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John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, Wisconsin 53705
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Harms, Craig A., Mark A. Babcock, Steven R. McClaran, David
F. Pegelow, Glenn A. Nickele, William B. Nelson, and Jerome A. Dempsey.
Respiratory muscle work compromises leg blood flow during maximal
exercise. J. Appl. Physiol.
82(5): 1573-1583, 1997.
We hypothesized that during
exercise at maximal O2 consumption (
O2 max),
high demand for respiratory muscle blood flow
(
) would elicit locomotor muscle vasoconstriction
and compromise limb . Seven male cyclists
(O2 max 64 ± 6 ml · kg
1 · min1)
each completed 14 exercise bouts of 2.5-min duration at
O2 max on a cycle
ergometer during two testing sessions. Inspiratory muscle work was
either 1) reduced via a
proportional-assist ventilator, 2)
increased via graded resistive loads, or
3) was not manipulated (control).
Arterial (brachial) and venous (femoral) blood samples, arterial blood
pressure, leg (legs;
thermodilution), esophageal pressure, and
O2 consumption
(O2) were
measured. Within each subject and across all subjects, at constant
maximal work rate, significant correlations existed
(r = 0.74-0.90;
P < 0.05) between work of breathing
(Wb) and legs (inverse), leg vascular resistance (LVR), and leg O2
(O2 legs;
inverse), and between LVR and norepinephrine spillover. Mean arterial
pressure did not change with changes in Wb nor did tidal volume or
minute ventilation. For a ±50% change from control in Wb,
legs changed 2 l/min or 11% of control, LVR
changed 13% of control, and O2
extraction did not change; thus
O2 legs
changed 0.4 l/min or 10% of control. Total
O2 max was unchanged
with loading but fell 9.3% with unloading; thus
O2 legs
as a percentage of total
O2 max was 81% in
control, increased to 89% with respiratory muscle unloading, and
decreased to 71% with respiratory muscle loading. We conclude that Wb
normally incurred during maximal exercise causes vasoconstriction in
locomotor muscles and compromises locomotor muscle perfusion and
O2.
vascular resistance; blood flow; work of breathing; maximal
exercise; sympathetic vasoconstriction; autonomic reflexes; sympatholysis
INTRODUCTION DURING STRENUOUS EXERCISE in humans, when the level of
ventilatory requirement is such that severe expiratory flow limitation is realized, the O2 cost of
breathing may approach 15% of total O2 consumption
( To date, the question of "competition" for redistribution of
The purpose of this study was to determine whether there is
competition for METHODS
O2 tot)
(1). Studies using microsphere techniques for measuring blood flow
() in running quadrupeds (rats, pigs, and ponies)
show substantial increases in to the diaphragm and
inspiratory and expiratory muscles, which often approximate the
to locomotor muscles during maximal exercise (4, 11, 13). Theoretically, the metabolic cost of breathing required by the
primary respiratory and stabilizing muscles of the chest wall, plus
their demand for perfusion to meet this
O2 cost, could limit the
available for locomotor muscles and thereby limit their work output.
with added muscle mass has been addressed only
during submaximal exercise. Secher et al. (27) determined that adding
arm work to legs already exercising at submaximal exercise resulted in reduced to the legs
(legs). They surmised that increased was made available to the working arms at the
expense of legs. However, several recent reports have
failed to corroborate these findings (20, 21, 23, 25). In these
investigations, when arm work was added to already exercising legs
during submaximal exercise, increased sympathetic excitation of the leg
vasculature occurred, as evidenced from increased norepinephrine (NE)
spillover, but reduced legs did not occur. Perhaps
clear, consistent demonstration of redistribution
and local vasoconstriction might only occur when muscle mass is added
at truly maximal workloads (WL), at which both cardiac output and the
arteriovenous O2 difference are at
maximal levels.
and
O2 between the respiratory
muscles and limb locomotor muscles during maximal exercise. We measured
, O2 extraction,
and O2 of the maximally
exercising limb and observed the effects of alterations in respiratory
muscle work during several repeated bouts of maximal exercise. We
hypothesized that, with an increased work of breathing (Wb),
would be redistributed to the respiratory
muscles from limb locomotor muscles and with decreased work of
breathing, greater and
O2 transport would be made
available to limb locomotor muscles. The latter respiratory muscle
"unloading" experiments also allowed us to examine the physiological importance to limb and
O2 transport of the
respiratory muscle work normally achieved at maximal
O2
(O2 max).
O2 tot,
and CO2 output were measured by
using equipment and techniques previously reported (1, 9). Wb was
defined as the integrated area of the pressure-tidal volume
(VT) loop (15). Wb
multiplied by the breathing frequency (f) represents the amount
of work done per minute on the lungs. We note that our use of the area
of the Pes-volume loop underestimates the actual work of breathing by
variable amounts (1, 7); thus our measurements report only a
conservative estimate of the total amount of work done by the
respiratory muscles during exercise and their changes with unloading
and loading.
Inspiratory unloading and loading.
A feedback controlled "proportional-assist" ventilator (PAV;
Winnipeg) was used to reduce the work of the inspiratory muscles during
exercise (29). Briefly, subjects breathed through a Hans Rudolph valve
that was connected (on the inspiratory side) to the PAV. The PAV
contains a linear motor that drives a piston (5-liter volume capacity)
that develops pressure in proportion to inspiratory airflow and volume.
The level of assist is controlled by potentiometers on the control
panel of the ventilator, and there are separate controls for volume
assist and flow assist. During inspiration, the PAV makes mouth
pressure positive in proportion to flow such that the proportional
assist (unloading) of the respiratory muscles occurs throughout the
inspiratory cycle. In practice, the amount of assist is set at the
maximal level each subject can tolerate, as determined from practice
sessions before testing. During practice sessions and during the
testing sessions, subjects were verbally coached to relax and permit
the PAV to assist each inspiration as much as possible.
To increase inspiratory work during exercise, ventilatory loads were
added that consisted of mesh screens in the inspiratory line with
resistances of 3-5
cmH2O · l1 · s.
These resistances were sufficient at the high flow rates achieved in
maximal exercise to increase Wb 25-95% above control levels.
Subjects participated in practice sessions to familiarize themselves
with the inspiratory loads.
and blood-gas measurements.
A 20-gauge arterial catheter (Arrow) was inserted percutaneously in the
brachial artery of the left arm under local 1% lidocaine anesthesia
for arterial blood sampling. Subsequently, a catheter 1.25 mm in
external diameter for cold-saline infusion (DSA 400L, Cook,
Bloomington, IN) was introduced percutaneously into the right femoral
vein 2 cm below the inguinal ligament and advanced ~7 cm toward the
knee. A second identical Cook catheter was advanced from near the same
location proximally toward the heart ~8 cm into the same femoral
vein. A thin (0.64-mm-diam) Teflon-coated thermocouple (IT-18,
Physi-temp Instruments, Clifton, NJ) was inserted through this catheter
with the tip extending ~1 cm beyond the catheter. The placement of
the catheter and thermocouple was checked at rest by infusion of 20 ml
of saline to produce a 0.5°C deflection in blood temperature. The
placement was not changed between trials of exercise. An assumption is
that the placement of the catheter reflects changes occurring only
within the exercising leg muscles. Poole et al. (18) have reported that
there is <5% contamination of venous blood from saphenous drainage
during strenuous exercise.
The constant-infusion thermodilution technique was used to determine
legs (2, 18). Saline temperature was measured with
a thermocouple at the catheter inlet within 15 cm of the catheter's
penetration of the skin. Infusion flows typically were ~190-240
ml/min and were continued for 15-20 s until femoral venous temperature had decreased and stabilized. Infusion rate of saline was
measured from timed changes in weight of a 250-ml bag of saline suspended in a plastic bag from a force-displacement transducer. A
chart (Gould) recording and computer-analysis output confirmed the
constancy of saline infusion rate and enabled the calculation of saline
inflow. The thermocouples were attached to junction boxes (TH5,
Sensortek), in which analog signals from the junction boxes were
recorded on a strip chart (Gould) and computer for timed measurements
of saline and blood temperature. This enabled direct observation of
changes in temperature that was necessary to ensure stable tracings.
Saline infusion rates were sometimes adjusted slightly immediately
after the first leg measurement within a
trial to ensure a plateau in the femoral venous temperature recordings,
because it was difficult to accurately predict the appropriate infusion
rate for each subject. Signals from the force transducer and
thermocouple junction box were calibrated at the beginning and end of
the experiments. leg was calculated on the basis of
thermal-balance principles described by Andersen and Saltin (2).
O2 legs
was calculated as the product of brachial arterial-femoral venous
O2 content
[(a-fv)CO2]
and (Fick equation). legs data and
O2 legs
are presented as twice the calculated value to represent both
exercising legs. The
(a-fv)CO2
was divided by arterial O2 content
to give O2 extraction. Leg
vascular resistance (LVR) was calculated as the ratio of mean arterial
blood pressure to legs.
Blood-gas measurements, blood pressure, blood lactate, and
electrolytes.
Duplicate 3- to 10-ml samples of arterial and venous blood were drawn
anaerobically over 10-20 s during each test for measurement of
PO2,
PCO2, and pH with a blood-gas
analyzer calibrated with tonometered blood (ABL300, Radiometer), and of O2 saturation and hemoglobin with
a CO-oximeter (OSM 3, Radiometer). Blood gases were corrected for
temperature changes during exercise by measuring with a thermocouple
placed intranasally in the esophageal lumen (Mon-a-Therm 6500) for
arterial blood temperature and from the femoral venous thermocouple.
Blood pressure was measured with an Ohmeda pressure transducer (model
P10EZ) attached to the arterial line. Blood lactate concentration was
analyzed by means of a YSI lactate analyzer (model 1500 Sport; YSI) and
plasma electrolytes (Na+,
K+,
Cl) were analyzed by
ion-specific electrodes (AVL Electrolyte Analyzer, series 9100).
Hematocrit was determined by microcentrifuge.
NE spillover technique.
Plasma epinephrine and NE were determined in duplicate by a
radioenzymatic assay (5) for the first of each condition (no breathing
intervention, inspiratory unload, and inspiratory load). Net overflow
of NE from skeletal muscle was calculated, by the Fick principle, from
the product of the venoarterial difference in plasma NE concentration
and the plasma flow. The rate of spillover of NE into plasma was
determined by using the following equation
![NE spillover = [(Cv − Ca) + Ca(Epi<SUB>e</SUB>)]LPF](/content/vol82/issue5/fulltext/1573/img001.gif)
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legs and the hematocrit (25).
Experimental protocols.
Subjects initially completed a progressive incremental
O2 max exercise test
on an electromagnetically braked cycle ergometer (Elema, Sweden)
beginning at 150 W (~30-40%
O2 max) followed by
an increase in work rate of 50 W every 2.5 min until exhaustion. Subjects selected their preferred pedaling frequency during the test,
and this cadence was maintained constant throughout all subsequent
testing. After a 20-min recovery, subjects cycled to exhaustion at
5-10% above their peak WL (as determined by the prior progressive
test) to verify
O2 max. A plateau
(<150 ml) or decrease in
O2 was observed for each
subject between the final two WL of the incremental
O2 max test
and/or between the final WL of the incremental test and the WL
of the repeat test. The mean
O2 max was 64.3 ± 5.6 ml · kg1 · min1
(range 55-74
ml · kg1 · min1).
On separate days, and on placement of the catheters, subjects completed
two testing sessions (separated by 2-4 wk). Each session consisted
of seven exercise tests (separated by 15-20 min). All tests were
performed at a WL that was at (3 subjects; 412 ± 45 W) or near (4 subjects; 398 ± 31 W; >95%
O2 max) their
O2 max and that could
be maintained 2.5-3.0 min (as determined from a separate practice
session). The first six tests (2.5 min each) consisted of two bouts
with no ventilatory interventions (control), two bouts of inspiratory
muscle unloading, and two bouts of inspiratory muscle loading. The
first test of each day was a trial with no ventilatory intervention
(control), whereas the order of the remaining five bouts was
randomized. Subjects first increased work rate progressively to maximum
over 30 s, and then, within the subsequent 2.5 min, the sequence of
measurements was blood sampling (1:00-1:15 min) followed by
simultaneously measured femoral venous and arterial blood pressure (1:16-1:30 min). This sequence was then repeated (2:00-2:30 min).
The seventh test of each day was a 3-min continuous WL test, consisting
of 30 s of progressive increase in work rate to maximum, 1 min of no
breathing intervention-1 min of either inspiratory muscle loading or
unloading-1 min of no breathing intervention. Blood sampling,
leg, and arterial blood pressure measurements were
made during the final 30 s of each minute. The rationale for this
continuous test was twofold. First, we were interested in the
transitions (10-15 s) from control to load/unload and back to
control to determine whether the changes in respiratory load transiently affected systemic blood pressure and heart rate. Second, we
wished to confirm, by using data obtained during the final 30 s of each
min of the 3-min exercise test, whether the change in
legs (LVR,
O2 tot)
with unloading/loading changed with a changing Wb in a direction
similar to the changes seen during the 2.5-min intermittent tests.
Statistical analysis.
We wished to determine whether, at exercise requiring
O2 max, significant
relationships existed between Wb and the dependent variables under
three conditions: control, inspiratory muscle load, and inspiratory
muscle unload. Therefore, we computed the best fit regression equations
across all exercise trials, first within a single subject and then
across all subjects. The software packages were Sigmaplot and SPSS. An
analysis of variance was used to determine treatment differences
between group mean values under each of the three conditions. Tukey's
post hoc test was used to determine where the differences existed.
Significance was set at P < 0.05.
RESULTS
Table 1 shows the reproducibility of
legs, arterial-femoral venous
O2 difference
[(a-fv)DO2],
leg O2, and LVR measurements within the 2.5-min trials for all tests and between the first trials
(controls) for each subject over both days. The coefficients of
variation (CV) were 
± 3.9% for the within-trial measurements and ± 8.3% for between-trial measurements. No systematic
changes (between-group mean values) were found over time within each
exercise trial or between trials at the 2.5-min time point
(P > 0.05).
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We present our findings concerning the effects of changing the Wb on
several variables of O2 transport
by showing the regression of Wb vs. each variable at
O2 max
1) in absolute values for each
subject and 2) as a percentage of
control across all subjects. The relationships between the dependent
variables and Wb during those 3-min trials in which inspiratory muscles
were unloaded or loaded within the trial were similar
(P > 0.05) to those obtained during
the constant-load exercise. Thus the findings from both types of trials
were combined to determine the relationships of Wb to several variables
of O2 transport. The group mean
changes for each variable measured during inspiratory unloading,
control, and inspiratory loading are summarized in Tables
2 and 3.
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O2 max. Table
2 shows the average change in Wb, peak inspiratory and expiratory Pes,
and ventilatory output achieved with inspiratory unloading and loading.
Inspiratory muscle unloading during exercise reduced the Wb by highly
variable amounts to average 36.7 ± 26.6% of control, whereas with
resistive loads, Wb was increased to 128.2 ± 25.2% from control
with all trials combined. Peak inspiratory Pes was reduced 50 ± 3%
with inspiratory unloading and increased 28 ± 5% with inspiratory
loading. Peak expiratory Pes was reduced 32 ± 4% with inspiratory
unloading but was not different from control with inspiratory loading.
The difference between peak inspiratory and peak expiratory Pes was 50.3 cmH2O during control, 29.1 cmH2O during unloading trials, and
55.2 cmH2O during loaded trials.
Mean Pes was 
6, 1, and 13 cmH2O during control, unloading,
and inspiratory loading, respectively. The Wb during the exercise when
no ventilatory intervention occurred varied randomly from trial to
trial and averaged 91.6 ± 26.6% of the initial control trial
(range 48-188%). Within each subject, VT, f, minute ventilation
(E),
arterial PCO2, pH,
PO2, O2 saturation, lactate,
hemoglobin, and arterial plasma electrolytes (Na2+,
K+,
Cl) did not change
systematically (P > 0.05) across the
range of Wb values (see Table 2). The ratio of inspiratory
time to total time was 0.48 ± 0.22 during unloading, 0.48 ± 0.24 during control, and 0.54 ± 3.2 during loading.
O2 max).
Representative loops are from control, inspiratory assist, and
inspiratory loaded trials. Pes, esophageal pressure.
Effects of changing Wb on O2 transport. Figure 2 shows individual absolute values and each subject's regression for
legs,
O2 legs,
O2 extraction, and mean arterial pressure (MAP) vs. Wb. legs and
O2 legs
changed linearly and significantly and at similar slopes with Wb in six
out the seven subjects. O2
extraction averaged 89-91%, and MAP averaged 125.7 ± 2.7 mmHg, neither of which varied across the range of Wb values.
O2 max.
A: leg blood flow (legs) vs. Wb in subject
1, r = 0.60;
subject 2,
r = 0.68; subject
3, r = 0.94;
subject 4,
r = 0.92;
subject 5,
r = 0.84; subject
6, r = 0.77; and
subject 7,
r = 0.81.
B: leg
O2 uptake [O2
(O2 legs)]
vs. Wb in subject 1,
r = 0.85; subject
2, r = 0.57;
subject 3,
r = 0.84; subject
4, r = 0.80;
subject 5,
r = 0.78; subject
6, r = 0.73; and
subject 7,
r = 0.91. C:
O2 extraction vs. Wb. There were
no significant slopes across Wb. D:
mean arterial pressure vs. Wb. There were no significant slopes across
Wb. Symbols represent individual subjects. Difference between each
subject's absolute values for legs and
O2 legs reflects different absolute maximal exercise loads.
Figure 3 shows the relationship between
legs and Wb and between
O2 legs
and Wb across all subjects. Table 3 compares the mean values during
control Wb and during unloading and loading. As seen in Fig.
3A, during maximal exercise,
legs (expressed as %control, across all subjects)
showed a significant curvlinear inverse relationship to Wb
(r = 0.84), with a greater
effect occurring during loaded conditions. In absolute terms, during unloading, with a 63% reduction from control in Wb,
legs increased an average of 0.8 ± 0.3 l/min
(P = 0.007), and, with a 28% increase from control in Wb, the decrease in legs averaged 1.3 ± 0.2 l/min (P = 0.002)
(Table 3). We also emphasize that the effect of the changing Wb on
legs was observed even when subjects' Wb varied
among control trials, showing that artificially altering intrathoracic
pressure at maximal work was not required to demonstrate these
cardiopulmonary dependencies.
legs and
O2 legs
for all subjects using all trials. Percent control is calculated from 1st test from each testing session.
A: legs is
significantly related to Wb at
O2 max.
B:
O2 legs
is significantly related to Wb at
O2 max. The second
measurements of blood flow, blood pressure, and blood samples of each
test (2:00-2:30 min) were used for interpretation of data.
Circles, control; squares, inspiratory unload; triangles, inspiratory
load. * Significantly different, P < 0.05.
(a-fv)DO2 and %O2 extraction at
O2 max across all
trials averaged 18.2 ml/dl and 90.3%, respectively. Figure
3B demonstrates that
O2 legs
was inversely related to Wb (r = 0.77), and this was due entirely to the change in
legs because no change in O2 extraction occurred (Fig.
2C). In absolute terms, with a 67% reduction from control in Wb,
O2 legs
increased an average of 0.10 ± 0.07 l/min
(P < 0.05) and with a 28% increase
from control in Wb,
O2 legs
decreased an average of 0.28 ± 0.06 l/min
(P < 0.05) (Table 3).
Effects on
O2 tot.
Figure 4A
demonstrates that pulmonary
O2 (i.e.,
O2 tot)
at O2 max did not
change systematically, as Wb was increased >100% of control. But
with ventilatory unloading and reduced Wb, O2 tot
decreased in most trials, although these effects were highly variable
from trial to trial. Also, mean
O2 tot
during all trials with unloading (3.96 ± 0.13) was significantly
lower than all trials with loading (4.29 ± 0.11;
P = 0.007) or control (4.22 ± 0.08; P = 0.02) (Table 3).
O2
(O2 tot;
respiratory O2) vs.
Wb at O2 max.
B:
O2 legs/ O2 tot
vs. Wb at O2 max. See
legend for Fig. 3. * Significantly different,
P < 0.05.
The significance of a decreased
O2 tot
with inspiratory unloading and unchanged
O2 tot
with inspiratory loading becomes apparent when viewed in relation to
the increase in
O2 legs when
Wb was decreased and reduced
O2 legs when
Wb was increased. Figure 4B shows the significant
relationship of the ratio
O2 legs/O2 tot to
Wb. O2 legs
as a percentage of
O2 tot
was 81 ± 1% during control, 89 ± 1% during trials with
unloading (P = 0.009), and 71 ± 1% during trials with loading (P = 0.005) (see Table 3).
LVR and NE spillover.
MAP averaged 125-126 mmHg at
O2 max under all
conditions. Figure 5,
A and
B, shows the significant linear
positive relationship between LVR and Wb within each individual subject
and across all subjects and trials, respectively. Mean values in Table
3 show that with unloading, LVR decreased an average of 7.1 ± 0.5%
or 0.5 ± 0.1 mmHg · l1 · min
(P = 0.04) and with loading, LVR
increased an average of 6.2 ± 0.8% or 1.0 ± 0.3 mmHg · l1 · min
(P = 0.001). Percent changes were
similar between LVR and leg vascular conductance.
O2 max for
subject 1,
r = 0.89; subject 2, r = 0.83;
subject 3,
r = 0.81; subject
4, r = 0.80;
subject 5,
r = 0.69;
subject 6,
r = 0.68; and subject
7, r = 0.78. B: LVR (%control) vs. Wb at
O2 max. As Wb
increases, LVR significantly increases.
C: LVR vs. norepinephrine (NE)
spillover at O2 max. Change in NE spillover is related to change in LVR. See legend for Fig.
3. * Significantly different, P < 0.05.
Figure 5C shows the relationship between LVR and NE spillover, and mean values are shown in Table 3. NE spillover was significantly related to LVR (r = 0.71). NE spillover increased an average of 78 ± 5% above control with loading, coinciding with a 12.6 ± 3.4% increase in LVR (P = 0.004). NE spillover decreased an average of 11 ± 3% below control with unloading and was related to a 1.8 ± 0.4% decrease in LVR (P = 0.02). Effect of transient changes in Wb during constant maximal work rate. Figure 6 shows a representative tracing from one subject of blood pressure, heart rate, and Pes during a 3-min trial at the transitions where inspiration was unloaded or loaded within the trial. Systemic arterial blood pressure or heart rate did not change significantly between the transition of the control period to the initiation of inspiratory load or from inspiratory load to control, although Pes changed markedly during these transitions. The 5-beat MAP and heart rate averages for all subjects were 125.6 ± 4.6 mmHg and 184 ± 4 beats/min, respectively, immediately before inspiratory loading (P > 0.05) and were 127.2 ± 4.9 mmHg and 185 ± 4 beats/min, respectively, at the onset of inspiratory loading (P > 0.05). With inspiratory unloading, the 5-beat MAP averages before and immediately after a decrease in Pes were 126.2 ± 3.9 and 128.1 ± 4.2 mmHg, respectively (P > 0.05), whereas systolic and diastolic blood pressure were unchanged. The 5-beat heart rates in these same time periods averaged 185 ± 5 and 184 ± 4 beats/min, respectively (P > 0.05).
O2 max showing blood
pressure, heart rate, and esophageal pressure (Pes) transitions during
a 3-min trial in which ventilatory conditions were control-inspiratory
unload-control (A) and
control-inspiratory load-control
(B). Note no change in blood
pressure or heart rate despite large changes in Pes.
Mean values for selected variables during the 3-min trials are shown in Table 4. During these continuous tests, a time-dependent effect was present, as noted in the difference in mean values between the first and second control periods of each test. Nevertheless, the changes in
legs and
O2 legs
with changing Wb were in a similar direction to those found in a
comparison of the intermittent 2.5-min tests with each test conducted
at a fixed respiratory load (as reported above). There were no
differences in MAP or heart rate between control and loading/unloading
conditions during these continuous tests.
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DISCUSSION
O2 in the healthy trained
human. We found that changing (increasing and reducing) Wb during
maximal exercise caused significant changes in locomotor muscle
vascular resistance and perfusion. Significant regressions of
legs to Wb were obtained both within individual subjects and across all subjects. The changes in legs
were not accompanied by changes in
O2 extraction across the limb;
thus O2 legs
also changed directly with legs and with the Wb.
Furthermore, with reduced Wb during maximal exercise,
O2 tot
(respiratory) fell significantly, an effect which, when considered in
combination with the corresponding increase in
O2 legs,
meant that reducing the normal amount of the work of the respiratory
muscles at maximal exercise resulted in a substantial increase in the
fraction of O2 tot
(and presumably total ) devoted to working
locomotor muscles. Changes in NE spillover across the working limb
suggested active, sympathetically mediated alterations in limb vascular resistance triggered by changes in respiratory muscle work, possibly mediated by a respiratory muscle chemoreflex effect. These findings suggest that the level of respiratory muscle work normally engendered during maximal exercise in humans attenuates the rise in
and O2 transport to working limb
locomotor muscles.
Evidence for cardiovascular effects of a changing Wb.
The interpretation of our findings is critically dependent on our
ability to detect systematic changes in the 1- to 3-liter/min range of
limb during maximal exercise. We believe this degree of sensitivity was achieved through our use of the thermodilution technique and by our experimental design.
The thermodilution technique for the determination of limb
does not have an absolute gold standard for
comparison. Thus, criteria for acceptable measurements are based on how
stable and reproducible the obtained values are, sensitivity of the
technique to be able to detect expected differences, and agreement with the values repeated by others. Accordingly, we found that the legs measurement showed no significant systematic
variation within subjects within a maximum WL trial or between trials
during maximal exercise. Furthermore, the random variations under these repeat-test conditions were <±8%. In a separate study with one subject, we also found that repeat legs
thermodilution measurements were highly sensitive to small (<10%)
changes in work rate. These limited observations agree with the
sensitivity previously reported by others (17). We also note that our
absolute legs values agree with those
obtained by others at similar levels of maximal work rate (17, 18, 20,
21).
Equally important, we employed a study design requiring randomly
assigned repetitions of maximal work rates under the three conditions
of respiratory muscle loading, unloading, and control. These multiple
trials allowed us several different means of testing the hypothesis of
a significant Wb-legs relationship, that is 1) within a single subject (at same
maximal work rate) as well as across subjects (each at different
maximal work rates); and 2) between
maximal work rates conducted intermittently, during which the levels of
respiratory muscle loading or unloading were constant throughout the
work load, vs. within a maximal work rate, during which loading and
unloading were altered during the exercise. These different approaches
consistently confirmed a significant association of respiratory muscle
work with limb locomotor at maximal exercise.
Furthermore, observed changes in legs and in LVR were
indirectly supported by appropriate directional changes in measurements
of NE spillover across the working muscle (see Fig. 5).
We presumed that the significant correlations of Wb to
legs at constant maximal work rate reflected cause
and effect. This interpretation required that our imposition of
mechanical unloading (via PAV) or loading (with increased inspiratory
resistors) did not exert some additional influences on cardiac output
or locomotor muscle vasoreactivity in addition to the postulated
effects of changes in intrathoracic pressure and Wb. We noted that
T and f during
maximal exercise remained unchanged with loading and unloading,1
as did arterial and femoral venous blood gases, acid-base status, and
electrolyte concentrations. These findings imply that at least the
potential vasomotor effects of pulmonary stretch receptor feedback (26)
and several known circulating vasoactive agents (K+,
H+,
PO2,
PCO2) remained unchanged with
respiratory muscle loading and unloading at maximal exercise.
Limitations.
For us, a major remaining unknown in quantifying the effects of changes
in Wb on local legs is the effect of a changing intrathoracic pressure on total cardiac output. Considerable literature reveals significant but variable effects of changing intrathoracic and
ventricular transmural pressures on preload and afterload (and
therefore stroke volume) of the healthy heart (19). During maximal
exercise, substantial negative and positive intrathoracic pressures
occur at peak inspiration (25 to 30
cmH2O) and expiration (20 to 25 cmH2O), respectively. Our
unloading and loading protocols had marked effects primarily on
inspiratory pressure, and to a lesser extent on expiratory pressure and
the difference in pressure from inspiration to expiration (see Table 2;
Figs. 1 and 6). Theoretically, a case may be made for either no effect
or an enhancing effect of a changing negative intrathoracic pressure
and abdominal pressure on stroke volume during exercise. This depends
on whether the dominant effect of these pressure changes is on venous
return (preload) or on transmural pressure across the myocardium
(afterload). Over several breaths, the effect on cardiac output may
also depend on changes in the magnitude of pleural pressure differences
between inspiration and expiration or the mean pleural pressures. In
addition, there may also be significant reflex sympathoexcitatory
affects on myocardial contractility and heart rate triggered via
feedback from respiratory muscles during respiratory muscle unloading
and loading (8, 19).
Our own indirect data on this question of effects of changing
intrathoracic pressure on cardiac output are inconsistent. We observed
no immediate transient changes with an increased or decreased inspiratory load (and Pes) on systemic pressures or heart rate (see
Fig. 6). This implied to us that left heart stroke volume had also
remained unchanged in response to the immediate increases or decreases
in intrathoracic pressure. Furthermore, with inspiratory muscle
loading,
O2 tot
did not change systematically, also implying that maximal cardiac
output had not changed, i.e., the measured reduction in limb
(and
O2 legs)
was presumably matched by an equal increase in respiratory muscle
(and O2).
However, with respiratory muscle unloading, we did observe a variable
yet significant 9.3% (0.39 ± 0.09 l/min) reduction in
O2 tot.
If no change occurred in the arterial to mixed venous
O2 content difference with
unloading, this reduction in
O2 tot
would mean that cardiac output was also reduced. As explained above,
direct measurements of cardiac output are needed to test this proposed effect of unloading.
Another unknown in our study is the actual muscle mass engaged in the
exercise. For example, with respiratory muscle loading, legs was reduced and
O2 legs
fell 280 ml/min, and yet the external work rate was maintained for 2.5 min. From what source is the energy expenditure derived to maintain
this work rate? An increased lactate metabolism may account for a small
portion of this (10), although this was not reflected in changes in circulating lactate concentrations across the working limb (Table 2). A
more likely explanation may be to recall that our
legs, (a-fv)DO2,
and O2 measurements pertain
principally to the quadriceps and hamstring muscles. Accordingly, as
and O2 are
reduced in these muscles during respiratory muscle loading, additional "nonfemoral" locomotor muscles such as the gluteus may have been recruited to maintain external power output.
Effects on limb of changing the mass of working
muscle.
Although we found that increases in the amount of working respiratory
muscle mass significantly reduced limb , most
previous studies using arm work added to leg work found no significant effect on limb (see above). Addition of arm work was
shown to increase LVR (21) and to increase NE spillover across the working muscle (20, 21, 25), and this is similar to our findings with
added respiratory muscle mass. However, in a study with added arm work,
Richter et al. (21) reported that systemic pressure also rose
sufficiently to preserve flow to the working limb. The difference in
our findings of a reduction in limb flow with added respiratory muscle
work is not attributable to the amount of added muscle mass because
respiratory and accessory muscles would weigh only about one-third of
the estimated 10-15 kg mass of added muscle with arm work (22).
There are two explanations for these disparate findings. First,
respiratory muscles may compete more effectively than limb muscles for
total (see below). This possibility is suggested by
the increase in diaphragm and decrease in limb
locomotor muscle during submaximal exercise in rats
when Wb was presumably increased via experimental congestive heart
failure (14). A second explanation for the apparent discrepancy in
findings is the exercise intensity used. That is, the use of submaximal
leg exercise intensities in previous studies (see above) meant that substantial reserve was available to increase cardiac output and MAP,
and therefore preserve local , whereas during our
maximal WL, these reserves were not available when extra working
(respiratory) muscle mass was added. A first step toward examining
these questions in humans would be to determine the effects of
respiratory muscle loading and unloading on locomotor muscle vascular
resistance and at several submaximal exercise
intensities.
redistribution effectmagnitude and mechanism.
Our data indicate that respiratory muscles under load competed
effectively with limb locomotor muscles for a significant portion of
available total cardiac output at maximal exercise. Across the range
achieved for respiratory muscle work (7 to 198% of control) at maximal
exercise, legs changes averaged 13% or ~2 l/min. Furthermore, changes in legs with changes in Wb were
greatest when ventilatory work was increased (rather than decreased) at maximal exercise. This substantial redistribution effect between locomotor and (presumably) respiratory muscles may reflect two important properties of respiratory muscles. The diaphragm and accessory respiratory muscles are of high oxidative capacity; accordingly, their resistance vessels may be especially responsive to
local vasodilator influences, as shown in the highly trained limb
muscle vasculature (11, 12). Second, increased work by the respiratory
muscles has been shown to promote reflex sympathoexcitation and
vasoconstriction of systemic vascular beds (8), similar to the reflex
pressor responses attributed to type III and IV afferents from
contracting limb muscles (Ref. 16; also see below for details). We do
not know whether the sensitivity of these vasoactive characteristics
are sufficiently different in limb and respiratory muscles to explain
the redistribution phenomena we have observed. Finally, a reduced total
available cardiac output during unloading (see
Limitations) may explain in
part why the increase in legs during unloading was
less than the reduction in legs with loading.
The change in vascular resistance and redistribution of
between respiratory and locomotor muscles as Wb was
altered at maximal exercise was accompanied by changes in NE spillover
across the working limb muscle. These findings imply an increased
muscle sympathetic nerve activity (MSNA) and vasoconstriction with
respiratory muscle loading and reduced MSNA and vasodilation with
respiratory muscle unloading (25). The vasodilatory effect in response
to respiratory unloading is consistent with the concept that a
significant level of sympathetically mediated vasoconstriction is
normally present in active limb skeletal muscle at maximal exercise
(24). Our findings imply further that a significant portion of this vasoconstrictor sympathetic outflow during maximal exercise may emanate
from tonically active respiratory muscle chemoreflexes (see below).
Two reflexes might be invoked to explain the changes in sympathetic
outflow. First, arterial baroreceptor stimulation may have triggered
reflex sympathetic excitation/withdrawal as changes in Wb caused
changes in respiratory muscle perfusion. However, the role of
baroreceptor feedback effects on sympathetic efferent activity is
difficult to evaluate in these complex conditions of large dynamic
changes in intrathoracic pressure during maximal exercise:
1) we did not observe even transient
changes in systemic blood pressure with loading or unloading (see Fig.
6); however, aortic arch baroreceptor tissue might undergo deformation
even in the absence of changing blood pressure, as shown during lower body negative pressure at rest (28);
2) ventricular mechanoreceptors sensitive to cardiac filling pressures would be influenced by any
changes in venous return; and 3)
aortic baroreceptors are also affected "directly" by changes in
intrathoracic, and therefore in aortic, transmural
pressures (3). The predicted changes in cardiac filling pressure or
aortic transmural pressure with respiratory muscle loading/unloading
would be in the opposite direction expected to elicit the observed
reflex vasoconstriction/vasodilation in limb locomotor muscle.
Furthermore, our findings that transient changes in heart rate did not
occur with unloading/loading are also indicative that systemic
baroreceptors were not influenced by the respiratory changes. A more
likely candidate for mediation of reflex vasoconstriction is the muscle
chemoreflex, a sensitive feedback mechanism known to originate from
type III and IV afferents in contracting limb muscles (24) and in the
diaphragm (8). On stimulation of their thin-fiber phrenic afferent
pathways in the diaphragm, sympathoexcitation and vasoconstriction in
both respiratory and resting limb skeletal muscle can be induced (8).
Effects of Wb on distribution of total maximal
O2 transport.
The effects of partial respiratory muscle unloading on increasing limb
muscle speak directly to the question of the
physiological relevance of Wb normally achieved during maximal exercise
to O2 transport to locomotor
muscles. It is not unexpected that the respiratory muscle work normally
achieved in maximal exercise would require a significant share of
maximal cardiac output. In humans, indirect estimates of the
O2 cost of maximal exercise hyperpnea are as high as 15% of
O2 tot
in highly fit subjects who achieve significant expiratory flow
limitation in heavy exercise and 8 to 12% in the normally fit who
undergo little or no airflow limitation at maximal exercise (1). Most
of our fit subjects in the present study would have been grouped with
those with the higher O2 cost of
breathing, although we would also expect to see significant but smaller
effects of unloading on legs in less fit subjects at
lower maximal work loads and with little or no expiratory flow
limitation.
Our findings from unloading the respiratory muscles also showed that
the Wb normally achieved at maximal exercise has a significant effect
on leg locomotor muscle O2.
At maximal exercise, reducing (or increasing) Wb had no effect on
O2 extraction across the leg locomotor muscles, which was probably at its maximum capacity; thus, as
legs increased, locomotor muscle
O2 also increased. Along with
this increase in
O2 legs,
respiratory muscle unloading also reduced
O2 tot.
Accordingly,
O2 legs,
as a fraction of O2 tot,
increased markedly with respiratory muscle unloading (see Fig.
7), showing that the effect of respiratory
muscle work on
O2 legs
is even more substantial in terms of redistributing the
"available" total O2
transport. The reduced
O2 tot
also indicates that with unloading, all O2 uptake
"released" by the respiratory muscles was not manifested in
O2 legs;
however, as discussed earlier, we are unable to evaluate the
cause of this reduced
O2 tot
until we know the coincident effects on cardiac output.
O2 tot
was significantly lower with unloading and unchanged with loading,
whereas
O2 legs
was significantly increased with unloading and decreased with loading.
B: respiratory muscle unloading
increased and respiratory muscle loading reduced the fraction of total
O2 consumed by the legs.
ACKNOWLEDGEMENTS
We are especially indebted to Dr. Magdy Younes, who invented the Proportional Assist Ventilator and loaned us one of his prototypes to conduct this study. We are also grateful for the very helpful advice and critique supplied by Dr. Loring Rowell. Drs. Russell Richardson, Greg Cartee, and Jack Barclay also provided valuable advice.
FOOTNOTES
Address for reprint requests: C. A. Harms, Dept. of Preventive Medicine, 504 N. Walnut St., Madison, WI 53705.
Received 26 November 1996; accepted in final form 23 January 1997.
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