J Appl Physiol
90: 83–89, 2001.
Peripheral circulatory factors limit rate of increase in muscle
O2 uptake at onset of heavy exercise
MAUREEN J. MACDONALD, HEATHER L. NAYLOR,
MICHAEL E. TSCHAKOVSKY, AND RICHARD L. HUGHSON
Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Received 7 March 2000; accepted in final form 26 July 2000
blood flow; metabolism; blood acid-base; O2 transport; Doppler ultrasound
limitations have an
impact on the ability of humans to adapt to the metabolic demands of increased exercise intensities. Slower
adaptation of O2 uptake (V̇O2) at the onset of very
heavy exercise might reflect the interaction of central
and peripheral circulatory limitations to O2 transport
and utilization (8, 15). Gerbino et al. (8) showed that
V̇O2 increased more rapidly in response to a second
bout of exercise, and MacDonald et al. (15) demonstrated even faster adaptation when arterial O2 content was increased. These studies suggest that better
adaptation is a consequence of improved O2 transport
in the second of two high-intensity exercise bouts.
CENTRAL AND PERIPHERAL CIRCULATORY
Address for reprint requests and other correspondence: R. L.
Hughson, Dept. of Kinesiology, Univ. of Waterloo, Waterloo, Ontario,
Canada N2L 3G1 (E-mail: [email protected]).
http://www.jap.org
Proposed mechanisms for the improved O2 transport
include elevated blood flow and greater O2 extraction.
Both could be consequences of alterations in local acidbase status, which might promote increased vascular
conductance and a right shift of the O2-hemoglobin
dissociation curve, but direct confirmation is not available.
Our laboratory developed a forearm exercise experiment model that allows continuous monitoring of arterial blood flow in conjunction with measurement of
arteriovenous O2 content difference for determination
of muscle V̇O2 (11). In the present study, we investigated the mechanisms that enable skeletal muscle V̇O2
to adapt more rapidly to the second of two high-intensity exercise bouts. We hypothesized that venous blood
would demonstrate an altered acid-base environment
after the first bout of exercise. This alteration would
then promote greater blood flow through more rapid
vasodilation, as well as greater O2 extraction, in the
second bout of exercise, thus allowing muscle V̇O2 to
increase more rapidly at the onset of exercise. The
metabolic consequence of this rapid adaptation of oxidative metabolism would be reduction in venous blood
lactate and less change in blood pH.
METHODS
Six healthy men (age 33 ⫾ 5 yr, height 181 ⫾ 2 cm, weight
74 ⫾ 3 kg, mean ⫾ SE) volunteered to participate in this
study. They were not specifically trained, and all gave written consent on a form that was approved by the Office of
Research Ethics at the University of Waterloo.
Exercise protocol. Subjects performed all exercises on a
handgrip ergometer, in which the resistance was varied by
adjusting the magnitude of load that was raised and lowered
by repeated contractions with the right hand. The subjects
were in a supine posture with the arm extended at heart
level. The exercise protocol for all tests involved raising the
weight for 0.5 s, lowering the weight for 0.5 s, and resting for
2 s before the next contraction, for a total cycle of 3 s.
Initially, each subject performed a ramp handgrip exercise
protocol, and the information from this test was used to
determine the workloads to achieve 75% of peak load for the
subsequent testing. In the ramp procedure, the resistance
was continually increased by adding water at a flow rate of 1
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8750-7587/01 $5.00 Copyright © 2001 the American Physiological Society
83
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MacDonald, Maureen J., Heather L. Naylor, Michael
E. Tschakovsky, and Richard L. Hughson. Peripheral
circulatory factors limit rate of increase in muscle O2 uptake
at onset of heavy exercise. J Appl Physiol 90: 83–89,
2001.—We used an exercise paradigm with repeated bouts of
heavy forearm exercise to test the hypothesis that alterations
in local acid-base environment that remain after the first
exercise result in greater blood flow and O2 delivery at the
onset of the second bout of exercise. Two bouts of handgrip
exercise at 75% peak workload were performed for 5 min,
separated by 5 min of recovery. We continuously measured
blood flow using Doppler ultrasound and sampled venous
blood for O2 content, PCO2, pH, and lactate and potassium
concentrations, and we calculated muscle O2 uptake (V̇O2).
Forearm blood flow was elevated before the second exercise
compared with the first and remained higher during the first
30 s of exercise (234 ⫾ 18 vs. 187 ⫾ 4 ml/min, P ⬍ 0.05). Flow
was not different at 5 min. Arteriovenous O2 content difference was lower before the second bout (4.6 ⫾ 0.9 vs. 7.2 ⫾ 0.7
ml O2 /dl) and higher by 30 s of exercise (11.2 ⫾ 0.7 vs. 10.8 ⫾
0.7 ml O2 /dl, P ⬍ 0.05). Muscle V̇O2 was unchanged before
the start of exercise but was elevated during the first 30 s of
the transition to the second exercise bout (26.0 ⫾ 2.1 vs.
20.0 ⫾ 0.9 ml/min, P ⬍ 0.05). Changes in venous blood PCO2,
pH, and lactate concentration were consistent with reduced
reliance on anaerobic glycolysis at the onset of the second
exercise bout. These data show that limitations of muscle
blood flow can restrict the adaptation of oxidative metabolism at the onset of heavy muscular exertion.
84
O2 LIMITATION AT ONSET OF EXERCISE
([K⫹]), and plasma pH by using selective electrodes in a
blood-gas electrolyte analyzer (NovaStat Profile Plus 9,
Waltham, MA). The analyzer was calibrated at regular intervals. Hemoglobin concentration was calculated from the
measured hematocrit by assuming normal mean corpuscular
hemoglobin of 33% of the total cell volume. O2 saturation and
content were obtained from the output of the analysis system
after application of standard equations.
Blood data analysis. Arteriovenous O2 content difference
was calculated from the difference in assumed arterial O2
content and actual forearm venous O2 content. To estimate
arterial O2 content, we assumed that it was constant for each
subject, using 97% saturation for the calculation (arterial O2
content ⫽ 1.34[hemoglobin] ⫻ O2 saturation/100). Assumption of a constant arterial O2 content is reasonable in this
study because we normally observe 97% saturation of arterial blood by noninvasive oximetry. Furthermore, forearm
handgrip exercise represents a relatively small cardiovascular challenge that does not compromise arterial blood oxygenation in the lungs.
A 10-s average of FBF, centered on the time over which the
blood samples were drawn, was used to match blood flow and
O2 extraction for calculation of forearm muscle V̇O2. Arterial
blood [La⫺] was estimated from the arterialized venous samples. Arterialized hand vein samples provided a reasonable
estimation of arterial lactate concentrations because the O2
saturation in the arterialized samples of a previous study
was calculated as 93.7 ⫾ 0.5 (SE) % (n ⫽ 6) (7).
Data analysis. Effects of previous arm exercise and time on
the values for FBF, arteriovenous O2 content difference,
muscle V̇O2, pH, [La⫺], [K⫹], and PCO2 were analyzed by
using a two-way repeated-measures ANOVA. This first level
of analysis revealed significant interaction effects of exercise
bout and time for all variables. Therefore, all subsequent
analyses are reported from one-way ANOVA comparisons at
each time point, thus testing for differences between the first
and second exercise bouts. The level of significance was set at
P ⬍ 0.05. Any differences were further analyzed with Student-Newman-Keuls post hoc test. All data are presented as
means ⫾ SE.
RESULTS
The peak workload achieved in the ramp exercise
protocol was 17.1 ⫾ 0.9 kg. The workload used during
the step test protocol was 12.8 ⫾ 0.7 kg, which represented ⬃75% of the peak workload.
At the onset of the first bout of exercise, FBF immediately began a rapid adaptation (Fig. 1), which is
characteristic of the response for both forearm and leg
Table 1. Resting, exercise, and recovery responses of brachial artery diameter
and MBV in first and second exercise bouts
Rest
Diameter, mm
First bout
Second bout
MBV, cm/s
First bout
Second bout
Exercise
Recovery
0 min
0.5 min
2 min
5 min
5.5 min
7 min
10 min
4.43 ⫾ 0.18
4.65 ⫾ 0.09
4.46 ⫾ 0.16
4.57 ⫾ 0.16*
4.57 ⫾ 0.12
4.63 ⫾ 0.12
4.57 ⫾ 0.12
4.63 ⫾ 0.12
4.77 ⫾ 0.14
4.70 ⫾ 0.10
4.65 ⫾ 0.09
4.70 ⫾ 0.10
4.65 ⫾ 0.09
4.60 ⫾ 0.15
1,574 ⫾ 116
1,602 ⫾ 177
1,668 ⫾ 120
1,740 ⫾ 286
1,931 ⫾ 187
1,952 ⫾ 242
1,122 ⫾ 194
1,029 ⫾ 234
653 ⫾ 129
878 ⫾ 203
225 ⫾ 25
653 ⫾ 129*
1,220 ⫾ 91
1,425 ⫾ 92
Values are means ⫾ SE; n ⫽ 6 subjects. Diameter, brachial artery diameter; MBV, brachial artery mean blood velocity. * Significantly
different from 1st exercise bout, P ⬍ 0.05.
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l/min into a bucket that was raised and lowered. On a
separate day, subjects reported to the laboratory in a rested
state, at least 2 h after eating. They assumed a supine
position, and a 21-gauge catheter (Angiocath, Becton-Dickinson, Sandy, UT) was inserted retrograde at the antecubital
fossa in a deep forearm vein in the right arm. Another
catheter was inserted in a dorsal hand vein on the left hand.
This hand was warmed to obtain arterialized venous blood
samples (7). The test session consisted of measurement of
resting data for 5 min, which was followed, sequentially, by 5
min of exercise, 5 min of rest, 5 min of exercise, and an
additional 5-min rest period.
Data collection. Forearm blood flow (FBF) was measured
by Doppler ultrasound, as described previously (6, 11, 20).
This is a highly reproducible method that has a coefficient of
variation of 3–4% for estimates of diameter and 13–20% for
measurements of velocity and blood flow (20). Most variations in velocity and flow appear to arise from spontaneous
fluctuations in the normal blood flow, as seen with beat-bybeat heart rate or blood pressure (2), and are not a function
of error in the method (6, 20). Brachial artery diameter was
estimated by echo Doppler ultrasound, with a 7.5-MHz linear
array probe (model SSH-140A, Toshiba, Tochigi-Ken, Japan).
Mean blood velocity (MBV) was determined with a 4-MHz
pulsed Doppler ultrasound probe (model 500V, Multigon Industries, Mt. Vernon, NY). Brachial artery diameter was
obtained twice at rest, at minutes 1 and 5 of each exercise
bout, and during recovery. The spectrum of the pulsed Doppler was processed on-line with a mean velocity processor (17).
Calibration signals in the Doppler shift frequency range were
generated from the Doppler signal processor. The blood flow
velocity of our system was calibrated against blood pumped
through tubing (20). MBV was obtained through integration
of the area under the curve for each heartbeat and by averaging the response over 3-s intervals, so that a contraction
and relaxation phase were included during exercise. FBF
was estimated beat by beat by multiplying the average MBV
by the cross-sectional area [area ⫽ ␲(D/2)2], where diameter
(D) was updated at the times indicated in Table 1. MBV and
heart rate signals were collected on a computer-based system
at 100 Hz.
Blood samples. Venous blood samples were obtained twice
during rest, at 30 s, 2 min, and 5 min of exercise, and at 30 s
and 2 min of recovery. Arterialized venous blood samples
were obtained twice during rest and during the fifth minute
of both exercise and recovery.
Approximately 1 ml of blood was collected in heparinized
syringes that were immediately capped, gently agitated, and
then stored in an ice bath. Within 1 h of collection, all whole
blood samples were analyzed at 37°C for PO2, PCO2, hematocrit, plasma concentrations of lactate ([La⫺]) and potassium
O2 LIMITATION AT ONSET OF EXERCISE
exercise (16, 21). The pattern of adaptation altered in
the second bout, resulting in a faster adjustment to
steady state. This response was mainly due to increases in MBV, with relatively small changes in diameter over the course of exercise or recovery, in either
the first or second bout (Table 1). In the second bout of
high-intensity exercise, FBF was significantly elevated
before the start of exercise (111 ⫾ 23 vs. 36 ⫾ 6 ml/min,
P ⬍ 0.05) and at 30 s of exercise (234 ⫾ 18 vs. 187 ⫾ 4
ml/min, P ⬍ 0.05) compared with the first bout of
exercise (Fig. 2). With cessation of muscle contractions,
there was a marked elevation in FBF after both the
first and second bouts of exercise (Fig. 1). Postexercise
hyperemia was prolonged after both exercise bouts,
with FBF still markedly elevated above the preexercise
resting value at the end of the 5-min recovery period.
Resting muscle V̇O2 was not significantly different
before the first or second exercise bouts (Fig. 2). This
was achieved by the combination of lower FBF and
greater arteriovenous O2 content difference in the true
resting state before the start of the first exercise bout.
Before the second exercise bout, FBF was elevated,
whereas the arteriovenous O2 content difference was
significantly reduced (4.6 ⫾ 0.9 vs. 7.2 ⫾ 0.7 ml O2 /dl,
P ⬍ 0.05) and higher by 30 s of exercise (11.2 ⫾ 0.7 vs.
10.8 ⫾ 0.7 ml O2 /dl, P ⬍ 0.05). At 30 s of exercise,
muscle V̇O2 was significantly greater in the second
compared with the first exercise bout (Fig. 2). The
elevated muscle V̇O2 was caused by significantly
greater FBF and arteriovenous O2 content difference in
the 30-s sample in the second exercise bout. The arteriovenous O2 content difference was significantly lower
in the second exercise bout compared with the first at
the 5-min sampling point. This did not result in a
difference in muscle V̇O2 at this time point, as the FBF
was slightly, but not significantly, elevated in the second test.
Arterialized venous pH, [La⫺], and [K⫹] did not
change significantly across the entire duration of the
exercise protocol.
The elevated venous [La⫺] and reduced venous pH in
the second exercise bout, before the start of exercise
and at 30 s, are consistent with the expected metabolic
acidosis in the exercising forearm after an initial bout
of high-intensity exercise (Figs. 3 and 4). Also, after the
first bout of exercise, there was an elevation in venous
blood PCO2. Before the start of the second bout, PCO2
had declined to the point that it was not significantly
elevated over the initial resting values. As exercise
progressed, the relative acidosis was greater in the
first exercise bout compared with the second. This was
observed as significantly lower venous [La⫺] and PCO2,
which contributed to the significantly greater pH at the
end of the second bout of exercise. The differences in
acid-base were maintained throughout recovery, showing the greater acidosis after the first exercise bout.
Before the onset of the second exercise bout, venous
plasma [K⫹] was reduced compared with the first bout.
Although there was a marked increase in venous [K⫹]
with exercise, there were no differences in [K⫹] between exercise bouts. At 30 s after the second exercise
bout, venous plasma [K⫹] was elevated compared with
after the first bout (Fig. 3).
DISCUSSION
This study provides confirmation that circulatory
factors can limit the adaptation of muscle V̇O2 at the
onset of high-intensity exercise. Muscle V̇O2 was measured during two, identical, high-intensity forearm exercise challenges in which the second challenge was
5 min after the first. We found that muscle V̇O2 was
significantly elevated during the first minute of the
second exercise bout compared with the first bout.
Consistent with our hypotheses, the residual effects of
the first exercise bout on the acid-base status of the
muscle were associated with an elevation in FBF and a
greater O2 extraction during the second exercise bout.
Despite the differences between the present model and
whole body exercise, these data, obtained in the exercising forearm, suggest that adaptation of aerobic metabolism at the onset of whole body high-intensity
exercise might also be limited by the availability of O2
in healthy subjects and in patients with heart disease
(1, 13, 22).
V̇O2 at the onset of exercise. The present experiments
allowed us to explore the potential roles of bulk O2
supply, as determined by FBF and O2 extraction, in
limiting V̇O2 at the onset of heavy exercise. Both factors
were proposed, in previous modeling (3) and experimental studies (8, 11, 15), as potential rate-limiting
steps in the delivery of O2 for aerobic metabolism. The
data from this experiment provide the first direct confirmation of the important role of both effects in mod-
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Fig. 1. Forearm blood flow (FBF) during the first (solid line) and
second (dotted line) bouts of high-intensity handgrip exercise and in
recovery. Time 0 indicates the onset of high-intensity exercise; the
second bout followed immediately after the first (i.e., from 10 min).
Values are means ⫾ SE; n ⫽ 6 subjects (see Fig. 2 for error bars).
85
86
O2 LIMITATION AT ONSET OF EXERCISE
ifying O2 utilization during the rest-to-exercise transition for small muscle mass exercise. The forearm
exercise model used in this study has a very different
feature compared with repeated, high-intensity cycling
exercise. Whereas cycling challenges both the central
and peripheral circulatory capacities, the forearm
model focuses on potential peripheral limitations. Thus
any improvements in exercise performance that occur
with whole body exercise might be further enhanced if
cardiac output increases in conjunction with the altered peripheral factors identified in this study (15).
The extent to which O2 transport contributes to muscle
V̇O2 at the onset of submaximal exercise is still being
debated (9, 11).
Limitations to the methodology. Limitations to the
methodology used in the present study include both
instrumental constraints as well as theoretical limitations of the model. As previously shown in our labora-
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Fig. 2. Time course of changes in muscle oxygen uptake
(V̇O2; top), FBF (middle), and arteriovenous O2 content
difference [(a-v)O2; bottom] during the first (F) and
second bouts (E) of high-intensity handgrip exercise.
Exercise started at time 0. Values are means ⫾ SE; n ⫽
6. Note that the first E at time ⫽ 0 min for the second
exercise bout is identical to the F at time ⫽ 10 min in
the first exercise bout. * Significant difference between
first and second exercise bouts (P ⬍ 0.05).
tory (20), and confirmed by Rådegran (18), Doppler
ultrasound is a highly reliable and accurate method for
determining both MBV and conduit artery diameter at
rest and during exercise. The estimation accuracy of
FBF in the present study may have been limited by the
lack of repeated data collections; however, FBF variability was similar to that previously observed using
these methods (18, 20).
In the present study, venous blood was sampled from
a single deep forearm vein. Possible limitations to this
include the assumption that the blood sampled from
this vein accurately reflected the metabolic rate of the
muscles of interest and that the distribution of venous
return from the forearm was not altered with changes
in flow. The patterns of change seen in the arteriovenous O2 content difference and venous O2 content
were consistent with previously published patterns
(11).
O2 LIMITATION AT ONSET OF EXERCISE
87
Fig. 3. Venous blood lactate concentration ([La⫺]; top) and venous
potassium concentration ([K⫹]; bottom) during rest, exercise (0–5
min), and recovery for the first (F) and second (E) exercise bouts.
Values are means ⫾ SE; n ⫽ 6. * Significant difference between first
and second exercise bouts (P ⬍ 0.05).
FBF. Blood flow adapts in the transition from rest to
forearm or leg exercise in a two-phase pattern. The
rapid increase in blood flow observed within the first
15–20 s of exercise is a consequence of the action of the
muscle pump emptying veins and allowing a greater
pressure gradient in combination with a limited vasodilation (19, 23). Subsequent increases in flow are
primarily a consequence of further vasodilation in response to release of local vasoactive metabolites (such
as K⫹ and H⫹, as shown in this study) and, possibly,
endothelial factors (14). During this adaptive phase,
blood flow distribution is coordinated to deliver more
blood flow to metabolically active sites.
It is important to note in the present experiments
that a relatively steady FBF was not achieved until ⬃2
min after the onset of exercise. These data are consistent with a negative feedback control mechanism. Even
though FBF appeared to be relatively steady, it is
obvious from the marked postexercise hyperemia that
FBF was inadequate during exercise. During highintensity exercise, FBF was unable to meet the de-
Fig. 4. Venous blood pH (top) and PCO2 (bottom) during rest, exercise
(0–5 min), and recovery for the first (F) and second (E) exercise bouts.
Values are means ⫾ SE. * Significant difference between first and
second exercise bouts (P ⬍ 0.05).
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mands because of periodic compression and occlusion
of blood vessels with each contraction. Indeed, on stopping the last contraction, the high value of FBF (⬃600
ml/min; Fig. 1) indicates how high flow was during the
muscle relaxation phases in the latter part of exercise.
Figure 5 shows the beat-by-beat values for MBV
throughout the entire protocol. It is apparent in all
tests that individual beat values achieved the same
high velocity in the pause between contractions as in
the period immediately after exercise. FBF recovered
during the 5-min period between exercise bouts, but it
did not return to resting baseline values. Thus, just
before the start of the second exercise bout, FBF was
approximately twice the value from before the first
bout. The two-phase pattern of blood flow adaptation
was also less obvious at the start of the second bout of
exercise, possibly due to the elevation of resting flow
and the increased vasodilation that may have existed
in the exercising muscle vascular bed. The elevated
FBF can be attributed, at least in part, to the vasodilatory effect of a significant reduction in pH, measured
in venous blood, along with the significant elevation in
88
O2 LIMITATION AT ONSET OF EXERCISE
[La⫺] and the slight increase in PCO2. Venous plasma
K⫹ was significantly reduced before the start of the
second exercise bout. This might have been a consequence of increased washout caused by the higher
FBF. Whereas this would, to some extent, counter the
vasodilatory properties, it is obvious that it did not
achieve total compensation, and thus FBF remained
elevated.
Metabolic consequences of altered O2 transport. The
more rapid increase in muscle V̇O2 that we found in the
second exercise bout would mean that a greater proportion of the total ATP resynthesis occurred through
oxidative metabolism. Consequently, utilization of
phosphocreatine stores and anaerobic glycolysis should
contribute less. We do not have information on the
phosphocreatine stores in the present study. It might
be anticipated that these stores were not completely
recovered before the onset of the second exercise bout,
but their final levels are unknown. Although we do not
have intracellular measurements of [La⫺], we do have
information from venous blood that indicates production was probably decreased in the second compared
with the first exercise bout. Previous investigations of
the effects of warm-up exercise have reported either no
effect on (8), or a reduction in, blood [La⫺] compared
with exercise without a warm-up (12). However, these
studies did not measure [La⫺] in blood as it left the
exercising muscle, and many factors could have impacted systemic venous blood [La⫺]. Because the total
muscle mass being exercised was quite small, our finding of no change in arterialized blood [La⫺] was expected.
In the first 30 s of the second exercise bout, we
observed a 30% increase in muscle V̇O2, which was a
consequence of a 25.1% increase in FBF and a 3.7%
increase in arteriovenous O2 content difference. These
relative contributions indicate that the major factor
that influenced muscle V̇O2 was the increase in FBF.
Indeed, the relatively small changes in the local acidbase environment had only a small contribution to
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Fig. 5. Beat-by-beat values of mean
blood velocity (MBV) for each subject
throughout protocol [rest, exercise bouts
1 and 2 (Ex 1 and Ex 2, respectively),
and recovery (Recov)]. The wide range
of individual values during exercise is a
function of varying vascular occlusion
due to muscle contraction and relaxation. MBV adapted more rapidly at the
onset of the second exercise bout.
O2 LIMITATION AT ONSET OF EXERCISE
We thank David Northey for excellent technical assistance.
This study was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC). M. J. MacDonald and
H. L. Naylor were recipients of NSERC Post Graduate Scholarships.
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increased O2 extraction. We used the mean values of
venous blood pH and PCO2 to estimate the 50% saturation of hemoglobin by O2 (P50). For exercise test 1 (pH ⫽
7.38, PCO2 ⫽ 49.5 Torr), the P50 was 27.7 Torr, whereas,
for test 2 (pH ⫽ 7.36, PCO2 ⫽ 51.0 Torr), the P50 was
28.3 Torr. The difference might be greater if the effect
of temperature was included. The slightly but significantly greater O2 extraction seen at the 30-s point of
test 2 probably reflects the small shift of the O2-hemoglobin dissociation curve as well as better distribution
of blood flow to the exercising muscle fibers. The relatively low O2 extraction from the blood, despite the
heavy workload, probably reflects the rapid transit of
red blood cells across the muscle due to very high FBF
during the pause between contractions.
These results from small muscle mass exercise might
have important implications for other conditions in
which O2 transport could be less than optimal at the
onset of exercise, including exercise with beta-blockers
(10) or in patients with impaired cardiac performance
(1, 4, 5, 13). Factors that limit O2 transport cause
greater stress on the phosphocreatine stores and anaerobic glycolysis during the rest-to-exercise transition. However, at least for heavy exercise, factors that
can promote improved O2 transport or O2 release to the
exercising muscles should result in less depletion of
phosphocreatine and lower concentrations of muscle
and blood lactate (10).
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