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Division of Cardiology, Toronto General and Mount Sinai Hospitals, and University of Toronto, Toronto, Ontario, Canada M5G 1X5
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Lower body negative
pressure (LBNP; 
5 and 15 mmHg) was applied to 14 men (mean age 44 yr) to test the hypothesis that reductions in preload without effect on
stroke volume or blood pressure increase selectively muscle sympathetic
nerve activity (MSNA), but not the ratio of low- to high-frequency
harmonic component of spectral power (PL/PH), a
coarse-graining power spectral estimate of sympathetic heart rate (HR)
modulation. LBNP at 5 mmHg lowered central venous pressure and had no
effect on stroke volume (Doppler) or systolic blood pressure but
reduced vagal HR modulation. This latter finding, a manifestation of
arterial baroreceptor unloading, refutes the concept that low levels of
LBNP interrogate, selectively, cardiopulmonary reflexes. MSNA
increased, whereas PL/PH and HR were unchanged. This discordance is consistent with selectivity of efferent sympathetic responses to nonhypotensive LBNP and with unloading of tonically active
sympathoexcitatory atrial reflexes in some subjects. Hypotensive LBNP
(15 mmHg) increased MSNA and PL/PH, but there
was no correlation between these changes within subjects. Therefore, HR
variability has limited utility as an estimate of the magnitude of
orthostatic changes in sympathetic discharge to muscle.
arterial baroreceptor reflexes; Bainbridge reflex; cardiopulmonary reflexes; microneurography; muscle sympathetic nerve activity; parasympathetic nervous system; power spectral analysis
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IN THE PRESENT EXPERIMENT, two generally accepted concepts concerning reflex regulation of the heart and circulation in normal humans were reevaluated using spectral analysis of heart rate (HR) variability (HRV) and microneurographic recordings of efferent sympathetic discharge to skeletal muscle [muscle sympathetic nerve activity (MSNA)]. The first concept is that incremental levels of lower body negative pressure (LBNP), which simulates upright posture by pooling blood in the venous compartment of the lower extremities, can be applied to discriminate between reflexes arising from afferent nerve endings situated in the atria, pulmonary veins, and left ventricle, which sense changes in filling pressures and chamber volumes, and reflexes arising from afferent nerve endings located in the aortic arch and carotid sinus, which sense changes in blood pressure and stroke volume (SV) (1, 20, 29, 34, 49). The second concept is that of selectivity or nonuniformity of responses to stimulation or inhibition of the afferent limbs of these two reflex pathways. In young sodium-replete subjects, the application of nonhypotensive LBNP lowers cardiac filling pressure and glomerular filtration rate and activates sympathetic vasoconstrictor outflow to skeletal muscle without affecting plasma renin activity or HR (13, 30, 49). Further reductions in preload cause a fall in systemic arterial pressure and splanchnic blood flow and a reflex increase in plasma renin activity and HR (1, 20, 49). Whereas efferent sympathetic nerve traffic to skeletal muscle and other vascular beds can be modulated by both sets of reflexes, the HR response appears to be governed selectively by the arterial baroreflex (13, 20, 34, 44, 49).
However, definitive proof of these concepts is lacking. Previous
experiments involving selective reductions in central venous pressure
(CVP) by nonhypotensive LBNP as a means of evaluating, in isolation,
sympathoneural responses to unloading of low-pressure mechanoreceptors
have not demonstrated consistent increases in MSNA (38, 39, 43,
47). Blood pressure was often measured intermittently in these
investigations, and additional influences on high-pressure baroreceptor
discharge, such as SV or cardiac output (CO) (18), were
not assessed. Some studies in which LBNP at up to 15 mmHg was applied
as a nonhypotensive stimulus comprised small numbers of healthy
volunteers and therefore may have been underpowered to detect
significant lowering of arterial blood pressure by this intervention.
The concept of selective regulation of efferent responses originated
from experiments comparing reflex changes in regional blood flow with
HR. However, HR represents the integrated response to perturbation of
several reflexes arising from the heart, great veins, and arteries,
with discrete and often opposing actions on cardiac sympathetic and
parasympathetic outflow. Determining whether sinoatrial discharge in
conscious humans is indeed indifferent to the stimulus of
nonhypotensive LBNP requires a method of discriminating between its
adrenergic and vagal modulation. Power spectral analysis of HRV has
achieved widespread acceptance as a noninvasive technique that can be
applied for this purpose (8, 14, 27, 31, 35-37, 41,
44).
The effects of nonhypotensive LBNP on MSNA, HR, or HRV have been examined individually (1, 3, 4, 7, 8, 13, 20, 34, 38, 39, 40, 43, 44, 47, 49), but no previous experiment has recorded these variables simultaneously in conjunction with SV and CO. Most previous studies of graded LBNP report responses in young men. Because advancing age influences reflexes arising from cardiopulmonary afferents and their interaction with the arterial baroreflex control of MSNA (19), it may not be possible to generalize their conclusions to older subjects. Indeed, results of experiments in youths may have limited applicability to the interpretation of disturbances in neurogenic regulation of the circulation in cardiovascular diseases, which in general afflict an older population.
We therefore applied low levels of LBNP (5 and 15 mmHg) to
middle-aged subjects to test the hypothesis that small reductions in
cardiac filling pressure lacking effect on SV, CO, or systemic arterial
pressure would increase MSNA reflexively without evoking an increase in
power spectral representations of the modulation of cardiac adrenergic
drive or a decrease in the modulation of efferent vagal discharge. If
present, such dissociation would provide novel frequency domain
evidence in support of these two important concepts. Conversely,
detection of a decrease in the vagal modulation of sinoatrial discharge
in the absence of any change in HR would effectively refute the concept
that incremental levels of LBNP can be applied to discriminate between
reflexes arising from low- and high-pressure mechanoreceptor afferents, whereas demonstration of a concordant increase in MSNA and the spectral
representation of cardiac adrenergic drive would refute the concept
that nonhypotensive LBNP increases selectively efferent sympathetic
nerve traffic to skeletal muscle, without affecting discharge directed
at the sinoatrial node.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Fourteen healthy middle-aged men [44.5 ± 1.7 (SE) yr] were studied. Their mean weight was 81.4 ± 3.5 kg, and their height was 180.4 ± 1.4 cm. None were taking medication. All subjects provided informed written consent as approved by our Institutional Human Subjects Review Committee, in accordance with the Declaration of Helsinki.Procedures
After voiding, subjects lay supine in a chamber custom-built for recording MSNA from the right peroneal nerve during LBNP (13). An airtight seal was obtained by a Neoprene kayak skirt fitted at the iliac crests. The right leg was held in position by form-fitting supports, and caudal displacement was prevented by bilateral foot plates. LBNP was applied briefly to familiarize subjects with this sensation and to lessen the possibility of inadvertent muscular contraction during the actual protocol.A volume-clamp cuff (Finapres 2300, Ohmeda) was then placed on the left middle finger for continuous noninvasive beat-by-beat blood pressure recording. After local anesthesia, a CVP catheter was introduced into an antecubital vein of the right arm and advanced to an intrathoracic position. A respiratory belt was secured around the abdomen. CVP and breathing excursions were measured continuously by pressure transducers (Statham P23ID, Gould, Cleveland, OH) and recorded simultaneously with lead II of the electrocardiogram, HR, and the MSNA neurogram by an ink recorder onto paper. Postganglionic MSNA was recorded from the right peroneal nerve (13, 33). SV was calculated over ~10 consecutive cardiac cycles from two-dimensional echocardiographic and continuous-wave Doppler recordings using previously reported methods (32). CO was determined from HR and SV.
Protocol
A 10-min baseline recording followed 20 min of supine bed rest. Then LBNP was applied at5 and 15 mmHg. Each level was sustained for 10 min. BP, HR, CVP, and MSNA were recorded continuously. SV was
derived over the last 2 min of baseline and each level of LBNP.
Data Analysis
MSNA. Pulse synchronous bursts of MSNA were identified by inspection of the mean voltage neurogram (13) by two trained but blinded assessors. Any inconsistency with respect to burst identification was resolved by the senior investigator. MSNA was expressed as burst frequency (bursts/min), incidence (bursts/100 cardiac cycles), and integrated nerve activity (the product of burst frequency and mean burst amplitude, in mm). In this multifiber recording preparation, the latter serves as a quantitative representation of postganglionic discharge.
Spectral analysis of HRV. The analog output of the electrocardiogram amplifier was discriminated to yield a train of rectangular impulses corresponding to the QRS complexes. The impulse train was processed on a real-time basis with a microcomputer via a 12-bit analog-to-digital converter (DAS-16, Metrabyte) at a sampling frequency of 1,000 Hz and stored sequentially for coarse-graining spectral analysis. The specific details of this technique have been reported elsewhere (8, 48). Seven minutes of data (2nd-8th min) were analyzed to determine HRV during each level of LBNP. Extra or missing beats were replaced by substitute R-R intervals calculated by linear interpolation from adjacent cycles. Spectra were calculated as ensemble averages of 256-beat sequences taken from a time series containing ~400-500 beats.
Total spectral power (PT) was divided into its fractal (PF), low-frequency harmonic (0.0-0.15 Hz, PL), and high-frequency harmonic (0.15-0.50 Hz, PH) components, with total harmonic power (PHP) comprising the sum of PL and PH. The parasympathetic nervous system is responsible for generating high-frequency power (27, 37, 41, 45). Therefore, the ratio PH/PT was used to estimate vagal contributions to PT. By convention (45), PL/PH was used to estimate sympathetic neural contributions to HR modulation. These two harmonic contributions to HRV are superimposed on a broad-band nonharmonic component, which occurs primarily in the very-low-frequency range, from 0.00003 to 0.1 Hz, and can be quantified separately from conventional harmonic components by plotting the logarithm of spectral power as a function of the logarithm of frequency (a 1/f
plot, with 
representing the slope of this linear regression) (8).
Statistical Analysis
Values are means ± SE. To test for significant time effects with respect to baseline supine measurements for LBNP, normally distributed data were submitted to a repeated-measures one-way analysis of variance, whereas nonnormally distributed data were submitted to the nonparametric Friedman repeated measures on ranks. Post hoc analysis was done with Student-Newman-Keuls test (SigmaStat 2.03, Jandel, San Rafael, CA). Linear regression and multiple linear regression analysis were applied to determine relationships and interrelationships between variables of interest. Statistical significance was accepted if P < 0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemodynamic Responses to LBNP
A continuous measure of CVP was obtained in 12 subjects. LBNP at5 mmHg caused a significant reduction in CVP, from 4.9 ± 1.0 to
3.3 ± 0.9 mmHg (P < 0.00001), but had no effect
on systolic or diastolic blood pressure, pulse pressure, HR, SV, or CO
(Table 1).
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LBNP at 15 mmHg lowered CVP further (to 1.7 ± 2.0 mmHg,
P = 0.004 compared with 5 mmHg LBNP) and, in
addition, reduced systolic blood pressure (from 122 ± 4 to
118 ± 3 mmHg, P < 0.04), SV (from 69 ± 4 to 57 ± 3 ml, P < 0.0001), and CO (from 4.3 ± 0.2 to 3.8 ± 0.2 l/min, P < 0.001). HR rose,
from 62 ± 2 to 67 ± 2 beats/min (P = 0.004;
Table 1). Diastolic pressure and pulse pressure were not affected by
this stimulus.
MSNA During LBNP
LBNP at5 mmHg increased mean values for MSNA burst frequency
(from 34 ± 2 to 37 ± 3 bursts/min, P = 0.051), burst incidence (from 53 ± 3 to 58 ± 4 bursts/100
heartbeats, P < 0.05), mean burst amplitude (from
7.2 ± 0.3 to 8.4 ± 0.6 mm, P < 0.05), and the product of burst frequency and amplitude (integrated MSNA; from
251 ± 25 to 321 ± 43 units, P < 0.05;
Table 1).
With 15 mmHg LBNP there were significant additional increases in MSNA
burst frequency (to 41 ± 2 bursts/min, P < 0.01 compared with baseline and 5 mmHg LBNP) and burst incidence (to
64 ± 3 bursts/100 heartbeats, P < 0.00005 compared with baseline and P = 0.009 compared with 5
mmHg LBNP). Burst amplitude (from 7.2 ± 0.3 to 9.6 ± 0.9 mm, P < 0.05) and integrated MSNA (from 251 ± 25 to 423 ± 52 units, P < 0.01) increased
significantly above baseline, but not 5 mmHg LBNP values (Table 1).
HR and HRV During LBNP
LBNP at5 mmHg had no effect on pulse interval, the reciprocal
of HR, on PL, or on mean values for the power spectral
estimate of sympathetic nervous system modulation of HR,
PL/PH (from 5.4 ± 2.1 to 15.5 ± 7.0, q = 2.646; Table 2). In
contrast, the power spectral estimate of parasympathetic nervous
system modulation of HR, PH/PT, fell
from 0.09 ± 0.01 to 0.06 ± 0.02 (P = 0.018).
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Individual responses appear in Fig. 1. In
the majority of subjects, PL/PH rose and
PH/PT fell. However, in four subjects, there
was a clear decrease in PL/PH. In two of these
four subjects, this was accompanied by a distinct increase in
PH/PT. In a third subject, 5 mmHg LBNP evoked
a small increase in PH/PT, with virtually no
change in PL/PH. There was no significant
correlation between changes in PL and changes in MSNA with
5 mmHg LBNP, whether expressed as burst frequency (r = 0.45) or units (r = 0.18).
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LBNP at 15 mmHg LBNP had no effect on PT, PF,
PHP, PH, and PL but decreased pulse
interval (from 941 ± 39 to 890 ± 32 ms, P < 0.001) and PH/PT, the power spectral
estimate of parasympathetic nervous system modulation of HR (to
0.05 ± 0.01, P < 0.01), and increased
PL/PH, the power spectral estimate of
sympathetic nervous system modulation of HR (from 5.4 ± 2.1 to
20.5 ± 6.5, P = 0.03; Table 2). However, there
was no significant correlation within subjects between changes in
PL/PH and MSNA from baseline values (r = 0.20).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The primary objective of this experiment was to test the hypothesis that small reductions in cardiac filling pressure without effect on SV, CO, or systemic blood pressure activate selectively sympathetic outflow to skeletal muscle without triggering an increase in cardiac adrenergic drive. For this purpose, the microneurographic technique provided a direct and quantitative measure of sympathetic outflow to skeletal muscle, whereas spectral analysis was applied to obtain an indirect estimate of the relative contribution of the sympathetic nervous system to the modulation of sinoatrial discharge frequency before and during graded increases in LBNP. No previous experiment has recorded MSNA, HR, and HRV simultaneously and in conjunction with SV and CO. The present study is also novel, in that these comparisons were performed in a middle-aged, but otherwise healthy, population.
There were four principal findings. First, reductions in CVP with 5
mmHg LBNP had no effect on blood pressure, SV, CO (determinants of
arterial baroreceptor discharge), or HR but elicited a significant reflex rise in sympathetic discharge to skeletal muscle. This was not
accompanied by any increase in mean values for
PL/PH or PL, the two frequency
domain representations of cardiac sympathetic modulation of HRV.
Second, 5 mmHg LBNP decreased PH/PT, the
power spectral estimate of the vagal contribution to HRV. Third,
cardiac sympathetic modulation of HR increased significantly with the application of 15 mmHg LBNP. This stimulus caused further reductions in preload, lowered SV, CO, and systolic blood pressure, and increased MSNA burst frequency, burst incidence, and HR. Fourth, there was concordance between the effect of 15 mmHg LBNP on group mean values
for these microneurographic and frequency domain estimates of
sympathetic outflow to skeletal muscle and the sinoatrial node but no
significant correlation between these two variables within subjects.
Results of previous experiments involving reductions in CVP of similar
magnitude have been inconsistent. Initially, 5 mmHg LBNP was reported
to reduce CVP in young adults by 2-2.5 mmHg and increase MSNA by
60-90% (43, 47). Because HR was unaffected, these
observations were considered evidence in support of the concept of
selective regulation of MSNA by low-pressure mechanoreceptor reflexes.
However, blood pressure was measured intermittently and noninvasively
in these studies, and important influences on high-pressure
baroreceptor discharge, such as SV and carotid or aortic arterial
dimensions (24, 46), were not assessed (43, 47). Thus the possibility that 5 mmHg LBNP increased MSNA by reducing discharge from arterial and low-pressure mechanoreceptors could not be excluded. Importantly, in a subsequent study from the same
institution, 5 mmHg LBNP lowered the CVP of young adults by 1.8 mmHg
but evoked only a nonsignificant 17% increase in integrated MSNA
(38). Other investigators have also failed to detect a significant effect of 5 mmHg LBNP on MSNA (39).
LBNP up to and including 15 mmHg has been considered a nonhypotensive
intervention. In a study of eight healthy subjects, Baily et al.
(3) reported no effect on blood pressure but parallel increases in MSNA, forearm norepinephrine spillover, and HR in response
to 15 mmHg LBNP. At first pass, these observations appear to refute
the concept of selectivity of reflex responses to unloading of
low-pressure receptors in humans. However, this conclusion assumes that
LBNP had no significant effect on blood pressure or on other
determinants of arterial baroreceptor discharge. In the present series,
comprising 14 subjects, LBNP at 15 mmHg caused a small (4 mmHg, or
3%), but nonetheless significant, reduction in systolic blood pressure
as well as significant reductions in SV (17%) and CO (12%). Thus a
more plausible explanation for such findings (3) and for
inconsistencies in this literature is that many studies, comprising
fewer subjects than in the present experiment, may have been
underpowered to detect a true hypotensive effect of 15 mmHg LBNP. Our
recent radiotracer kinetic studies in middle-aged subjects with normal
left ventricular function, demonstrating increased total body
norepinephrine spillover with nonhypotensive LBNP, in the setting of
reduced SV and CO (2), add to the concern that graded
application of LBNP cannot dissociate reliably reflex responses arising
from unloading of low-pressure mechanoreceptors from those arising from
high-pressure mechanoreceptors (10).
LBNP at 10 mmHg has been shown to reduce left atrial volume without
affecting left ventricular end-diastolic volume or SV. This finding has
reinforced the concept that this particular intensity of LBNP can be
applied to elucidate the role of nonventricular cardiopulmonary
baroreceptor afferents in circulatory regulation (34).
However, in the present series, even LBNP at 5 mmHg elicited a
significant decrease in mean values for PH/PT.
The obvious interpretation of this finding is that arterial
baroreceptors were indeed unloaded, resulting in a reflex reduction in
the parasympathetic modulation of sinoatrial discharge. If this
conclusion is correct, it then follows that LBNP at or greater than 5
mmHg cannot be applied to middle-aged men to discriminate between these
two sets of baroreceptor reflexes. Three potential objections to this
conclusion should be considered. The first is that a similar decrease
with 5 mmHg was not noted in a previous study by other investigators
involving eight healthy young subjects (7). However, there
was a strong trend in this direction, suggesting that their study was
not powered to detect a true effect on a ratio with such high
between-subject variability as PH/PT. The
second objection is the lack of any detectable hemodynamic stimulus to
arterial baroreceptor unloading (such as reductions in blood pressure,
SV, or CO). However, arterial baroreceptors can respond to 1- to 2-mmHg
changes in blood pressure (12), participate in the
maintenance of systemic blood pressure during LBNP at less than 5
mmHg (9), and may also function as rheoreceptors
(18). In humans, nonhypotensive hypovolemia has been shown
to reduce carotid artery and ascending aortic caliber (24,
46). This, in turn, could alter baroreceptor discharge properties. The third objection is the absence of any parallel reflex
increases in spectral representations of cardiac sympathetic modulation
of HR, or in HR itself, in response to this stimulus. However, in some
subjects, such activation may have been offset, or obscured, by
the simultaneous unloading of atrial, ventricular, or aortic
receptors that activate cardiac-specific sympathoexcitatory reflexes
(26).
In some subjects, LBNP at 10 mmHg can induce a slight fall, rather
than an increase, in HR (4, 29), and bradycardia with
syncope can occur during LBNP in patients with ventricular deafferentation after transplantation (16). Conversely,
volume loading to raise left ventricular end-diastolic (and presumably atrial) pressure, but with no effect on end-systolic pressure, can
cause a modest, but significant, tachycardia (6). In
experimental preparations, stimulation of right and left atrial
mechanoreceptors by volume loading increases cardiac sympathetic and
reduces cardiac vagal nerve discharge (5, 6, 17, 21, 23,
25). Efferent cardiac sympathetic nerves, which fire in response
to stimulation of these atrial receptors, differ from those responsive
to alterations in arterial baroreceptor discharge (25). If
a tonically active Bainbridge reflex was functionally important in
humans, nonhypotensive LBNP should exert the opposite effect, i.e.,
decrease cardiac sympathetic and increase efferent vagal firing. As
revealed by Fig. 1, in several of these subjects, 5 mmHg LBNP did
elicit a marked decrease in PL/PH and a clear
increase in PH/PT, as might be anticipated if
the predominant effect of this stimulus in these individuals was to
unload atrial receptors mediating cardiac-specific excitatory reflexes,
possibly via sympathetic afferent fibers (26).
Whether spectral analysis of HRV is capable of quantifying, specifically, the intensity of cardiac sympathetic nerve activity is a subject of vigorous debate (11, 22, 27, 28). In healthy subjects, the low-frequency component of the HR power spectrum and PL/PH rise, appropriately, in response to an orthostatic stimulus (8, 31, 35, 37), and infusion of sodium nitroprusside to lower blood pressure results in concordant increases in the low-frequency component of the HR and MSNA power spectra (36). Because power spectra estimate the relative contribution of oscillations in parasympathetic and sympathetic discharge at these specific frequencies to the modulation of HR, rather than the intensity of these autonomic inputs to the sinoatrial node, any relationship between these frequency domain indexes and a direct measure of sympathetic nerve firing, such as MSNA, might well be tenuous. Under resting conditions, there is no between-subject relationship between MSNA and HRV estimates of cardiac sympathetic tone (22, 33, 42). Saul et al. (42) noted a weak but significant correlation between PL/PH and MSNA when nitroprusside was infused to unload arterial baroreceptors, but only when burst frequency exceeded 40/min.
The present experiment addresses the issue of within-subject
comparisons in response to an orthostatic stimulus. Of the proposed spectral representations of sympathetic modulation of HR, low-frequency power was not affected significantly by either level of LBNP. There was
qualitative concordance between mean PL/PH and
MSNA responses but no significant within-subject correlation between the effect of LBNP at 15 mmHg on these two indexes. By contrast, in a
recent experiment the stimulus of 75° tilt enhanced the coupling between low-frequency oscillations in HR and low-frequency oscillations in MSNA in healthy volunteers (15).
Conclusions
The present observations have implications for concepts concerning neural regulation of the circulation and also for the application of spectral analysis of HRV as a noninvasive estimate of changes in the intensity of central sympathetic outflow. LBNP at5 mmHg had no
effect on HR but caused a significant reduction in
PH/PT, the power spectral representation of
parasympathetic modulation of HR, a response that cannot be attributed
to unloading of inhibitory reflexes arising from low-pressure
mechanoreceptors. This observation therefore refutes the concept that
low levels of nonhypotensive LBNP can be used to interrogate,
selectively, cardiopulmonary reflexes without perturbing arterial
baroreceptor reflexes. LBNP at 5 mmHg also elicited a selective
increase in sympathetic discharge to skeletal muscle without altering
spectral representations of cardiac adrenergic drive.
The mechanism or mechanisms responsible for this selectivity, i.e., the discordance between HR power spectral and microneurographic representations of central sympathetic outflow, cannot be established with certainty. Recent observations, from our laboratory, utilizing the isotope-dilution technique indicate that nonhypotensive LBNP can increase total body norepinephrine appearance rate in plasma without affecting left ventricular norepinephrine spillover (2). However, neither sympathetic outflow to the sinoatrial node nor its modulation can be quantified by this radiotracer method. Power spectral analysis may lack the sensitivity to detect changes in sympathetic, as opposed to parasympathetic, modulation of HR in response to modest baroreceptor unloading. Finally, this intervention may have engaged several reflexes with independent and opposite effects on cardiac sympathetic and parasympathetic tone. In some subjects, there was evidence for withdrawal of cardiac sympathetic modulation and enhanced vagal modulation of sinoatrial discharge, perhaps due to diminished stimulation of atrial sympathetic afferents or inhibition of the Bainbridge reflex. This may have obscured activation of sympathetic outflow to the sinoatrial node, in the remainder, in response to this stimulus, when mean PL/PH responses were considered.
In contrast, LBNP at 15 mmHg caused significant reductions in blood
pressure, SV, and CO and, therefore, arterial baroreceptor discharge
and elicited concordant increases in MSNA, the spectral representation
of cardiac adrenergic modulation, and HR. However, the absence of any
significant within-subject relationship between changes in MSNA and
PL/PH in response to hypotensive LBNP indicates that neither variable can be considered representative of the intensity, in a particular individual, of the sympathetic response to
orthostatic stimuli directed at other vascular beds.
Perspectives
LBNP, MSNA, and spectral analysis of HRV have yielded novel and important insights into mechanisms of cardiovascular regulation by the autonomic nervous system in intact conscious humans. The strengths and limitations of these methods continue to be explored and debated. The present observations signal caution in interpreting the results of experiments involving nonhypotensive LBNP. Responses elicited by this stimulus should not be attributed exclusively to unloading of low-pressure receptors with vagal afferents. Our observations, which indicate that arterial baroreceptor reflexes, and possibly sympathetic afferents, are also modified by this intervention, should stimulate careful reevaluation of previous conclusions based on studies that may have inadequate power to detect such changes. Frequency domain analysis should be appreciated primarily for the insight it provides into the oscillations of regulatory systems and for its prognostic value in patients with cardiovascular disease. Enthusiasm for its uncritical application as a method for quantifying the intensity of neural discharge to the heart and regional vascular beds should be tempered. These recommendations should not be considered exclusive to the investigation of healthy subjects but given perhaps even greater emphasis when considering the design or interpretation of studies of cardiovascular regulation in pathological states, such as hypertension or heart failure, that are characterized by altered neural regulation of the circulation.| |
ACKNOWLEDGEMENTS |
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We thank Beverley L. Senn for technical assistance and Prof. Richard Hughson (University of Waterloo) for the gift of the coarse-graining spectral analysis program.
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FOOTNOTES |
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This study was supported by Heart and Stroke Foundation of Ontario Grants-in-Aid T3054 and T4050. J. S. Floras holds a Career Investigator Award of the Heart and Stroke Foundation of Ontario. G. C. Butler received a Fellowship from the Medical Research Council of Canada. S.-I. Ando received a Canadian Hypertension Society/Merck Frosst Fellowship and was supported, in addition, by the George R. Gardiner Foundation (Toronto). S. C. Brooks received a John D. Schultz Science Student Scholarship from the Heart and Stroke Foundation of Ontario.
Address for reprint requests and other correspondence: J. S. Floras, Suite 1614, 600 University Ave., Toronto, ON, Canada M5G 1X5 (john.floras{at}utoronto.ca).
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 16 January 2001; accepted in final form 20 March 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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