBR.
MSNA and Limb Vascular Resistance
Changes in MSNA in response to changes in left ventricular filling pressure are displayed in Fig. 3. Despite the reduction in resting PCW pressure, baseline MSNA, expressed in terms of bursts per minute, was unchanged after bed rest. During LBNP, when left ventricular filling was decreased after bed rest, MSNA was appropriately increased compared with before bed rest (P < 0.05 for15 mmHg). In fact, the relationship
between PCW pressure and MSNA followed a curvilinear relationship that
was indistinguishable between the two conditions. When MSNA was
expressed in terms of total nerve activity (as a percentage of change
from baseline), MSNA was increased at 15 and 30 mmHg compared with
before bed rest (P < 0.05 in both cases).
|
The changes in resting limb vascular resistance after bed rest were
heterogenous; whereas resting calf resistance increased after HDBR,
forearm vascular resistance did not change (Table 1). This finding is
consistent with the observation that TPR was significantly elevated
over pre-bed rest levels at baseline and each level of LBNP. During
LBNP, the increase in forearm vascular resistance was not greater
despite a greater rise in MSNA (Figs. 3 and 4). Thus although total
MSNA increased during LBNP of 30 mmHg to 417 ± 80% of baseline
after bed rest compared with 280 ± 38% before bed rest
(P < 0.05), the increase in arm vascular resistance
was no different: 47 ± 13% or 11.2 ± 4.4 peripheral resistance unit (PRU) after bed rest versus 42 ± 6% or 11.5 ± 3.0 PRU before bed rest (P = not significant).
Similarly, during volume infusion the decrease in leg vascular
resistance was not different after bed rest compared with before bed
rest (56 ± 3% or 33.2 ± 3.4 PRU after vs. 48 ± 7%
or 22.3 ± 5.8 PRU, P = 0.08). When arm and limb
data were related to MSNA, no differences in the slope of the
relationships for either limb could be identified after HDBR (Fig.
4), suggesting that vascular smooth
muscle responses to sympathetic stimulation were not affected by bed
rest deconditioning.
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS AND PROCEDURES
RESULTS
DISCUSSION
REFERENCES
|
|---|
Three novel observations were made in this investigation. First, the relationship between MSNA and cardiac filling pressure is fundamentally unchanged after 18 days of HDBR deconditioning. Although MSNA was augmented during LBNP after HDBR, this response was consistent with the greater reduction in SV and cardiac filling pressure attendant to deconditioning; i.e., sympathetic neural responses were altered appropriately for the cardiac adaptations produced by HDBR. Therefore, we rejected the hypothesis that impaired baroreflex regulation of MSNA is a primary cause of orthostatic intolerance after bed rest.
Second, MSNA responses after HDBR are difficult to interpret without being referenced to a stimulus variable (e.g., left ventricular end-diastolic pressure). Assuming that measurments were made during periods of hemodynamic stability, one might speculate that previous HDBR studies (28, 36-38) reported discordant information about MSNA because the loading conditions of cardiac mechanoreceptors differed at the time of study. In this investigation we expanded knowledge of reflex regulation of MSNA to the greatest variation of cardiac filling pressure yet reported, which more than doubles the range of previously published data (45) and reveals the curvilinear nature of the filling pressure-MSNA stimulus-response relationship. Though several reports (24, 31, 41) demonstrate increases in MSNA in response to diminished filling pressure, this information has been paired only rarely with increases in filling pressure (45). The results from the present investigation reveal that supine humans can reduce MSNA to extremely low levels with further increases in filling pressure, indicating that before or after HDBR, humans operate within a range of cardiac filling pressures that necessitates continuous regulation of vascular resistance via adrenergic mechanisms.
Third, we have provided the first data relating sympathetic neural and peripheral vascular responses to assess the effects of sympathetic innervation of vascular smooth muscle after HDBR. These relationships were not altered after bed rest, suggesting that neither the release of norepinephrine from sympathetic nerve terminals nor receptor-mediated events in vascular smooth muscle were significantly affected by inactivity and diminished gravitational stress. Thus we did not identify a change in sympathetically mediated regulation of the neuro-effector junction that could account for the reduction in orthostatic tolerance that results from HDBR.
How Would Baroreflex Responsiveness Affect Orthostatic Tolerance?
During an orthostatic challenge the prevailing level of MSNA is largely established by the combined action of cardiopulmonary and arterial baroreflex disinhibition. Therefore, baroreflex responsiveness can be assessed by relating a stimulus variable (cardiac filling pressure or blood pressure) to the MSNA response. Because orthostatic intolerance increases after HDBR, we hypothesized, like others, that MSNA would be lower during an orthostatic challenge after HDBR (37). Changes in baroreflex regulation of MSNA could elicit this response by at least one of three potential mechanisms, depicted conceptually in Fig. 5. First, the stimulus-response relationship could move leftward and/or downward, so that a given stimulus would result in a lower response without a change in slope (Fig. 5A). This is the classic definition of "resetting" to lower tonic sympathetic activity. Second, the slope of the stimulus-response relationship could decrease (Fig. 5B), which has been defined classically as a reduction in reflex "sensitivity" or "responsiveness." Third, the stimulus-response relationship could be unaltered, but a new operating point could be established along a less steep portion of the curve (Fig. 5C).
|
Figure 3 reveals that HDBR did not alter the shape of the MSNA stimulus-response relationship. The only notable change can be categorized as a shift in operating point like Fig. 5C, but with one important difference: at any level of LBNP or volume infusion, PCWP tended to be lower after HDBR, and MSNA responses were appropriately higher. Thus the form of the stimulus-to-response curve was not changed; rather, the operating point was shifted leftward because of the combined effect of hypovolemia (reduction in plasma volume) and cardiac atrophy (27). This finding is consonant with other reports that MSNA responses to head-up tilt are not changed after HDBR (28, 38).
In this report we described baroreflex responsiveness utilizing the PCWP-MSNA stimulus-response relationship. We chose to relate MSNA to PCWP for several reasons. First, PCWP approximates left ventricular end-diastolic pressure, thus representing one of the most accurate methods available to assess left ventricular filling pressure in humans. Second, the left ventricle is richly populated with cardiac mechanoreceptors; deactivation of the mechanoreceptors may disinhibit vasoconstriction during hypovolemia. Moreover, vasodepressor reflexes, such as the von Bezold-Jarisch reflex, originate from the left ventricle (4). Third, measurements of PCWP are independent of geometric assumptions needed to calculate another index of ventricular mechanoreceptor activation (left ventricular end-diastolic volume).
Though it is logical to employ PCWP as a stimulus variable, our findings should be interpreted judiciously in the context of baroreflex regulation for the following reasons. First, both ventricular pressure and volume contribute to regional ventricular wall stress (the likely stimulus to ventricular mechanoreceptors). Second, left ventricular compliance decreases after HDBR because of cardiac atrophy (27). Finally, one might hypothesize that the distribution of mechanoreceptors in the left ventricle would be altered by HDBR (though we have no direct evidence that this hypothesis is correct). Thus the specific HDBR-induced changes in ventricular geometry and morphology that might affect mechanoreceptor activation have yet to be determined accurately.
Orthostatic tolerance, measured by tolerance to progressive LBNP, decreased after HDBR, as has been reported after actual (5, 18) or simulated (2, 3, 6, 8) spaceflight deconditioning. Consistent with previous reports (16), HR was further elevated during mild LBNP after HDBR. This response is consistent with the hypovolemia we noted. Others have suggested that carotid-cardiac baroreflex responsiveness decreases after HDBR (7, 8, 11) or spaceflight (19). Though the magnitude of tachycardia may be blunted by this mechanism, the consistently greater orthostatic HR reported after HDBR and spaceflight (5, 18, 37) suggest that downregulation of baroreflex control of HR is not a primary mechanism of orthostatic intolerance in this population.
Is Sympathetic Activation Less Likely to Cause Vasoconstriction after HDBR?
Diminished adrenergic activity has been hypothesized to contribute to the diuresis and orthostatic intolerance that accompanies HDBR (33). Measurements of plasma and urinary catecholamines during HDBR are consistent with this hypothesis (20, 21). However, analysis of sympathetic activity using MSNA are more conflicting. After HDBR, resting MSNA has been reported to increase (28), decrease (36), or remain unchanged (38). In this investigation, we were unable to identify any statistically significant changes in resting MSNA after HDBR, despite the use of extremely sensitive criteria to ensure that all MSNA bursts would be counted (signal-to-noise ratio of band-pass filtered MSNA). One might speculate that hydration state could vary sufficiently between different studies to cause minor shifts in operating point on the stimulus-response relationship, changing resting MSNA. Furthermore, we can only assume that subject postures and hemodynamic stability were maintained in other investigations. Thus without precise knowledge of posture, hemodynamics, and cardiac filling pressure (i.e., stimulus-response characteristics) of the subject groups in the aforementioned studies, further comparison between investigations is equivocal.Orthostatically intolerant astronauts (i.e., those unable to complete a 10 min "stand test") have lower levels of systemic vascular resistance (5) and plasma catecholamines (18) compared with those who can complete the test. Yet subjects classified as orthostatically intolerant by comparable criteria have similar levels of MSNA during head-up tilting after HDBR compared with those classified as tolerant (37). This apparent discrepancy can be reconciled if one hypothesizes that central control of sympathetic discharge is not altered by HDBR, but that neuronal release of norepinephrine, or its effect on vascular smooth muscle, is reduced after HDBR.
The closely coupled relationship between MSNA and limb vascular
resistance has been well established (35, 45).
Accordingly, we related the changes in forearm and calf vascular
resistance to MSNA over a wide range of filling pressure. Whether
compared as absolute (Fig. 4) or relative values, we were unable to
detect any difference in the relationship between MSNA and limb
vascular resistance after HDBR. This finding is consistent with other
reports demonstrating that leg vascular responses to infused
-adrenergic agonists change neither after spaceflight (C. G. Blomqvist, personal communication) nor after bed rest deconditioning
(10). Thus the effects of norpinephrine on limb vascular
smooth muscle contraction did not seem to be affected by HDBR. However,
TPR was greater at rest and during LBNP after HDBR. Therefore we cannot
exclude the possibility that sympathetic regulation of regional
vascular beds other than those we studied were affected by HDBR, though the particular region(s) remain unidentified at this time.
We can only speculate why our findings differ from the spaceflight findings mentioned above, but several points deserve consideration. First, as mentioned above, TPR such as reported by Buckey et al. (5) includes other circulations not studied in the present investigation. Second, assessments of sympathetic activity by using plasma catecholamines are highly dependent on sampling time, which may be delayed in presyncopal subjects, biasing data to low absolute values. Third, the "intolerant" subjects reported by others (5, 18) may not have been hemodynamically stable at the time of sampling; different than our subjects.
Limitations
MSNA analysis. We quantified MSNA as burst frequency because the recorded amplitude of spontaneous MSNA is influenced by position of the recording electrode relative to the fascicles being recorded (14, 40). Thus important information about MSNA amplitude could not be compared directly, a traditional drawback to sympathetic microneurography. Rather, we related total MSNA (i.e., frequency × amplitude) to baseline (initial) values to normalize for changes in MSNA amplitude associated with differences in electrode position that might occur with the test-retest experimental design. With the use of either approach (burst frequency or percentage change in total MSNA) we identified a greater MSNA response to LBNP consistent with a hyperadrenergic, hypovolemic state.
Interpretation of stimulus-to-response relationships.
What baroreceptor population was responsible for the reflex adjustment
of MSNA as filling pressure was changed? It would be improper to
conclude that these curves represent either cardiopulmonary or carotid
stimulus-response characteristics exclusively. Because filling
pressure, SV, and HR changed concomitantly during LBNP and volume
infusion, both carotid and cardiopulmonary baroreflexes were engaged.
Thus the MSNA responses described here could result from
cardiopulmonary baroreflex activity associated with changing central
blood volume, and/or arterial baroreceptor activity stimulated by
alterations of SV and arterial pulsatility. In fact, the degree of
arterial and cardiopulmonary baroreflex involvement may be indeterminate in humans; even mild (5 mmHg) LBNP dramatically reduces
aortic dimensions (42). Thus the curves presented here are
based on the recognized baroreflex-mediated association between MSNA,
vascular resistance and cardiac filling pressure (45), but
the relative contribution of cardiopulmonary and arterial baroreflexes
cannot be ascertained.
Arm and leg blood flow.
The decision to combine arm and leg blood flows to determine limb
vascular responses to changes in filling pressure is subject to some
controversy. For example, Essandoh et al. (13) reported differential effects of low-level (less than 20 mmHg) LBNP on calf
and forearm blood flow, although a similar degree of vasoconstriction was present when LBNP was increased further. Because of the complexity of the experimental design in the present investigation, the same limb
could not be used for both volume infusion and LBNP trials, i.e., LBNP
precluded measurement of calf blood flow, and catheter use during
volume infusion prevented the measurement of forearm blood flow.
Furthermore, because baseline vascular resistance is different between
the two limbs (12, 23, 45), responses could be merged and
compared only when normalized to their respective baseline value. Two
lines of evidence suggest that the approach is valid for the present
study. First, the relative distribution of MSNA to arm and leg does not
vary when cardiac filling pressure is reduced (32).
However, we cannot be certain that this holds true after HDBR. Second,
MSNA and vascular resistance respond similarly between the calf and
forearm during sustained LBNP (45), and vascular
resistance responds similarly in both limbs during steady-state
exercise (43). Because of the nonspecific variation in
resting forearm and calf vascular resistance, and the differential effect of HDBR on these values, we chose to present data for each limb
independently in Fig. 4. For either limb, the slope of the limb
vascular resistance-MSNA relationship was unchanged after HDBR,
suggesting that HDBR did not alter the effect of norepinephrine release
on vascular smooth muscle.
| |
ACKNOWLEDGEMENTS |
|---|
The authors thank Robyn Etzel, Stacey Blaker, Kevin Harper, and Susie McMinn for technical support. The authors also thank the staff of the General Clinical Research Center at the University of Texas Southwestern Medical Center for outstanding care, and the subjects for their cheerful cooperation.
| |
FOOTNOTES |
|---|
This work was supported by National Aeronautics and Space Administration Center for Outreach, Research and Training Grant NGW-3582 (to C. G. Blomqvist), National Institutes of Health Grant MO1-RR006633, and National Aeronautics and Space Administration Grant NAGW3489 (J. A. Pawelczyk).
Address for reprint requests and other correspondence: J. A. Pawelczyk, Noll Physiological Research Center, The Pennsylvania State University, 119 Noll Laboratory, University Park, PA 16802 (E-mail: jap18{at}psu.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 10 December 1999; accepted in final form 3 January 2001.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS AND PROCEDURES
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Akers, R,
and
Buskirk ER.
An underwater weighing system utilizing "force cube" transducers.
J Appl Physiol
26:
649-652,
1969
2.
Arbeille, P,
Gauquelin G,
Pottier JM,
Pourcelot L,
Guell A,
and
Gharib C.
Results of a 4-week head-down tilt with and without LBNP countermeasure. II. Cardiac and peripheral hemodynamics-comparison with a 25-day spaceflight.
Aviat Space Environ Med
63:
9-13,
1992[Medline].
3.
Beck, L,
Baisch F,
Gaffney FA,
Buckey JC,
Arbeille P,
Patat F,
ten Harkel AD,
Hillebrecht A,
Schulz H,
and
Karemaker JM.
Cardiovascular response to lower body negative pressure before, during, and after ten days head-down tilt bedrest.
Acta Physiol Scand Suppl
604:
43-52,
1992[Medline].
4.
Bishop, VS,
Malliani A,
and
Thoren P.
Cardiac mechanoreceptors.
In: Handbook of Physiology. The Cardiovascular System. Peripheral Circulation and Organ Blood Flow. Bethesda, MD: Am. Physiol. Soc, 1983, sect. 2, vol. III, pt. 2, chapt. 15, p. 497-556.
5.
Buckey, JCJ,
Lane LD,
Levine BD,
Watenpaugh DE,
Wright SJ,
Moore WE,
Gaffney FA,
and
Blomqvist CG.
Orthostatic intolerance after spaceflight.
J Appl Physiol
81:
7-18,
1996
6.
Butler, GC,
Xing HC,
Northey DR,
and
Hughson RL.
Reduced orthostatic tolerance following 4 h head-down tilt.
Eur J Appl Physiol
62:
26-30,
1991[ISI].
7.
Convertino, VA,
Doerr DF,
Eckberg DL,
Fritsch JM,
and
Vernikos-Danellis J.
Carotid baroreflex response following 30 days exposure to simulated microgravity.
Physiologist
32:
S67-S68,
1989[Medline].
8.
Convertino, VA,
Doerr DF,
Eckberg DL,
Fritsch JM,
and
Vernikos-Danellis J.
Head-down bed rest impairs vagal baroreflex responses and provokes orthostatic hypotension.
J Appl Physiol
68:
1458-1464,
1990
9.
Convertino, VA,
Doerr DF,
and
Stein SL.
Changes in size and compliance of the calf after 30 days of simulated microgravity.
J Appl Physiol
66:
1509-1512,
1989
10.
Convertino, VA,
Polet JL,
Engelke KA,
Hoffler GW,
Lane LD,
and
Blomqvist CG.
Evidence for increased 
-adrenoreceptor responsiveness induced by 14 days of simulated microgravity in humans.
Am J Physiol Regulatory Integrative Comp Physiol
273:
R93-R99,
1997
11.
Eckberg, DL,
and
Fritsch JM.
Influence of ten-day head-down bedrest on human carotid baroreceptor-cardiac reflex function.
Acta Physiol Scand Suppl
604:
69-76,
1992[Medline].
12.
Eklund, B,
Kaijser L,
and
Knutsson E.
Blood flow in resting (contralateral) arm and leg during isometric contraction.
J Physiol (Lond)
240:
111-124,
1974
13.
Essandoh, LK,
Houston DS,
Vanhoutte PM,
and
Shepherd JT.
Differential effects of lower body negative pressure on forearm and calf blood flow.
J Appl Physiol
61:
994-998,
1986
14.
Fagius, J,
and
Wallin BG.
Long-term variability and reproducibility of resting human muscle nerve sympathetic activity at rest, as reassessed after a decade.
Clin Auton Res
3:
201-205,
1993[Medline].
15.
Foldager, N,
and
Blomqvist CG.
Repeated plasma volume determination with the Evans Blue dye dilution technique: the method and a computer program.
Comput Biol Med
21:
35-41,
1991[ISI][Medline].
16.
Fortney, SM,
Schneider VS,
and
Greenleaf JE.
The physiology of bed rest.
In: Handbook of Physiology. Environmental Physiology. Bethesda, MD: Am. Physiol. Soc, 1996, sect. 4, vol. II, chapt. 39, p. 889-942.
17.
Fritsch-Yelle, JM,
Charles JB,
Jones MM,
Beightol LA,
and
Eckberg DL.
Spaceflight alters autonomic regulation of arterial pressure in humans.
J Appl Physiol
77:
1776-1783,
1994
18.
Fritsch-Yelle, JM,
Whitson PA,
Bondar RL,
and
Brown TE.
Subnormal norepinephrine release relates to presyncope in astronauts after spaceflight.
J Appl Physiol
81:
2134-2141,
1996
19.
Fritsch, JM,
Charles JB,
Bennett BS,
Jones MM,
and
Eckberg DL.
Short-duration spaceflight impairs human carotid baroreceptor-cardiac reflex responses.
J Appl Physiol
73:
664-671,
1992
20.
Gharib, C,
Maillet A,
Gauquelin G,
Allevard AM,
Guell A,
Cartier R,
and
Arbeille P.
Results of a 4-week head-down tilt with and without LBNP countermeasure. I. Volume regulating hormones.
Aviat Space Environ Med
63:
3-8,
1992[Medline].
21.
Goldstein, DS,
Vernikos J,
Holmes C,
and
Convertino VA.
Catecholaminergic effects of prolonged head-down bed rest.
J Appl Physiol
78:
1023-1029,
1995
22.
Hokanson, DE,
Sumner DS,
and
Strandness DE.
An electrically calibrated plethysmograph for direct measurement of limb blood flow.
IEEE Trans Biomed Eng
BME-22:
25-29,
1975[Medline].
23.
Jacob, G,
Costa F,
Shannon J,
Robertson D,
and
Biaggioni I.
Dissociation between neural and vascular responses to sympathetic stimulation: contribution of local adrenergic receptor function.
Hypertension
35:
76-81,
2000
24.
Joyner, MJ,
Shepherd JT,
and
Seals DR.
Sustained increases in sympathetic outflow during prolonged lower body negative pressure in humans.
J Appl Physiol
68:
1004-1009,
1990
25.
Levine, BD,
Buckey JC,
Fritsch JM,
Yancy CW, Jr,
Watenpaugh DE,
Snell PG,
Lane LD,
Eckberg DL,
and
Blomqvist CG.
Physical fitness and cardiovascular regulation: mechanisms of orthostatic intolerance.
J Appl Physiol
70:
112-122,
1991
26.
Levine, BD,
Lane LD,
Buckey JC,
Friedman DB,
and
Blomqvist CG.
Left ventricular pressure-volume and Frank-Starling relations in endurance athletes. Implications for orthostatic tolerance and exercise performance.
Circulation
84:
1016-1023,
1991
27.
Levine, BD,
Zuckerman JH,
and
Pawelczyk JA.
Cardiac atrophy after bed-rest deconditioning: a nonneural mechanism for orthostatic intolerance.
Circulation
96:
517-525,
1997
28.
Mano, T,
Iwase S,
and
Kamiya A.
Sympathetic nerve responses in humans to short and long term simulation of microgravity.
J Gravit Physiol
5:
93-96,
1999.
29.
Pawelczyk, JA,
and
Levine BD.
Cardiovascular responses to rapid volume infusion: the human Bainbridge reflex.
Circulation
92:
I69,
1995.
30.
Pawelczyk JA, Levine BD, Prisk GK, Shykoff BE, Elliot AR, and Rosow
E. Accuracy and precision of flight systems for determination of
cardiac output by soluble gas rebreathing. Proceedings of the
NASA/AIAA Life Sciences and Space Medicine Conference, Houston,
TX, February 1995.
31.
Rea, RF,
Hamdan M,
Clary MP,
Randels MJ,
Dayton PJ,
and
Strauss RG.
Comparison of muscle sympathetic responses to hemorrhage and lower body negative pressure in humans.
J Appl Physiol
70:
1401-1405,
1991
32.
Rea, RF,
and
Wallin BG.
Sympathetic nerve activity in arm and leg muscles during lower body negative pressure in humans.
J Appl Physiol
66:
2778-2781,
1989
33.
Robertson, D,
Convertino VA,
and
Vernikos J.
The sympathetic nervous system and the physiologic consequences of spaceflight: a hypothesis.
Am J Med Sci
308:
126-132,
1994[ISI][Medline].
34.
Scherrer, U,
Vissing SF,
and
Victor RG.
Effects of lower-body negative pressure on sympathetic nerve responses to static exercise in humans. Microneurographic evidence against cardiac baroreflex modulation of the exercise pressor reflex.
Circulation
78:
49-59,
1988
35.
Seals, DR.
Sympathetic neural discharge and vascular resistance during exercise in humans.
J Appl Physiol
66:
2472-2478,
1989
36.
Shoemaker, JK,
Hogeman CS,
Leuenberger UA,
Herr MD,
Gray K,
Silber DH,
and
Sinoway LI.
Sympathetic discharge and vascular resistance after bed rest.
J Appl Physiol
84:
612-617,
1998
37.
Shoemaker, JK,
Hogeman CS,
and
Sinoway LI.
Contributions of MSNA and stroke volume to orthostatic intolerance following bed rest.
Am J Physiol Regulatory Integrative Comp Physiol
277:
R1084-R1090,
1999
38.
Shoemaker JK and Sinoway LI. Sympathetic contributions to
orthostatic tolerance and vascular tone following bed rest.
Proceedings of the 1st Biennial Space Biomedical Investigators'
Workshop, Clear Lake, TX, 1999.
39.
Sigaudo, D,
Fortrat JO,
Allevard AM,
Maillet A,
Cottet-Emard JM,
Vouillarmet A,
Hughson RL,
Gauquelin-Koch G,
and
Gharib C.
Changes in the sympathetic nervous system induced by 42 days of head-down bed rest.
Am J Physiol Heart Circ Physiol
274:
H1875-H1884,
1998
40.
Sundlöf, G,
and
Wallin BG.
The variability of muscle nerve sympathetic activity in resting recumbent man.
J Physiol (Lond)
272:
383-397,
1977
41.
Sundlöf, G,
and
Wallin BG.
Effect of lower body negative pressure on human muscle nerve sympathetic activity.
J Physiol (Lond)
278:
525-532,
1978
42.
Taylor, JA,
Halliwill JR,
Brown TE,
Hayano J,
and
Eckberg DL.
"Non-hypotensive" hypovolaemia reduces ascending aortic dimensions in humans.
J Physiol (Lond)
483:
289-298,
1995[ISI][Medline].
43.
Taylor, JA,
Joyner MJ,
Chase PB,
and
Seals DR.
Differential control of forearm and calf vascular resistance during one-leg exercise.
J Appl Physiol
67:
1791-1800,
1989
44.
Triebwasser, JH,
Johnson RL,
Burpo RP,
Campbell JC,
Reardon WC,
and
Blomqvist CG.
Noninvasive determination of cardiac output by a modified acetylene rebreathing procedure utilizing mass spectrometer measurements.
Aviat Space Environ Med
48:
203-209,
1977[Medline].
45.
Vissing, SF,
Scherrer U,
and
Victor RG.
Relation between sympathetic outflow and vascular resistance in the calf during perturbations in central venous pressure. Evidence for cardiopulmonary afferent regulation of calf vascular resistance in humans.
Circ Res
65:
1710-1717,
1989
This article has been cited by other articles:
|
|
 |
|
  D. Fischer, P. Arbeille, J. K. Shoemaker, D. D. O'Leary, and R. L. Hughson Altered hormonal regulation and blood flow distribution with cardiovascular deconditioning after short-duration head down bed rest J Appl Physiol, December 1, 2007; 103(6): 2018 - 2025. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Jarvis, B. D. Levine, G. K. Prisk, B. E. Shykoff, A. R. Elliott, E. Rosow, C. G. Blomqvist, and J. A. Pawelczyk Simultaneous determination of the accuracy and precision of closed-circuit cardiac output rebreathing techniques J Appl Physiol, September 1, 2007; 103(3): 867 - 874. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-i. Iwasaki, B. D. Levine, R. Zhang, J. H. Zuckerman, J. A. Pawelczyk, A. Diedrich, A. C. Ertl, J. F. Cox, W. H. Cooke, C. A. Giller, et al. Human cerebral autoregulation before, during and after spaceflight J. Physiol., March 15, 2007; 579(3): 799 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. B. Farquhar, M. M. Wenner, E. P. Delaney, A. V. Prettyman, and M. E. Stillabower Sympathetic neural responses to increased osmolality in humans Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2181 - H2186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Mueller, M. J. Sullivan, R. R. Grindstaff, J. T. Cunningham, and E. M. Hasser Regulation of plasma vasopressin and renin activity in conscious hindlimb-unloaded rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2006; 291(1): R46 - R52. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. V. Pancheva, V. S. Panchev, A. V. Suvandjieva, and B. D. Levine Lower body negative pressure vs. lower body positive pressure to prevent cardiac atrophy after bed rest and spaceflight. What caused the controversy? J Appl Physiol, March 1, 2006; 100(3): 1090 - 1090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Hesse, H. Siedler, S. P. Luntz, B. M. Arendt, R. Goerlich, R. Fricker, M. Heer, and W. E. Haefeli Modulation of endothelial and smooth muscle function by bed rest and hypoenergetic, low-fat nutrition J Appl Physiol, December 1, 2005; 99(6): 2196 - 2203. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. P. Arbeille, S. S. Besnard, P. P. Kerbeci, and D. M. Mohty Portal vein cross-sectional area and flow and orthostatic tolerance: a 90-day bed rest study. J Appl Physiol, November 1, 2005; 99(5): 1853 - 1857. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Gore, W. G. Hopkins, and C. M. Burge Errors of measurement for blood volume parameters: a meta-analysis J Appl Physiol, November 1, 2005; 99(5): 1745 - 1758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Foley, P. J. Mueller, E. M. Hasser, and C. M. Heesch Hindlimb unloading and female gender attenuate baroreflex-mediated sympathoexcitation Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2005; 289(5): R1440 - R1447. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. P. Bleeker, P. C. E. De Groot, G. A. Rongen, J. Rittweger, D. Felsenberg, P. Smits, and M. T. E. Hopman Vascular adaptation to deconditioning and the effect of an exercise countermeasure: results of the Berlin Bed Rest study J Appl Physiol, October 1, 2005; 99(4): 1293 - 1300. [Abstract] [Full Text] [PDF]
|
|
|
|
) and after
(
) 18 days head-down tilt bed rest (HDBR). Heart rate
and mean arterial presure (MAP) represent steady-state responses during
a 3-min data collection period. TPR, total peripheral resistance; PCW,
pulmonary capillary wedge; SV, stroke volume. *P < 0.05 compared with corresponding pre-bed rest value.
