© 1999 American Heart Association, Inc.
Clinical Research |
Role of Respiratory Motor Output in Within-Breath Modulation of Muscle Sympathetic Nerve Activity in Humans
From the Departments of Preventive Medicine (C.M.S., M.S., J.A.D.), Surgery (B.J.M.), and Medicine (J.B.S.), University of Wisconsin and the Middleton Memorial Veterans Hospital, Madison, Wis.
Correspondence to Jerome A. Dempsey, PhD, Department of Preventive Medicine, University of Wisconsin-Madison, 504 N Walnut St, Madison, WI 53705. E-mail jdempsey{at}facstaff.wisc.edu
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Abstract—We measured muscle sympathetic nerve activity (MSNA, peroneal microneurography) in 5 healthy humans under conditions of matched tidal volume, breathing frequency, and end-tidal CO2, but varying respiratory motor output as follows: (1) passive positive pressure mechanical ventilation, (2) voluntary hyperventilation, (3) assisted mechanical ventilation that required the subject to generate –2.5 cm H2O to trigger each positive pressure breath, and (4) added inspiratory resistance. Spectral analyses showed marked respiratory periodicities in MSNA; however, the amplitude of the peak power was not changed with changing inspiratory effort. Time domain analyses showed that maximum MSNA always occurred at end expiration (25% to 30% of total activity) and minimum activity at end inspiration (2% to 3% of total activity), and the amplitude of the variation was not different among conditions despite marked changes in respiratory motor output. Furthermore, qualitative changes in intrathoracic pressure were without influence on the respiratory modulation of MSNA. In all conditions, within-breath changes in MSNA were inversely related to small changes in diastolic pressure (1 to 3 mm Hg), suggesting that respiratory rhythmicity in MSNA was secondary to loading/unloading of carotid sinus baroreceptors. Furthermore, at any given diastolic pressure, within-breath MSNA varied inversely with lung volume, demonstrating an additional influence of lung inflation feedback on sympathetic discharge. Our data provide evidence against a significant effect of respiratory motor output on the within-breath modulation of MSNA and suggest that feedback from baroreceptors and pulmonary stretch receptors are the dominant determinants of the respiratory modulation of MSNA in the intact human.
Key Words: autonomic nervous system • cardiorespiratory interaction • positive pressure ventilation
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Introduction |
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The independent influence of the respiratory rhythm generator on the timing of sympathetic outflow has been studied using reduced preparations in which peripheral reflex mechanisms were eliminated by vagotomy and/or sinoaortic denervation. In these deafferented animal preparations, sympathetic neurons fire mainly during inspiration (ie, in synchrony with phrenic discharge), with their minimum activity occurring during expiration.1 2 The close temporal relationship between phrenic discharge and sympathetic activity recorded in anesthetized, paralyzed, and vagotomized animals has led to the hypothesis that the 2 neural outputs either arise from the same brain stem neurons or are driven by a common oscillator.1 3 However, in the intact human, sympathetic outflow to skeletal muscle (muscle sympathetic nerve activity; MSNA) declines during inspiration, reaching its nadir at end inspiration/early expiration, and then rises, reaching its peak at end expiration.4 5 The influence of central respiratory motor output on the within-breath modulation of MSNA has not been studied in humans.
The purpose of the present study was to examine the relative contribution of central respiratory drive in generating the respiratory modulation of MSNA in intact human subjects. We varied respiratory motor output using passive positive pressure mechanical hyperventilation at high tidal volume (VT) to eliminate respiratory motor output, and voluntary elevation of VT and inspiratory flow rate, with and without added inspiratory resistance, to increase respiratory motor output. We also determined the effects of intrathoracic pressure on the modulation of MSNA and cardiac frequency and controlled for the effects of lung inflation and chemoreceptor reflexes.
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Materials and Methods |
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General Procedures
Six men ages 27 to 59 years served as subjects after providing written, informed consent. All subjects were normotensive and free from cardiopulmonary disease. All experimental procedures and protocols were approved by the University of Wisconsin Center for Health Sciences and the Middleton Memorial Veterans Hospital Human Research Review Committees. Airflow rates, VT, mask pressure (Pm), and end-tidal partial pressure of CO2 (PETCO2) were measured using equipment and techniques described previously.6 A single-lead ECG was continuously recorded. Diaphragmatic electromyogram (EMGdi) was obtained from surface electrodes placed over the sixth and seventh intercostal spaces in the anterior axillary line. The raw EMGdi signal was amplified and band-pass filtered from 30 to 1000 Hz (model P511, Grass Instruments). Arterial pressure was measured beat by beat using the finger photoplethysmography technique (Finapres model 2300, Ohmeda) and with an automated sphygmomanometer (Dinamap, Critikon) at 1-minute intervals.
Recordings of Sympathetic Nerve Activity
Multiunit recordings of postganglionic MSNA were
obtained from the peroneal nerve of the right leg as described
previously.7 8 The neural signals were passed to a
differential preamplifier, an amplifier, a band-pass filter (700 to
2000 Hz), and an integrator (time constant=100 ms; total
gain=100 000). When acceptable MSNA recordings (spontaneous
pulse synchronous activity with signal-to-noise ratio >3:1) were
obtained, the subject was instructed to maintain the leg in a relaxed
position for the duration of the study. Segments of the neural
recording that showed evidence of mechanoreceptor or
-motoneuron activity were excluded from the analysis. MSNA
data from one subject were discarded because of inadequate neural
recordings.
Experimental Protocols
Subjects were studied supine in the postabsorptive state. All
protocols were performed during the application of a nonhypotensive
level (applied pressure, <20 mm Hg) of lower body negative
pressure (LBNP) to augment basal MSNA,9 thereby
facilitating the study of respiratory modulation. In a single subject,
who was studied both with and without lower body suction, LBNP
increased MSNA frequency compared with normal resting conditions
(35.4±1.5 versus 26.4±2.6 bursts per minute). However, in agreement
with previous reports,5 we saw that the respiratory
modulation of MSNA under all experimental conditions was unaffected by
LBNP.
The experimental protocols used are summarized in Table 1
. These different protocols were
designed to study the effects of increasing or decreasing central
respiratory motor output on the within-breath modulation of MSNA and to
control for the effects of changing lung volume, intrathoracic
pressure, and systemic arterial pressure.
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Voluntary Hyperventilation
The subject voluntarily maintained VT at twice the
eupneic level, using visual feedback from an oscilloscope. The subject
maintained a constant respiratory frequency (f) and a duty
cycle [inspiratory time (Ti)/total time
(TTOT)] of 50% using auditory feedback
with distinct inspiratory and expiratory tones.
VT, f, and
Ti/TTOT were
held at the same level for each of the subsequent experimental
protocols.
Passive Positive Pressure Mechanical Ventilation (Passive
PPV)
PPV was applied until the respiratory muscles were inhibited and
was then continued for a minimum of 5 minutes during which blood
pressure, ECG, and nerve activity were continuously recorded.
Respiratory muscle inhibition was determined from specific criteria, as
previously outlined,10 including the absence of
EMGdi, stabilization of the
Pm waveform, constancy of peak positive
end-inspiratory Pm, and a significant
(>10-second) prolongation of expiratory time on cessation of
mechanical ventilation (Figure 1).
Subjects visited the laboratory on a separate occasion for a
familiarization session so that they were able to relax during the
passive mechanical ventilator trials on the test day.
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Assisted Positive Pressure Mechanical Ventilation (Assisted
PPV)
Each subject had to generate a threshold
Pm of –2.5 cm H2O to
trigger each positive pressure mechanical breath. The subjects were
asked to maintain the set f by following computer-generated
audio signals. The aim of this protocol was to produce positive
intrathoracic pressure changes during inspiration and at the same time
require a high amount of respiratory muscle activation, as determined
by the EMGdi.
Inspiratory Resistor
In 3 subjects, the voluntary hyperventilation trials were
repeated with the addition of an inspiratory resistive load.
Before each series of voluntary hyperventilation, passive PPV, and assisted PPV protocols, baseline measurements of ventilatory and cardiovascular variable data were made during 5 minutes of spontaneous breathing. These measurements of MSNA made during spontaneous breathing (22.7±4.7 and 22.6±3.1 bursts per minute, respectively; P>0.05) showed that baseline nerve traffic did not change over time. The voluntary hyperventilation trial served as a "control" protocol, during which all potential mechanical and neural influences on the respiratory modulation of MSNA were present. The sequence of the trials was as follows: (1) passive PPV, (2) voluntary hyperventilation, (3) assisted PPV, (4) repeat passive PPV, (5) repeat voluntary hyperventilation, and (6) inspiratory resistor. This sequence ensured that each experimental protocol was bracketed by a voluntary hyperventilation trial with which any within-breath and per-minute changes in MSNA were compared. This design ensured that potential baseline shifts and/or time-dependent changes in MSNA did not affect our results.
Data Analysis
Respiratory and cardiovascular
parameters were computed as described
previously.11 Bursts of MSNA were identified by visual
inspection of the integrated neurogram by one investigator (C.M.S.).
The amplitude of each burst of MSNA and the beat-to-beat levels of
arterial blood pressure were determined by computer. MSNA
was expressed both as burst frequency and total activity (calculated as
the product of burst frequency and relative burst amplitude and
presented in arbitrary units).
Time Domain Analyses
The blood pressure signal was advanced by 0.2 seconds to correct
for the propagation time from the central circulation to the finger on
the basis of previous studies (B. Morgan, A. Xie, unpublished data,
1998) of the delay between the peak of the R-wave from the ECG
signal and the corresponding peak in the blood pressure waveform.
Bursts of MSNA were also advanced in time to account for nerve
conduction delays using the subject's height and an estimate of
conduction velocity in the peroneal nerve of 1.11 m/sec.12
The exact locations and amplitudes of the bursts of MSNA and the
arterial pressure waves within the breath cycle were
determined for each breath in each protocol both as a function of time
and breath volume. Both burst frequency and total MSNA
(frequencyxrelative amplitude) in each 12.5% time interval from the
onset of inspiration to end expiration were then normalized (as a
percentage of the number of bursts and total MSNA for each breath and
averaged over the entire condition). Arterial pressure was
expressed as the change from the last quartile of expiration (end
expiration). To statistically test for differences in the within-breath
patterns of modulation of MSNA among the 4 conditions (spontaneous
breathing, voluntary hyperventilation, passive PPV, and assisted PPV),
principal component analysis13 on the
covariance matrix of the time series data were used to identify
independent patterns that contributed to the composite pattern
represented by the raw data points. A principal component
was considered statistically significant if it explained >5% of the
total observed variance. This technique computes both the common shape
and the individual relative importance of each significant pattern in
the MSNA in each subject, under each condition.
Total minute values for MSNA, heart rate, and blood pressure were calculated during all protocols and compared using 1-way ANOVA with repeated measures. Post hoc analyses were performed if differences were detected. Significance was set at P<0.05.
Frequency Domain Analyses
Power spectral densities were obtained from analyses of
16-second epochs of arterial pressure, respiration
(airflow), and sympathetic nerve activity. The power spectra for the
R-R interval data were obtained using previously described
methods.11
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Results |
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Differences in Respiratory Motor Output
Figure 1
and Table 2 show the
different conditions across which respiratory motor output was varied.
Note that with voluntary hyperventilation, the 2-fold increase in
VT above spontaneous eupnea was accompanied by increased
EMGdi, more negative swings in
Pm, and reduced
PETCO2. This is
contrasted with passive mechanical hyperventilation with similar
VT, duty cycle, and
PETCO2, but
with positive Pm and no discernable
EMGdi during mechanical ventilation and with a
postventilator apnea. The assisted PPV condition matched the
VT and positive Pm during the passive
mechanical ventilation condition, only at high levels of respiratory
motor output, as evidenced by the EMGdi. Finally,
the increased inspiratory resistance trial matched the VT
and breathing pattern of voluntary hyperventilation, only at
exaggerated levels of respiratory motor output (see
EMGdi) and negative Pm.
Average heart rate, systolic pressure, and
diastolic pressure over the entire condition were not
different among any of the conditions studied (Table 2).
However, there was a small but significant (P<0.05)
increase in mean MSNA (burst frequencyxburst amplitude) for the 5
subjects during passive PPV (range, 19 to 38 arbitrary units/min) when
compared with spontaneous breathing (range, 19 to 32 arbitrary
units/min), voluntary hyperventilation (range, 19 to 33 arbitrary
units/min), or assisted PPV (range, 18 to 33 arbitrary units/min).
Nevertheless, there was no significant difference (P>0.05)
in burst frequency among any of the 4 conditions (Table 2).
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Within-Breath Modulation of Arterial Pressure and MSNA:
Frequency Domain Analyses
During spontaneous eupneic breathing, power spectral
analyses of MSNA and diastolic pressure identified
2 distinct peaks in power at frequencies corresponding to the
respiration and heart period in all subjects.
Representative spectra from 1 subject are
presented in Figure 2. In all 5
subjects, the amplitude of the peak power in MSNA at the respiratory
frequency was increased during voluntary hyperventilation
(VT=1.2 L) when compared with eupneic breathing
(VT=0.6 L). However, there were no further changes in the
amplitude of the peak power of MSNA at either the respiratory or
cardiac frequency, as respiratory motor output was varied from 0
(passive PPV) to very high (added inspiratory resistance), and
Pm was changed from negative to positive, at the
same VT and frequency.
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Within-Breath Modulation of Arterial Pressure and MSNA:
Time Domain Analyses
Data for MSNA are presented only in terms of total
activity (burst frequencyxrelative burst amplitude), because the
pattern and amplitude of the within-breath variations in burst
frequency and total activity were the same under all conditions. During
spontaneous breathing at low VT, when respiratory motor
output was low, a within-breath variation of MSNA was evident in all
subjects (Figure 3A), with
peak activity occurring at end expiration (mean, 22.7±7.5% of total
within-breath activity) and minimum activity (mean, 4.2±3.8% of total
activity) at end inspiration. The amplitude of this respiratory
modulation of MSNA was accentuated during voluntary hyperventilation,
when both VT and respiratory motor output were increased
and Pm was more negative (Figure 3B). In
all 5 subjects, MSNA fell progressively from onset to late inspiration,
with the nadir at end inspiration (mean, 2.2±1.6% of total activity),
and then rose sharply to a peak at end expiration (mean, 25.5±6.8% of
total activity). There was some variability among subjects, with 2 of
the 5 showing peak activity slightly earlier in expiration.
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Respiratory motor output was eliminated during passive PPV
(Figure 3C), but the within-breath pattern of MSNA was
qualitatively similar to that observed during active ventilation at the
same VT. However, during passive PPV, the maximum activity
(31.4±10.2% of total activity) occurred at a slightly earlier
quartile in expiration, rather than end expiration. The variability in
MSNA among subjects was also more pronounced during the ventilator
trials, with one subject showing a pattern that was markedly different
from the remaining 4 during both passive and assisted mechanical
ventilation. Assisted mechanical ventilation with positive pressure
during inspiration and high respiratory motor output showed a similar
within-breath modulation of MSNA, as did passive mechanical ventilation
at equal VT and positive Pm, but no
respiratory motor output.
Three subjects completed the resistor trials. VT,
f,
Ti/TTOT, and
PETCO2
were the same as during the voluntary hyperventilation trials, but
inspiratory effort was greatly augmented, as shown by the 7-fold
decrease in the nadir for inspiratory Pm (Table 2) and
the much larger EMGdi (Figure 1).
The respiratory modulation of MSNA was qualitatively the
same during both voluntary hyperventilation (Figure 4A) and voluntary breathing, with
increased inspiratory resistance (Figure 4B). In all 3 subjects,
MSNA decreased from onset to late inspiration and increased during
expiration, reaching a peak at end expiration/early inspiration.
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Changes in diastolic pressure during inspiration and
expiration for spontaneous breathing, voluntary hyperventilation,
passive PPV, and assisted mechanical ventilation are shown in Figure 3.
The within-breath pattern of change in systolic, mean
arterial, and pulse pressures (not shown) were the same as
those shown for diastolic pressure under all conditions. On
average, during inspiration, arterial pressure increased 1
to 2 mm Hg (relative to end expiration) and decreased during
expiration under all 4 conditions, with considerable variability among
subjects. The within-breath pattern of change in diastolic
pressure shown during voluntary hyperventilation (Figure 4A) was
more pronounced during resistor breathing (Figure 4B), with
diastolic pressure increasing by >4 mm Hg during
inspiration in 2 of the 3 subjects. The third subject showed a
continual increase in diastolic pressure from early
inspiration to late expiration.
Principal Component Analysis
Principal component analysis of both MSNA and
diastolic pressure for each of the 4 conditions revealed 2
distinct patterns, as follows: (1) a basic underlying pattern that was
similar to the mean responses pictured in Figure 3, and (2) an
asymmetry component reflecting the variability among subjects. When
combined, these 2 components explained >90% of the total variance in
each variable, for each condition. Marked differences in
respiratory motor output among the 4 conditions (spontaneous eupnea,
voluntary hyperventilation, passive PPV, and assisted PPV) had no
effect on either the shape or the relative importance of the individual
significant patterns. For MSNA, the basic pattern accounted for 70% to
88% (asymmetry, 10% to 29%) of the total variance. The asymmetry
component was relatively more important in describing the average
arterial pressure pattern, reflecting the greater
variability among subjects in this variable, explaining 28% to
39% of the total variance, with the basic pattern explaining the
remaining 47% to 61%. Neither of the 2 principal components
describing the within-breath pattern of change in either MSNA, nor in
diastolic pressure, were significantly different among the
4 conditions (P>0.05). Cross-correlation of the principal
components describing the within-breath patterns of variation in MSNA
and diastolic pressure revealed a significant inverse
relationship between diastolic pressure and MSNA under all
conditions with correlation coefficients of –0.75 (spontaneous),
–0.89 (voluntary hyperventilation), –0.87 (passive PPV), and –0.72
(assisted PPV).
Effects of Arterial Pressure Versus Lung Volume on
Within-Breath Modulation of MSNA
To "control for" within-breath changes in
diastolic pressure and to examine the effects of changing
lung volume on the respiratory modulation of MSNA, we compared the MSNA
at any given change in diastolic pressure that occurred at
higher lung volumes (the latter 50% of inspiration plus the first 50%
of expiration) versus the (remaining) lower lung volumes (Figure 5). The mean level of MSNA at any given
change in diastolic pressure was significantly higher at
low versus higher lung volumes (P<0.05). This effect of
lung volume on MSNA held for all conditions of active and passive
ventilation. In addition, the MSNA at any given lung volume showed a
significant negative correlation with the change in
diastolic pressure during both voluntary hyperventilation
and passive PPV. The slope of this relationship was significantly
higher (P<0.05) at the lower lung volumes.
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Posthyperventilation Apnea
The apneas that followed passive PPV showed a dissociation between
central respiratory motor output and MSNA (Figure 6). In the 3 instances in which the
duration of the apnea was >30 seconds, we observed the following: (a)
in the initial seconds of the postventilator apnea (when
PETCO2 was
still low and arterial pressure stable), MSNA burst
frequency and amplitude remained unchanged relative to voluntary
hyperventilation or the mechanical ventilation period; (b) as the apnea
proceeded, and CO2 was rising, MSNA burst
frequency and amplitude increased before any appearance of significant
respiratory motor output, as noted by the unchanging
Pm or VT; and (c) at apnea
termination, MSNA remained high coincident with the appearance of
significant respiratory motor output.
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Respiratory Sinus Arrhythmia (RSA): Frequency Domain
Analyses
During spontaneous eupneic breathing, power spectral
analyses of the R-R interval data in each subject revealed a
small peak in power at the respiratory frequency (see
representative subject in Figure 2). The
amplitude of the peak in power was markedly increased during voluntary
hyperventilation at high VT. In all subjects,
assisted PPV at the same VT markedly reduced the amplitude
of the power at the respiratory frequency compared with voluntary
hyperventilation. The amplitude of RSA was further reduced with passive
mechanical ventilation.
RSA: Time Domain Analyses
All subjects showed a small RSA during spontaneous breathing that
was characterized by a decrease in R-R interval throughout inspiration
and an increase during expiration (Figure 3A). The RSA was
significantly accentuated with increased VT during
voluntary hyperventilation (Figure 3B). When respiratory motor
output was eliminated during passive PPV at the same elevated
VT, RSA was eliminated in 4 of the 5 subjects and markedly
reduced in the fifth subject (Figure 3C). The RSA was also
considerably reduced during assisted mechanical ventilation when
respiratory motor output was high, but positive
Pm was equal to that during passive mechanical
ventilation (Figure 3D). During the resistor trials, when
inspiratory effort was greatly increased and Pm
markedly decreased, the RSA amplitude was enhanced (Figure 4).
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Summary of Findings
We examined the breathing-induced variations in MSNA under conditions in which feedback influences, such as within-breath changes in systemic arterial pressure, lung volume, and intrathoracic pressure, either remained constant or were controlled, and the magnitude of respiratory motor output was varied from undetectable to severalfold greater than normal. We found that maximum MSNA always occurred at end expiration and minimum MSNA occurred at end inspiration, and the amplitude of this modulation was not different among widely varying amounts of respiratory motor output. Similarly, variations in intrathoracic pressure, per se, were also without systematic, independent effects on MSNA; this was demonstrated by comparing negative pressure (voluntary) with positive pressure ventilation at comparable levels of respiratory motor output, intravascular pressure, and lung volume. We propose that central respiratory motor output provides a relatively minor, if any, contribution to the respiratory modulation of MSNA in intact humans. Rather, our findings support the postulate that peripheral reflexes elicited by changes in systemic arterial pressure and lung volume are the dominant influences on the within-breath modulation of MSNA.
Influence of Central Respiratory Motor Output on MSNA
Our data provide evidence against a significant independent effect
of central respiratory motor output on the within-breath modulation of
MSNA in the intact human. These findings were consistent across
several types of change in respiratory motor output, including (1)
voluntary increases in respiratory motor output, (2)
hypocapnia-induced elimination of respiratory motor output,
and (3) chemoreceptor stimulation during the latter stages of
posthyperventilation apnea.
These findings differ from the strong central respiratory component inferred from studies in anesthetized animals deprived of vagal and baroreceptor feedback.1 2 Why did our findings not reveal this strong contribution from central respiratory motor output? We hypothesize that feedback mechanisms from baroreceptors and pulmonary stretch receptors are the dominant determinants of the respiratory modulation of MSNA in the intact state. This idea is confirmed in part by studies in intact, anesthetized cats, which showed a pattern of inspiratory inhibition and expiratory activation of MSNA during eupnea that was similar to the pattern observed in intact humans.2 However, when respiratory motor output was increased via CO2 inhalation in this animal model, the MSNA modulation showed inspiratory excitation and expiratory inhibition.2 This pattern implies that the role of central respiratory motor output is important even in the intact cat and remains quite different from that in the human, in whom inspiratory inhibition and expiratory excitation of MSNA occurs even when respiratory motor output is increased via high CO2 or high voluntary drive to breathe (Figure 8, Seals et al5 ).
Our findings showing a dissociation between respiratory motor output
and MSNA during and after hypocapnia-induced apnea imply
quite different chemoreceptor thresholds for activation of the
respiratory and sympathetic outputs (see Figure 6). This concept
is consistent with 2 sets of findings in anesthetized
cats. Huang et al14 showed that transient carotid
chemoreceptor stimulation (via sodium cyanide) during
hypocapnia-induced apnea stimulated cervical sympathetic
outflow in the absence of phrenic nerve activity. Trzebski and
Kubin15 demonstrated that the
PaCO2 threshold for sympathetic
activation during posthyperventilation apnea was 36 mm Hg,
whereas the threshold for resumption of phrenic activity was 44
mm Hg.
Our conclusions concerning the absence of an effect of respiratory motor output on MSNA are predicated on the assumption that passive PPV eliminated central respiratory motor output. Truly passive mechanical ventilation markedly reduces phasic output from medullary respiratory neurons.16 17 However, it may not inhibit all medullary respiratory neuronal activity; in fact, tonic expiratory nerve activity16 and oscillatory glossopharyngeal nerve activity18 have been shown to persist during phrenic apneas secondary to mechanical hyperventilation. The significant prolongation of expiratory time after each passive trial indicated that any residual component of central respiratory drive that remained during the mechanical ventilation was not sufficient to initiate a breath once the ventilator was turned off. So, phasic respiratory motor output, if not completely eliminated, must have been markedly inhibited. Furthermore, despite this greatly reduced central respiratory motor output during passive PPV, the amplitude of the within-breath variation in MSNA was observed to be equal to that shown during active voluntary hyperventilation against a resistive load, when a very large amount of inspiratory effort was required to generate the same VT.
Influence of Arterial Pressure Changes
In agreement with most previous studies in humans4 5
and intact cats,2 we showed that MSNA changed reciprocally
with changes in arterial pressure. This correlation between
the within-breath pattern of change in arterial pressure
and the respiratory modulation of MSNA was unaffected by PPV in a
background of either very high (assisted) or 0 (passive) respiratory
motor output, or by dramatically increasing inspiratory effort by
voluntary efforts during resistor breathing. Whereas the within-breath
changes in diastolic pressure averaged <3 mm Hg
under all conditions, small changes in baroreceptor input have been
shown to trigger large changes in MSNA both in humans and intact
animals.19 20 A strong influence of breathing-related
arterial baroreceptor activity on sympathetic outflow was
also demonstrated in anesthetized cats. Respiratory modulation
of MSNA (peroneal nerve) during hyperventilation-induced phrenic
silence was unaffected by vagotomy but was eliminated by bilateral
carotid occlusion.2
Our findings suggest that during normal negative-pressure breathing, sympathetic inhibition during inspiration is caused, at least in part, by activation of carotid and aortic baroreceptors resulting from a rise in intravascular pressure and decline in intrathoracic pressure.21 Interestingly, during PPV, the aortic arch baroreceptors were most likely deactivated during inspiration at the same time that the carotid sinus baroreceptors were activated; ie, the 2 sets of receptors provided conflicting information to the central nervous system. In this situation, we also observed sympathetic inhibition during inspiration similar to that observed during normal negative pressure ventilation. Does this mean that carotid sinus baroreceptors predominate over aortic arch baroreceptors in the respiratory modulation of MSNA? Other investigators have advanced the hypothesis that neither set of receptors is predominant under all conditions.22 Instead, when inputs from aortic arch and carotid sinus baroreceptors conflict, the net sympathetic response is determined by the input from the set of receptors that is activated. In the present study, the sympathoinhibition observed during inspiration with positive pressure ventilation was most likely the result of activation of carotid sinus baroreceptors caused by a rise in intravascular pressure, suggesting that the carotid reflex was dominant in that instance.
Influence of Lung Stretch
Activation of pulmonary stretch receptors also has a
direct inhibitory action on sympathetic activity in
anesthetized cats and rats.23 24 However, data
from patients without intact pulmonary innervation below the
carina (as a result of orthotopic heart-lung transplantation) suggest
that intact lung inflation reflexes are not obligatory for the
respiratory oscillation in MSNA during eupneic breathing,
but that vagally mediated lung inflation feedback is the primary
mechanism through which the within-breath variation in muscle
sympathetic discharge is augmented at high VT in the
human.5 We showed that the level of MSNA, at any given
change in diastolic pressure, was higher at low versus
higher lung volume phases of the breath cycle, which is suggestive of
an independent effect of lung inflation on sympathetic outflow.
However, the greatest influence of afferent input from
pulmonary stretch receptors may be in modulating sympathetic
responsiveness to baroreceptor influences. In fact, our data showed
that the slope of the relationship between changes in
diastolic pressure and MSNA was greater at lower lung
volumes (see Figure 5). These correlative findings are
consistent with reports showing that the sensitivity of the
sympathetic nervous system to baroreceptor influence fluctuates during
breathing, with the greatest responsiveness occurring at low lung
volumes when spontaneous MSNA is highest.4 25
Influence of Intrathoracic Pressure
The use of positive intrathoracic pressure to produce passive
ventilation introduced additional confounding influences on venous
return, cardiac filling, and aortic transmural pressure. However, we
did not find any effect of positive pressure, per se, on the
respiratory modulation of MSNA as shown by the similarities in the
patterns of MSNA modulation observed during voluntary hyperventilation
(negative pressure) and assisted mechanical ventilation (positive
pressure) at similar high levels of central respiratory motor output
and VT. Macefield and Wallin26 also showed no
significant effect of PPV on respiratory modulation of MSNA in humans;
however, they also reported that respiration-associated changes in
arterial pressure were in the opposite direction during
positive versus negative pressure ventilation.26
RSA
Strong evidence in support of a dominant role for central
respiratory motor output in causing RSA was provided by the persistence
of heart rate modulation, occurring synchronously with phrenic nerve
activity, reported in the anesthetized dog during constant flow
mechanical ventilation, which eliminated phasic inputs related to
respiration.27 Similarly, our findings also point to an
effect of central respiratory motor output as indicated by the
reduction in RSA amplitude during passive versus active mechanical
ventilation (see Figure 3C versus 3D) and also during voluntary
increases in VT at high versus very high levels of
respiratory motor output (see Figure 4A versus 4B). However, we
also observed that RSA was greatly attenuated during assisted PPV, even
when respiratory motor output was very high (see Figure 3B
versus 3D). These findings are consistent with the previously
reported effects of PPV in greatly attenuating RSA compared with the
persistent RSA observed during negative pressure mechanical
ventilation.28 Such findings point strongly to atrial
stretch and cardiac vagal afferent activity as important modifiers of
RSA. Secondly, intact neural feedback from pulmonary stretch
receptors also seems to be obligatory to RSA as shown by the absence of
neurally mediated RSA in lung transplant patients (with intact
hearts)–even in the presence of large superimposed respiration
synchronous swings in intrathoracic pressure and also in central
respiratory motor output.11 In turn, as with the
respiratory modulation of MSNA (see previous section), feedback from
lung inflation may be important to RSA because of its ability to limit
accessibility of medullary vagal neurons to sensory input from systemic
baroreceptors.25 So, to date, two apparently obligatory
feedback mechanisms for RSA have been identified in the human, namely
those related to intrathoracic pressure and those related to lung
inflation. These mechanisms are clearly not redundant, because neither
one alone will produce RSA; rather, they may be mutually dependent.
In summary, it is clear that cardiovascular and pulmonary feedback mechanisms have different relative influences on the within-breath changes in MSNA as compared with the respiratory modulation of heart rate. First, passive PPV abolished RSA but had no effect on the respiratory modulation of MSNA. Second, the within-breath variation in heart rate was critically dependent on input from pulmonary stretch receptors,11 whereas lung denervation did not alter breathing-related oscillations in MSNA during eupneic breathing.5 Finally, our present data using passive versus active mechanical ventilation also showed that central respiratory motor output, per se, had a negligible independent role in the respiratory modulation of MSNA in the intact human but did contribute to the amplitude of RSA.
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Acknowledgments |
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This work was supported by the National Heart, Lung, and Blood Institute (Grants R01-15469 and R29-57401), the Veterans Affairs Medical Research Service, and (in part) by a research fellowship from the American Heart Association of Wisconsin and the Hazel Mae Mayer Foundation (to C.M.S.). We thank D. Puleo, D.F. Pegelow, and A. Jacques for technical support, and Dr B. Goodman for his assistance with the statistical analyses.
Received March 23, 1999; accepted July 6, 1999.
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