1576
Skeletal Muscle Metaboreceptor Stimulation
Opposes Peak Metabolic
Vasodilation in Humans
Lawrence Sinoway and Steven Prophet
The total blood flow requirements of a large muscle mass can exceed the maximal cardiac
output generated by the heart during exercise. Therefore, to maintain blood pressure, muscle
vasodilation must be opposed by sympathetic vasoconstriction. The primary neural signal that
increases sympathetic outflow is unclear. In an effort to isolate the vasoconstricting mechanism
that opposes vasodilation, we measured the peak forearm vascular conductance response after
the release of 10 minutes of forearm circulatory arrest under five separate study conditions:
1) no leg exercise, 2) low-level supine leg exercise, 3) low-level supine leg exercise with leg
circulatory arrest after exercise, 4) high-level supine leg exercise, and 5) high-level supine leg
exercise with leg circulatory arrest after exercise. We found that both high-workload conditions
reduced peak forearm conductance below the no-leg exercise condition (a 34% reduction
during leg exercise and a 52% reduction during leg exercise followed by leg circulatory arrest).
In addition, at each workload, leg circulatory arrest after exercise, which isolated the skeletal
muscle metaboreceptor contribution to vasoconstriction, reduced forearm conductance by
approximately 20%o below the values noted for leg exercise alone (combined central command
and metaboreceptor stimulation). In a separate group of subjects, peak forearm blood flow was
measured during lower-body negative pressure to levels up to -40 mm Hg, a maneuver that
unloads high- and low-pressure baroreceptors. This intervention did not affect peak forearm
blood flow. We conclude that 1) metaboreceptor stimulation is the crucial mechanism causing
the vasoconstriction that opposes metabolic vasodilation, 2) some volitional influence during
exercise acts to oppose metaboreceptor-mediated constriction, and 3) baroreceptor unloading
does not influence maximal forearm conductance. (Circulation Research 1990;66:1576-1584)
A lam and Smirk1 first demonstrated that if
circulatory arrest of exercising muscle is
initiated during or immediately before the
end of exercise, the resultant blood pressures are
higher than resting values. It was postulated by these
authors that the accumulation of ischemic metabolites stimulated sensory nerves within skeletal muscle
and triggered a pressor reflex. Traditionally, this
reflex has been viewed as a system that acts to
increase blood flow to exercising skeletal muscle; that
From the Division of Cardiology, The Milton S. Hershey
Medical Center, The Pennsylvania State University, Hershey,
Pennsylvania.
Presented as a preliminary report on March 20, 1989, at the
Annual Meeting of the Federation of American Societies for
Experimental Biology.
Supported in part by a grant-in-aid from the American Heart
Association, Pennsylvania Affiliate. L.S. is a recipient of Clinical
Investigator Award 1 K08 HL-01749 and First Award 1 R29
HL-44667-01.
Address for correspondence: Lawrence I. Sinoway, MD, The
Milton S. Hershey Medical Center, The Pennsylvania State University, Division of Cardiology, P.O. Box 850, Hershey, PA 17033.
Received June 21, 1989; accepted January 19, 1990.
is, it has been assumed that vasoconstriction does not
occur in metabolically active muscle beds.2 This
would be consistent with studies that have suggested
that the metabolites that cause vasodilation can
override sympathetic vasoconstriction and cause a
functional sympatholysis.3
However, it has recently been suggested that in
humans heavy exercise by a large percentage of total
body muscle mass can lead to muscle flow requirements that exceed the maximal cardiac output.45
Thus, if vasodilation to active muscle were unopposed, blood pressure would drop. This strongly
suggests that vasoconstriction in metabolically active
skeletal muscle must occur. The afferent signal for
this vasoconstriction is unknown, although it has
recently been postulated that skeletal muscle
metaboreceptor stimulation may be responsible.6
In this report, we examined whether stimulation of
metaboreceptors within skeletal muscle would actually cause a vasoconstrictor response that was capable of opposing a potent metabolic vasodilator stimulus, a metabolic stimulus of a magnitude similar to
Sinoway and Prophet Metaboreceptor Stimulation Opposes Peak Vasodilation
that seen with vigorous physical exercise. To separate
the presumed metabolic vasodilator and vasoconstrictor stimuli that would occur during exercise, we
performed leg exercise at two workloads with and
without leg circulatory arrest after exercise (vasoconstrictor stimulus) and simultaneously examined
changes in forearm blood flow and vascular conductance in response to 10 minutes of forearm circulatory arrest (vasodilator stimulus). Our results suggest
that metaboreceptor stimulation causes a workloaddependent vasoconstriction that opposes peak metabolic vasodilation. Moreover, our results provide
evidence that metaboreceptor stimulation may be
crucial in preventing muscle vasodilation from outstripping maximal cardiac output.
Subjects and Methods
Study Design
Seven healthy male subjects ranging in age from 24
to 35 years (29±2 years) were studied. All subjects
were in good health, and none took medication. All
subjects signed an informed consent form that was
approved by the Hershey Medical Center Clinical
Investigation Committee. Before the 4 days of forearm blood flow and exercise measurements, systemic
oxygen consumption at the maximum workload (max
Vo2) was measured during a progressive upright
bicycle ergometer test.
The overall plan of the study was to examine two
different levels of exercise to grade metaboreceptor
and central volitional influences. At both levels of
exercise two study conditions, leg exercise and leg
circulatory arrest after exercise, were used in an
effort to isolate metaboreceptor influences.
The ability of these various conditions to cause a
vasoconstrictor stimulus capable of opposing peak
metabolic vasodilation was then tested. This was
accomplished by measuring the peak forearm vascular conductance response that followed the release of
10 minutes of forearm circulatory arrest (peak reactive hyperemic blood flow [RHBF]) during each of
these separate exercise conditions (Figure 1). Thus,
peak forearm blood flow response was measured
during four protocols: 1)12 minutes of supine leg
exercise at 25% max Vo2 (25% protocol), 2) approximately 9 minutes of supine leg exercise at 25% max
V02 followed by 2 minutes of two-legged circulatory
arrest (25%+CA protocol), 3) 11-12 minutes of
supine leg exercise at 75% max Vo2 (75% protocol),
and 4) approximately 9 minutes of supine leg exercise
at 75% max Vo2 followed by approximately 45 seconds
to 2 minutes of leg circulatory arrest (75%+CA protocol). For all four protocols, leg exercise was begun at
the time of forearm circulatory arrest. For the leg
circulatory arrest studies, leg occlusion took approximately 5-10 seconds. The subjects then stopped pedaling, and their legs were placed flat on the exercise
table. Approximately 20 seconds later, forearm arterial occlusion was released, and forearm blood flows
were measured (see below). The 25% protocol was
1577
PEAK RHBF
40
FOREARM OCC
l
A
l
25%
LEG EXERCISE
B
25%
LEG EXERCISE__oc5
C
75%
LEG EXERCISE
7%
D
g
LEG EXERCISE
r~~~~~~~
.-1
0
l
a
9:30 10
l
12
TIME (MIN)
FIGURE 1. Schematic representation of the four leg exercise
protocols (A-D) performed by each of the seven subjects.
Supine leg exercise and forearm arterial occlusion (OCC) were
initiated at the same time in each protocol. Protocols B and D
demonstrate that leg circulatory arrest was initiated 9 minutes
and 30 seconds into exercise (first single dotted line). This was
followed approximately 10 seconds later by the stopping of leg
exercise (solid line following dotted line). Leg occlusion (LEG
OCC) was continued past the point of peak forearm blood
flow measurements. The time of peak reactive hyperemic
blood flow measurements (peak RHBF) is shown by arrows at
the top of the figure. The correspondingprotocols from the text
are as follows:A, the 25% protocol; B, the 25%+CA protocol;
C, the 75% protocol; and D, the 75% +CA protocol.
always performed first to determine if the subjects
could tolerate the least stressful protocol. We reasoned that if a subject could not tolerate this intervention, he would be unable to tolerate either circulatory
arrest after exercise or exercise at 75% max Vo2. The
75%+CA protocol was performed last in six of seven
subjects. In addition, on each of these 4 days of study,
the RHBF was measured without leg exercise.
In six separate subjects (mean age, 29±2 years;
range, 29-35 years), we examined the influences of
lower-body negative pressure (LBNP) at -15 and
-40 mm Hg on peak forearm vascular conductance.
This was done to examine directly the effects of the
removal of tonic baroreceptor activity on peak forearm blood flow. LBNP was begun 7 minutes after
forearm arterial occlusion was begun. The sequence
during LBNP study was 1) peak forearm blood flow
without LBNP, 2) peak forearm blood flow during
-15 mm Hg LBNP, 3) peak forearm blood flow
during -40 mm Hg LBNP.
1578
Circulation Research Vol 66, No 6, June 1990
In an additional six subjects (mean age, 27±2
years; range, 23-36 years), the effects of leg circulatory arrest alone on peak forearm blood flow were
determined. In these studies, leg arrest was begun
approximately 20 seconds before the release of forearm arterial occlusion.
Max Vo2 Determination
In all seven subjects, an incremental workload
protocol using an upright bicycle ergometer (Collins,
Braintree, Massachusetts) was used to determine the
max Vo2.7 The workload was increased by 50 W every
3 minutes until fatigue. The heart rate was monitored
by electrocardiogram. Oxygen consumption was measured with a Beckman metabolic cart (model MMC1,
Sensormedics, Anaheim, California). Expired 02 was
measured with a polarographic analyzer, and CO2
measurements were performed by an infrared analyzing system. Both 02 and CO2 analyzers were
calibrated using two standard gas calibration tanks
(Sensormedics). The metabolic cart was recalibrated
after every other 3-minute workload during the
entire exercise test. Minute 02 consumption, minute
CO2 production, and total ventilation were recorded
every 30 seconds. The ventilatory gas exchange ratio
was defined as minute CO2 production divided by
minute 02 consumption.
Forearm Blood Flow Measurements and Supine
Leg Exercise
Subjects reported to the human research laboratory in the postabsorptive state. The subjects were
placed supine on the exercise table (see below).
Forearm blood flows were measured with the venous
occlusion technique.8'9 The left forearm of each
subject was studied. The midforearm was raised
approximately 10 cm above the heart; the wrist and
elbow were supported, and the midforearm was free.
A single-strand, mercury-in-Silastic strain gauge10
was placed 7 cm below the olecranon process. The
gauges were externally calibrated before being
placed on the forearm.8'9 A rapidly inflatable occlusion cuff was placed on the upper arm; the venous
occlusion pressure was 50 mm Hg. A separate occlusion cuff was placed at the wrist.11 Before any flow
measurement, the hand circulation was arrested for
at least 1 minute. A 1-minute period of forearm
arterial occlusion was then performed since prior
studies have shown that the first in a series of peak
flow measurements is the lowest. The blood flow
response to 10 minutes of circulatory arrest (RHBF)
was then measured. Previous studies have shown this
to be a stimulus sufficient to produce maximal metabolic forearm vasodilation.12 Upon release of arterial occlusion, temporary venous occlusions were
performed at 5-8 seconds, 15 seconds, and every 15
seconds after release for 2 minutes. The peak flow
was always determined within 30 seconds of the
release of arterial occlusion. After the dissipation of
forearm paresthesias, forearm occlusion was initiated
again, and one of the four supine exercise protocols
was begun. The supine leg exercise protocols (25%,
25%+CA, 75%, 75%+CA) were performed on a
cardiac stress testing system (Engineering Dynamics,
Lowell, Massachusetts). The subjects performed
exercise at approximately 60 rpm. Upon release of
forearm occlusion, blood flows were measured in the
same manner as described above. Mean blood pressures (MAPs) were measured in the opposite forearm with an automated device that employed the
oscillometric method (Dinamap, Tampa, Florida).
The MAPs were determined at the approximate time
of the release of forearm circulatory arrest and then
every 15-20 seconds. Blood flows are presented as
milliliters per minute per 100 ml, and forearm vascular conductance (forearm blood flow divided by
MAP) is expressed as milliliters per minute per 100
ml divided by millimeters mercury. For the vascular
conductance measurements, MAP closest in time to
the flow measurements was used in the calculations.
Since our measurements of forearm conductance in
the above protocol were dependent on indirect measurements of MAP, we performed additional experiments validating this noninvasive method during
supine exercise. In two subjects, MAP measured by
this indirect method was compared with direct intraarterial catheter measurements. A 20-gauge sterile
catheter was placed in the radial artery, and noninvasive blood pressure was measured in the opposite
forearm. The arterial catheters were filled with heparinized saline and attached to calibrated pressure
transducers placed at the midchest level (American
Edwards, Irvine, California). In these experiments,
MAP was compared during baseline and supine exercise at 50, 100, 150, and 200 W of work.
Statistical Analysis
The effects of the various exercise regimens on the
various parameters (blood flow, conductance, MAP)
were evaluated using an analysis of variance for repeated measures within an individual. When a significant F value was found, post hoc analysis was performed with the Newman-Keuls method. Day-to-day
variability of the various parameters during RHBF
without exercise was analyzed in a similar manner. A
value ofp <0.05 was considered statistically significant.
All values are presented as mean+SEM.
Results
Noninvasive Blood Pressure Validation
The MAP measured by the oscillometric method
(indirect method) showed a strong correlation with
blood pressure obtained by radial artery catheter
with an r value of 0.98 (p<0.001) (Figure 2).
Oxygen Consumption Data
Max V02 was 45.3 +3.4 ml/kg/min. The heart rate
at end exercise was 175 beats/min (92% of predicted), and the respiratory quotient was 1.01±0.02. The
maximal workload was 225.0+15 W. The mean work-
Sinoway and Prophet Metaboreceptor Stimulation Opposes Peak Vasodilation
y = 17.837 + 0.81719x
1579
r= 0.98
FIGURE 2. Graph comparing the mean artenial
blood pressure obtained by the oscillometric method
(indirect method) with mean arterial blood pressure
obtained by indwelling arterial catheters placed in
the opposite radial artery (direct method). In these
experiments, pressures were compared at rest, during
50, 100, 150, and 200 Wof supine exercise in the two
subjects. The r value for this comparison is 0.98
(p<0.001). The dotted line represents the line of
identity (y=x), and the solid line represents the
regression equation. Squares, values at each of four
exercise levels and rest for two subjects.
INDIRECT
METHOD
(mm Hg)
90
100
110
120
1 30
DIRECT METHOD (mm Hg)
loads used for the 25% and 75% protocols
W and 168-+-11
were
56±4
W, respectively.
Hemodynamic Data
The MAP, peak forearm blood flow, and vascular
conductance responses obtained without leg exercise
on the four separate study days of the primary experiment were not different. There were no significant
sequence effects for any of the three parameters.
Because of this, the data obtained during forearm
occlusion without leg exercise obtained on the four
separate days of study were averaged. These averaged
values were then used in our statistical analysis and are
presented as the respective "baseline" responses to 10
minutes of forearm circulatory arrest.
MAP During Peak Forearm Blood Flow
Figure 3 shows the mean data for MAP (as well as
RHBF and forearm conductance) during the various
exercise conditions for the seven subjects. MAP was
higher during the 75% and 75% +CA protocols than
during RHBF without leg exercise. At each workload, leg circulatory arrest did not change the MAP
response. Based on the regression equation in Figure
2, our reported pressures may be underestimated by
approximately 4 mm Hg at the higher workload.
Peak Forearm Blood Flow
Peak blood flow values obtained during the
25%+CA and 75%+CA protocols were lower than
values obtained during the 25% and 75% protocols.
When compared with "baseline" levels of peak flow,
only the values at the 75% +CA protocol were lower
(Figure 3). This represented a 34% reduction in peak
flow. In addition, it should be noted that the RHBF
value during the 75%+CA protocol was lower than
the value during the 25%+CA protocol, a finding
consistent with greater metabolic stimulation at the
higher workload. Representative blood flow tracings
are shown during baseline and the 75%+CA protocol in Figure 4.
Foreann Conductance
Both the 75% and 75% +CA protocols led to lower
vascular conductances than noted during forearm
arterial occlusion without leg exercise. The reduction
noted during the 75%+CA protocol represented
52%. In addition, conductance during the 75%+CA
protocol was statistically lower than at the 25% +CA
protocols. Finally, the peak forearm conductance
values during the 25%+CA and 75%+CA protocols
were lower than values obtained during the respective levels of leg exercise alone. The reduction in
conductance attributable to the leg circulatory arrest
was 19% at the low workload (25% vs. 25%+CA)
and 21% at the high workload (75% vs. 75%+CA).
The potential error in conductance measurements
due to the use of noninvasive pressures should be 5%
or less under all study conditions.
Changes in forearm vascular conductance over the
90 seconds after the release of arterial occlusion are
shown for each of the five study conditions in Figure
5 (no leg exercise and the four protocols). The rate of
reduction in vascular conductance shown by the
curve for no leg exercise and the curve for the 25%
protocol seem relatively similar. However, each successive curve thereafter shows a trend toward a more
rapid reduction in forearm conductance.
LBNP and Leg Occlusion Studies
LBNP had no effect on peak forearm blood flow.
This was true at both -15 and -40 mm Hg. Baseline
RHBF was 54.3 +5.3 ml/min/100 ml; during LBNP at
-15 mm Hg, 52.0+7.3 ml/min/100 ml; during LBNP
at -40 mm Hg, 46.8+6.6 ml/min/100 ml (F= 1.17, 2,
and 10; p=NS). Not surprisingly, LBNP to -40
mm Hg was associated with a 7-mm Hg reduction in
mean MAP. Thus, conductance during LBNP of -40
Circulation Research Vol 66, No 6, June 1990
1580
BASELINE 75% + CA
NS
I,
T *-
130-
120T-
E
1-
NS
110-
I
90-
80S..
60
*.
BASE
E
0
50
cc 0
40-
w E
30-
-
._
0
LL
lA *.
25%
25%+CA
pc.05|
60
-
LL
m
i
-T1riri
100-
m-r-
1[
1.
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.
25%
25%+CA
E
E
0
0
U.
0.5-l
0.41
0.31
z
0.2.
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0.1
MAP
88
124
C
0.40
0.10
* *-J
-l
75%
75%+CA
= 0:=
pc.05
pc05
.
ONE SECOND
I
75%
75%+CA
p.C.05
p.c.05
a.,
12.0
l
1200.I3
0.61
35.5
VENOUS OCCLUSION
BASE
W
Q
I
PpC.05
11
-~~
a
-T
BASE
25°S
25%W+CA 75% 75%+CA
FIGURE 3. Bar graphs showing the mean arterial blood
pressure (MAP), peak reactive hyperemic blood flow (RHBF),
and conductance responses during the five conditions. BASE,
responses after 10 minutes offorearm circulatory arrest without leg exercise; 25%, responses after 12 minutes of supine leg
exercise at 25% maximum Vo2; 25%+ CA, responses after 9
minutes of supine leg exercise at 25% maximum VO2 followed
by 2 minutes of leg circulatory arrest (CA); 75%, responses
after 11-12 minutes of supine leg exercise at 75% maximum
Vo2; 75%+CA, responses after 9 minutes of supine leg
exercise at 75% maximum V02 followed by 45 seconds to 2
minutes of CA. Of note, MAP was higher than base during
75% and 75% +CA. Forearm RHBF and conductance
showed both a workload effect (25% +CA vs. 75% +CA) and
an effect of circulatory arrest at each workload (25% vs.
25%+CA and 75% vs. 75%+CA). Bars above columns
represent +SEM. *p<0.OSforcomparisons with BASE (analysis of variance within subject comparisons).
mm Hg was unchanged from baseline peak forearm
flow conditions.
In addition, leg circulatory arrest alone had no
effect on peak forearm blood flow (baseline RHBF,
49.3 +6.9 ml/min/100 ml; RHBF during leg occlusion,
49.2+6.8 ml/min/100 ml; p=NS).
FIGURE 4. Strain-gauge plethysmographic tracings from one
of the subjects after the release of 10 minutes of forearm
circulatory arrest (peak reactive hyperemic blood flow
[RHBF]). Baseline, RHBF without leg exercise; 75%+CA,
RHBF during leg circulatory arrest (CA) that follows 75%
maximum Vo2; Q, foreann blood flow (mllmin/100 ml);
MA4P, mean arterial blood pressure (mm Hg); C, forearm
vascular conductance (mllmin/100 mllmm Hg). Both studies
were performed with very similar calibration constants for the
plethysmograph (0.25% change in length approximately equals
30 mm). Therefore, the values of tangent 0 shown above can
be compared (tan 6 is proportional to blood flow). It can be
seen that 75% +CA caused a marked decrease in tan 6. Thus,
75% +CA causes a marked reduction in forearm blood flow.
Discussion
Study Rationale
In the present paper, we have postulated that two
opposing forces would control skeletal muscle blood
flow during exercise. The first is the dilatory response
to exercise that is presumably mediated by an
increase in ischemic metabolites. The second is a
reflex vasoconstriction whose afferent limb originates
in the exercising skeletal muscle. Thus, it was hypothesized that skeletal muscle metaboreflex activation
would vasoconstrict metabolically active muscle beds
in an effort to prevent blood flow demand from
exceeding blood flow supply.
To examine this postulate, we separated the local
vasodilating and vasoconstricting influences by providing a "pure" vasodilator stimulus to the forearm,
10 minutes of forearm circulatory arrest, while having
the subjects perform the various leg exercise regimens that were designed to increase sympathetic
tone. Previous studies in our laboratory have shown
that after the release of a 10-minute forearm circulatory arrest, plethysmographically determined forearm blood flow was maximal.'2 However, circulatory
arrest for periods up to 20 minutes did not cause a
reflex rise in heart rate, MAP, or calf vascular
resistance.'3 Thus, 10 minutes of forearm circulatory
Sinoway and Prophet Metaboreceptor Stimulation Opposes Peak Vasodilation
1581
.*-*--^" NO LEG EXERCISE
0.6-
25%
a
---- 25% + CA
0.5
75%
-
CD
0.4
E
0.3
E
E
0.2'
--0-- 75% + CA
I
W E
: z
cc
0 m
U-. z
0
C.)
0
CD
._
0.1*
J(
.
0
.
.
.
20
.
.
40
.
.
60
.
.
.
.
FIGURE 5. Graph showing the time course of
changes in forearm conductance after the release
of forearm circulatory arrest. 25%, responses after
12 minutes of supine leg exercise at 25% maximum
VO2; 25%+CA, responses after 9 minutes of
supine leg exercise at 25% maximum Vo2followed
by 2 minutes of leg circulatory arrest (CA); 75%,
responses after 11-12 minutes of supine leg exercise
at 75% maximum Vo2; 75% +CA, responses after
9 minutes of supine leg exercise at 75% maximum
V02 followed by 45 seconds to 2 minutes of CA. It
can be seen that each successive intervention tends
to shift downward the forearm conductance at any
given time point. Thirty seconds of data collection
was obtained for all subjects for all interventions.
In six of seven subjects, data were obtained at 45
seconds for 75% +CA; at 90 seconds, data were
obtained in six of seven subjects for 75% and in
four of seven during 75%+CA.
.
80
100
SECONDS POST RELEASE
a large amount of vasodilation without
activating the sympathetic nervous system.
To increase sympathetic tone, we chose two workloads: 25% max Vo2 and 75% max Voz. The workloads were normalized for the max Vo2 because
plasma norepinephrine, an index of sympathetic activation, correlates better with the percent of maximal
workload than with the absolute workload.14 Because
of this finding, we believed that the degree of sympathetic stimulation (at each workload) would tend
to be more comparable in the different subjects.
During exercise, multiple neural systems are triggered and initiate a pattern of sympathetic discharge
that is related to the level of exercise.15 These
multiple neural inputs include 1) the stimulation of
mechanoreceptors16 and metaboreceptors13"17"18 in
skeletal muscle, 2) potential changes in baroreceptor
activity during exercise,19 and 3) increased central
volitional influences (central command) during
exercise.202' In this paper, we postulated that
changes in forearm conductance after the release of
forearm circulatory arrest during 25% max Vo0 and
75% max Vo2 workloads would provide information
regarding the sum of the vasoconstrictor effects due
to the above mechanisms at the two different
workloads.
It is believed that the sympathetic response due to
metaboreceptor stimulation can be separated and
arrest causes
isolated if circulation to muscle is arrested seconds
before the end of exercise. Recent studies in human
subjects using 31P nuclear magnetic resonance spectroscopy have suggested that the initiation of this
reflex may be linked to skeletal muscle cellular
acidosis.13"8 Thus, in our present series of experiments, we suspected that any hemodynamic effects
observed during the 25%+CA and 75%+CA protocols would be due to stimulation of metaboreceptors
within the exercising muscle. We also postulated that
the metaboreceptor-induced vasoconstricting influences would be greater at the 75%+CA protocol
than at the 25%+CA protocol since the response to
circulatory arrest after exercise should be greater at
the higher workload; that is, the production of lactic
acid and other potential vasoconstricting metabolites
should be greater at the higher workload.22
Study Findings
There are several findings in the present paper
worthy of mention: 1) Vigorous leg exercise (at 75%
max Vo2) reduced the forearm vascular conductance
response below values noted during the baseline
study condition. 2) Leg circulatory arrest, which isolated efferent activity due to metaboreceptor stimulation, reduced forearm conductance below values
during exercise alone. This was true for both the low
and high workloads. 3) Leg circulatory arrest after
1582
Circulation Research Vol 66, No 6, June 1990
the higher workload led to a lower forearm conductance than noted during circulatory arrest after the
25% workload. 4) LBNP to -40 mm Hg did not alter
peak forearm blood flow or vascular conductance.
We believe these observations suggest that
metaboreceptor-mediated responses during exercise
are capable of vasoconstricting maximally dilated
vascular beds. The magnitude of the vasoconstriction
depends on the level of exercise (25%+CA vs.
75%+CA). Moreover, we suggest that during the
exercise without leg circulatory arrest some activityrelated influence acts to oppose metaboreceptorinduced vasoconstriction to active skeletal muscle.
Finally, our data would suggest that baroreceptor
unloading is incapable of causing the degree of
vasoconstriction noted during the supine exercise
studies.
The possibility that metaboreceptor stimulation
may be responsible for the sympathetically mediated
constriction that opposes metabolic vasodilation has
recently been suggested by Rowell and Sheriff.6 We
believe that the findings of the present report are the
first in human subjects to confirm this hypothesis.
Our finding that metaboreceptor stimulation is workload dependent is consistent with recent human
studies in which muscle sympathetic nerve activity in
the peroneal nerve increased as the level of upper
body arm crank exercise increased15 and studies in
which the increase in calf vascular resistance in
response to static forearm exercise was also dependent on the amount of exercise.13 The present findings expand on these studies by examining the ability
of different degrees of metaboreceptor stimulation to
regulate peak blood flow delivery to metabolically
active skeletal muscle.
Interactions Between Metaboreceptors and Central
Neural Influences
Our results do not support the concept that central
command increases sympathetic outflow during
exercise.2021 This is not to imply that central command cannot increase sympathetic outflow under
certain experimental conditions but, rather, to suggest that during exercise, when all systems are intact,
some central volitional influence actually acts to
oppose metaboreceptor-mediated forearm vasoconstriction. This observation is consistent with the
contention of Mark et a123 that central volitional
influences act to oppose metaboreceptor-mediated
increments in sympathetic nerve traffic. In addition,
our findings could also be explained by a central
process that causes a cholinergic forearm vasodilation during leg exercise that is not present during the
periods of circulatory arrest after leg exercise. However, the magnitude of the differences in blood flow
between the two conditions (exercise and exercise
followed by circulatory arrest) is larger than has been
previously described for cholinergically mediated
vasodilation in humans.24 Further studies will be
necessary to clarify these potential explanations.
Our results are also at odds with those of Rowell et
al,25 who used leg exercise (100-150 W) after circulatory arrest as a maneuver to alter resting forearm
blood flow. In this previous study, a forearm vasodilation was observed during leg occlusion in four of
five subjects. These authors suggested that the increments in forearm flow were mediated by a large
baroreflex drive that opposed the metaboreflexmediated rise in blood pressure. Much of the difference in results between these two studies may stem
from the fact that in Rowell's report a skin vasodilation to dissipate heat may have overshadowed any
changes in blood flow in the metabolically inactive
skeletal muscle. In our studies, increments in peak
skin flow are not likely to overshadow changes in
muscle flow since changes in muscle flow are very
substantial and represent the major contributor to
the peak reactive hyperemic blood flow response.9 In
addition, our 75%+CA protocol may have caused a
greater degree of leg metaboreceptor stimulation
than noted in the Rowell et al study (approximately
170 W in our study vs. 100-150 W in their previous
study).
Our study was not designed to specifically address
the role of baroreceptors in regulating vascular conductance during exercise. However, at each workload
leg circulatory arrest had no effect on MAP, yet leg
circulatory arrest was associated with a reduction in
maximal conductance. This suggests that arterial
baroreceptor influences cannot explain the reduction
in forearm conductance associated with leg circulatory arrest. Changes in low-pressure baroreceptor
tone were not likely to be important since the subjects
were performing supine exercise, and it is unlikely that
central venous pressure fell substantially during leg
circulatory arrest. Furthermore, the studies using
LBNP to -40 mm Hg during maximal forearm vascular conductance measurements suggest that enhanced
sympathetic tone secondary to changes in baroreceptor activity are incapable of altering peak forearm
vascular conductance. This observation is consistent
with prior human studies.26,27
Potential Limitations
There are several important issues that must be
considered before accepting our results at face value.
First, in our paper we are assuming that the vasodilation associated with 10 minutes of circulatory arrest
mimics the vasodilation associated with maximal
exercise. This is a potential concern since the normalized (ml/min/100 ml tissue) levels of peak blood
flow reported with plethysmographic techniques are
lower than those reported with thermodilution
techniques.4 This difference is likely explained by the
fact that the thermodilution technique predominantly measures flow from the quadriceps femoris, a
relatively homogeneous mass of skeletal muscle,
whereas the strain-gauge method includes flow to
tissues with limited vasodilator potential such as skin
and bone. In addition, plethysmography measures
flow to many skeletal muscles. Because different
Sinoway and Prophet Metaboreceptor Stimulation Opposes Peak Vasodilation
skeletal muscles can have very different vasodilation
potentials,28 it is not surprising that plethysmography
will yield lower peak flows than those noted with the
thermodilution method.
Second, it could be argued that the forearm vasoconstriction seen with leg circulatory arrest is due
primarily to the pain of cuff occlusion. This is unlikely
since in a group of six individuals leg occlusion alone
at the time of the release of 10 minutes of forearm
circulatory arrest did not affect peak forearm blood
flow. Along similar lines, we cannot exclude that the
pain due to ischemia of the large muscle mass during
the 75%+CA protocol was an important factor in
lowering conductances. This factor could influence
our results regarding central command and metaboreceptor stimulation. However, at the time of peak
forearm flow measurements, leg occlusion had been
in effect only 30 seconds, and the subjects reported
that leg discomfort was no worse than during leg
exercise alone. Furthermore, MAP during the leg
circulatory arrest protocols was not statistically
greater than during the comparative levels of exercise. If pain were a major factor, we would have
anticipated the blood pressure to be higher during
the leg circulatory arrest protocols. Finally, if pain
were the critical factor responsible for the reduction
in forearm conductance during circulatory arrest at
the 75% workload, we would not have anticipated the
20% reduction in conductance associated with the
less painful leg circulatory arrest at the 25% workload. Despite the experiments with leg occlusion
alone and the above arguments, the potential influences of pain cannot be entirely excluded, and our
results regarding central command and metaboreceptors must be viewed in light of this limitation.
The last potential limitation of our data is that to
separate the influences of metabolic "dilation" from
metabolic constriction it was necessary to generate
the constricting stimulus in a different muscle bed
(legs) than the muscle beds that were metabolically
dilated (forearm). This raises concern because it is
possible that sympathetic outflow to the forearm
actually overestimates sympathetic responses that
occur in the legs during exercise. Wallin et a129 have
recently compared muscle sympathetic nerve traffic
with the inactive radial and peroneal nerves of subjects during muscle ischemia after exercise. They
found that radial nerve activity increased more than
peroneal nerve activity. However, in these studies,
the stimulus that increased nerve activity was ischemia after handgrip and not circulatory arrest after
leg exercise. As suggested by Wallin et al, this raises
the possibility that a portion of the increase in radial
nerve sympathetic activity was due to a segmental
spinal sympathetic reflex. This clearly could not be
the case in the present study. Therefore, we believe
that our data support the conclusion that metaboreceptor stimulation strongly opposes metabolic vasodilation in metabolically active beds.
In conclusion, the present report provides evidence that stimulation of the skeletal muscle meta-
1583
boreflex causes a vasoconstriction capable of significantly limiting extreme peripheral vasodilation.
Furthermore, our results are entirely consistent with
the concept that metaboreceptor-mediated vasoconstriction is the predominant and crucial mechanism
responsible for preventing cardiac output from being
outstripped by the massive levels of vasodilation that
occur during heavy systemic exercise.
Acknowledgment
The authors wish to thank Miss Patricia Cassel for
her expert typing of the manuscript.
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KEY WORDS * reflexes * reactive hyperemia * metaboreceptors
* central command