Download Effect of aerobic conditioning on the peripheral circulation

958
lACC Vol. 4, No, 5
November 1984:958-63
Effect of Aerobic Conditioning on the Peripheral Circulation During
Chronic Beta-Adrenergic Blockade
WILLIAM R. HIATT, MD, RANDALL C. MARSH, MD, H.. L. BRAMMELL, MD, CIDNEY FEE, RPT,
LAWRENCE D. HORWITZ, MD, FACC
Denver, Colorado
The relation of peripheral circulatory adjustments to
exercise training during long-term beta-adrenergic
blockade has not been investigated. In 12 healthy men
aged 22 to 34 years, blood flow in the calf was evaluated
with submaximal exercise before and after a 6 week
aerobic conditioning program. During conditioning, six
subjects received no drug and six received propranolol,
80 to 120 mglday in divided doses. Treated and control
subjects were studied on entry and at the conclusion of
a conditioning program, 72 hours after drug withdrawal
in subjects given propranolol. The training was intensive
and equivalent in both groups.
Control subjects increased maximal oxygen uptake
from 47.5 ± 1.1 to 51.4 ± 0.4 mllkg per min (p < 0.05),
whereas those on propranolol did not improve. Immediately after exercise, bloodflow in the calf was measured
with strain gauge plethysmography after 3 minutes of
Skeletal muscle blood flow during submaximal exercise is
regulated primarily by the local metabolic environment (1---4).
Exercise conditioning increases skeletal muscle oxidative
enzymes and capillary density, resulting in improved extraction and utilization of oxygen and metabolic substrates
(5-7). Perhaps as a consequence of enhanced oxidative metabolism, submaximal exercise blood flow in the calf is
decreased through autoregulation (7-9). Propranolol inhibits the expected increase in muscle oxidative enzymes in
aerobically trained rats (10). These data suggest a possible
mechanism for the attenuation of conditioning in normal
subjects receiving beta-adrenergic blocking agents (II). If
such agents impair skeletal muscle metabolic and circulatory
From the Department of Medicine, Divisions of General Internal Medicine and Cardiology, University of Colorado Health Sciences Center,
Denver, Colorado. This work was supported by a Research and Training
Center Grant (GOO8003049) from the National Institute for Handicapped
Research, U. S, Department of Education, Washington, D,C, Dr, Hiatt
is a Henry J, Kaiser Family Foundation Faculty Scholar in General Internal
Medicine. Manuscript received January 9, 1984; revised manuscript received June 12, 1984, accepted June 22, 1984.
Address for reprints: William R, Hiatt, MD, University of Colorado,
Health Sciences Center, Division of General Internal Medicine, 4200 East
Ninth Avenue, Box B-180, Denver, Colorado 80262,
© 1984 by the American College of Cardiology
supine exertion on a cycleergometer. In control subjects,
flow decreased from 15.7 ± 1.6 to 14.0 ± 1.4 mIllOO
ml per min at 300 kg-m/min of exertion (p < 0.05) and
from 26.5 ± 3.8 to 21.8 ± 2.3 mlll00 ml per min at
700 kg-m/min (p < 0.05). Vascular resistance was unchanged in these subjects at 300 kg-m/min (6.1 ± 0.8
to 6.7 ± 1.0 pru) (p = NS), but increased at 700 kgmlmin (4.2 ± 0.8 to 4.8 ± 0.7 pru) (p < 0.05). In
subjects given propranolol, no change in flow or resistance occurred after training at either work load.
It is concluded that the decrease in blood flow and
increase in vascular resistance during submaximal exercise after conditioning in control subjects indicates an
improved metabolic environment in trained skeletal
muscle. Propranolol prevented this response, suggesting
that the peripheral circulatory and metabolic adaptations to conditioning may not have occurred.
adaptations to training, then changes in submaximal exercise
blood flow in muscle may serve as an indicator of these
adaptations. To investigate this possibility we studied 12
normal subjects who underwent exercise conditioning receiving either propranolol or no drug. To evaluate the peripheral circulation, we measured submaximal exercise blood
flow and resistance in the calf before and after training.
Methods
Subjects and experimental design. Twelve healthy male
volunteers aged 22 to 34 years were recruited. All had led
a sedentary life-style for at least 6 months before entry.
Subjects were paired according to maximal oxygen consumption (\10 2 max), with one member of each pair randomly assigned to receive either propranolol or no drug.
This study was not blinded because in previous work (II)
it was apparent to the participants and investigators which
subjects received a beta-adrenergic blocking agent. The study
design is depicted in Figure I.
Measurements of maximal oxygen consumption and
exercise duration. All subjects were given an initial ex0735-1097/84/$3,00
JACC Vol. 4, NO.5
November 1984:958-63
HIATT ET AL.
BETA·BLOCKERS AND PERIPHERAL CIRCUL ATION
Maximal
Treadmill
Vascular
Testing
Propranolol
Aerobic
Conditioning
2
3
4
5
6
7
Weeks
Figure 1. Study design. Subjects underwent treadmill and vascular testing before (Pre) and after (Post) training. Propranololtreated subjects were tested for maximal heart rate after I week
of receiving the drug. Propranolol was continued until 3 days
beforeexit testing. The aerobic conditioningprogramwas 6 weeks
in duration.
erci se treadmill test for screening purposes and to familiarize
them with the protocol before entry into the study . After
the initial treadmill test , a control maximal treadmill test
was performed to exhaustion for measurement of blood pressure , heart rate, 12 lead electrocardiogram, oxygen consumption by expired gas analysis (using a fuel cell oxygen
analyzer) and exercise duration . Treadmill stages were 2
minutes each, increasing in 7 mllkg per min increments for
the first three stages and then in 3.5 ml/kg per min increments thereafter. After randomization, subjects who received propranolol were retested for the determination of
maximal heart rate after a stable propranolol blood level
was achieved. All subjects underwent a final maximal treadmill test at the completion of aerobic conditioning and, in
those taking propranolol, at least 72 hours after drug
withdrawal.
Measurements of calf blood flow and vascular resistance. On entry and exit , subjects were studied in the supine
position with their feet resting on the pedals of a cycle
ergometer (Quinton Uniwork model 845). The calf was
placed above the level of the heart to allow the veins to
empty , a necessity for plethysmographic measurements . Blood
flow was measured in the left calf with venous occlusion
plethysmography, using a single-stranded mercury in Silastic strain gauge calibrated with a 2 mm stretch. The strain
gauge was placed around the maximal calf circumference.
The signal was then amplified and recorded on a strip chart
recorder (12) . For each measurement , an ankle cuff was
inflated to 250 mm Hg and then a thigh cuff was rapidly
inflated to 40 mm Hg. Blood flow (mllIOO ml per min) was
taken as the maximal rate of change in the calf volume
during venous occlusion divided by the initial volume. This
measurement technique has been previously validated at rest
959
and during exercise by comparison with direct measurements of flow (13).
The electrocardiogram was monitored continuously utilizing lead V5, and blood pres sure was measured with a cuff
on the left arm. Mean arterial pressure was calculated as
one-third of the pulse pres sure added to the diastolic pressure . Vascular resistance was calculated by dividing mean
blood pressure by blood flow and is expressed as peripheral
resistance units (pru). Although calf and arm blood pressures
are not equal, changes in pressure are equivalent in both
location s, allowing a reasonable estimation of vascular
resistance.
Subjects exercised on the cycle ergometer at two target
work loads of300 and 700 kilogram -meters per minute (kgmlmin] . One minute was spent at a lower load for accli matization, followed by 3 minutes at the target load. During
the last minute of exercise, heart rate and blood pressure
were recorded. At the termination of exercise, an electronically activated catch on the ergometer allowed the left foot
to come to a fixed reproducible position and the calf to
rapidly relax . The first measurement of flow was obtained
at 2.5 seconds after exercise, then repeated every 5 seconds
for four measurements to determine the hyperemic response.
The highest postexercise flow (usually the first) was used
for anal ysis. Cycle exercise was performed in triplicate to
provide an average of three flow values for each target work
load. Subjects rested between exercise periods until heart
rate and blood pressure returned to basal conditions.
Drug dosing. Propranolol was administered in dose s
sufficient to produce submaximal beta. vadrenergic blockade , defined as 50% of maxim al blockade. Previous work
(14) has shown that maximal bcta.vadrenergic blockade in
the age group studied is obtained at propranolol plasma
levels of at least 100 ng/ml with a corresponding reduction
in maximal exercise heart rate of 59 ± 3 beats/min. We
defined submaximal blockade as a 30 beat/min reduction in
maximal exercise heart rate. The initial dose of propranolol
was 20 mg every 6 hours, which was increased to 30 mg
every 6 hours if the desired reduction in maximal heart rate
was not obtained by the lower dose. Repeat treadmill exercise testing was used to determine the adequacy of dosing .
Trough propranolol levels were determined using a previously described method (15). Compliance with medication
was monitored with weekly pill counts and random trough
drug level measurements during conditioning .
Training program. After completion of the entry studies, subjects began a 6 week inten sive aerobic conditioning
program . All were required to exercise above 75% of the
maximal heart rate on the entry treadmill exercise test for
the control group and the second pretraining treadmill exercise test for the propranolol group. Supervised conditioning sessions were held three time s per week using telem etry
monitoring. Each session began with 5 minutes of stretching
and warm-up exercises, followed by 8 minutes of continuous
exercise on each of three devices: motor-driven treadmill,
960
HIATI ET AL.
BETA-BLOCKERS AND PERIPHERAL CIRCULATION
Table
JACC YoL 4. No.5
November 19X4:95X-6:l
1. Comparison of Control and Propranolol Groups on Entry
Maximal heart rate (beats/min)
V0 2 max (rnl/kg per min)
Exercise duration (min)
Calf blood flow (ml/IOO ml per min)
300 kg-m/rnin
700 kg-mlmin
Control
Propranolol
194 ± 2
47.5 ± 1.1
18.3 ± 0.7
194 ± 3
47.2 ± 1.9
17.9 ± 0.8
15.7 ± 1.6
26.5 ± 3.8
16.7 ± 2.3
26.3 ± 2.8
Values are mean ± standard error of the mean. Differences between the groups are not significant for all
variables. kg-rn/rnin = work load (kilogram-meters/min); V0 2 max = maximal oxygen consumption.
cycle ergometer and steps (repeated step-ups with a single
step of fixed height). A I or 2 minute period of rest was
allowed between the different modes of exercise. Average
steady state heart rate was recorded on each exercise device.
The subjects then performed, as a group, a 20 minute supervised run. In addition to the supervised sessions, all
subjects were required to exercise 2 additional days per
week, monitoring and reporting their own steady stale pulse
rate during 30 to 40 minutes of continuous running or bicycling. Human subjects approval was obtained on March
8, 1982.
Statistical analysis. Mean changes in control and drug
groups were compared using Student's t test for paired data.
Mean differences between groups were compared using a
two-tailed unpaired t test. Results are reported as mean ±
standard error of the mean (SEM) with p < 0.05 considered
significant.
Results
Description of subjects on entry. Table 1 compares the
control and propranolol groups on entry into the study. There
were no differences between the groups in regard to maximal
heart rate, oxygen consumption or exercise duration on max-
imal treadmill exercise testing. OXygen consumption was
observed to plateau at exhaustion in a majority of subjects.
Calf blood flow at the two work loads of 300 and 700 kgm/min was also equivalent between groups.
Drug dosing. Five of six subjects had an adequate reduction in maximal heart rate while taking 80 mg of propranolol per day, and one required 120 mg per day. The
mean reduction in maximal exercise heart rate was 32 ± 4
beats/min. Trough blood levels of propranolol averaged
16.5 ± 4.6 ng/ml.
Compliance with medication and training. Subjects
treated with propranolol demonstrated consistent betaadrenergic blockade during the conditioning period as confirmed by plasma drug levels and heart rate measurements
taken during supervised sessions. All subjects participated
in 92% of the training sessions. Table 2 summarizes observations concerning the intensity of training during supervised exercise. Training heart rates are the average of
all values from telemetry monitoring. Subjects taking propranolol had an average training heart rate of 140 ± 4
beats/min, which was significantly less than the 161.5 ±
3 beats/min in the control group (p < 0.01). However,
propranolol-treated subjects exercised at a higher percent of
maximal heart rate (while taking the drug) than did control
subjects (p < 0.05).
Table 2. Intensity of Training
Training Value
Maximal Value*
Average
% of Maximal
Control group
Heart rate (beats/min)
Oxygen consumption (ml/kg per min)
194 ± 2
47.5 ± I
161.5 ± 3
34 ± I
83%
71%
Propranolol Group
Heart rate (beats/min)
Oxygen consumption (rnl/kg per min)
161 ± 4t
46.4 ± 1.5
140 -+- 4t
37 ± 1
87%t
81%:1:
*Maximal values in the control group are on entry into the study; those in the propranolol group are during
treatment with propranolol. tp < 0.01 for differences in subjects receiving propranolol compared with values
for the cootrol group. Maximal heart rate in propranolol-treated subjects was determined while they were
receiving the drug (second treadmill test). :j:p < 0.05 for differences in subjects receiving propranolol compared
with values for the control group. Percents are the training value divided by the maximal value in each group.
The training heart rates are the average of all values from telemetry monitoring during the supervised sessions.
lACC Vol. 4. No.5
November 1984:958-63
Maximal oxygen consumption (VO z max) was similar in
subjects tested while taking propranolol and in the control
group. The intensity of training was estimated from the
observed oxygen consumption from maximal treadmill testing that matched the average training heart rate for each
individual, and again both groups were equivalent. However, propranolol-treated subjects trained at an estimated
higher percent of VO z max than did control subjects (p <
0.05). Since these values are estimates, we conclude that
the training was intensive and equivalent in both groups.
Effects of training on "02 max and exercise duration. Figure 2 illustrates results that have been previously
reported (16). The control group demonstrated a mean increase in VQz max of 3.9 ml/kg per min (from 47.5 ± 1.1
to 51.4 ± 0.4 mllkg per min) (p < 0.05). Exercise duration
increased from 18.3 ± 0.7 to 20.7 ± 0.7 minutes (p <
0.01). VO z max did not change in the propranolol-treated
group after training and drug washout (47.2 ± 1.9 to 47.4
± 1.5 mllkg per min). However, exercise duration increased from 17.9 ± 0.8 minutes on entry to 19.0 ± 0.6
minutes on exit (p < 0.05). Differences between groups
after training were significant for both VOz max (p < 0.05)
and exercise duration (p < 0.01). These results were not
influenced by persistent beta.vadrenergic blockade because
maximal exercise heart rates after training and drug washout
were 191 ± 2 beats/min in the control group and 191 ±
3 beats/min in the propranolol-treated group.
Vascular effects of training. As a result of conditioning, calf blood flow at the 300 kg-mlmin work load in the
control group decreased from 15.7 ± I. 6 to 14.0 ± 1.4
mlllOO ml per min (p < 0.05) and at 700 kg-m/min from
26.5 ± 3.8 to 21.8 ± 2.3 mlllOO ml per min (p < 0.05).
In the propranolol-treated group, flow was unchanged after
training at both work loads. The change in flow from entry
to exit was significantly different between groups at 700 kgmlmin (p < 0.05) (Fig. 3).
Figure 2. Results of exercise conditioning. Control subjects had
significant increases in both maximal oxygen consumption (V0 2
max) and exercise duration. Propranolol-treated subjects had no
increase in \102 max, but did have an increase in exercise duration.
*p < 0.05 between groups after training; ** p < 0.01 between
groups after training.
55
I
lSo
I
I
Pre
Training
Vascular resistance in the control group at 300 kg-mlmin
did not change, with mean value of 6.1 ± 0.8 pru on entry
to 6.7 ± 1.0 PfU on exit. However, at 700 kg-mlmin,
resistance increased from 4.2 ± 0.8 to 4.8 ± 0.8 pru (p
< 0.05). In the propanolol-treated group, vascular resistance was unchanged at both work loads after training. The
change in resistance from entry to exit was significantly
different between groups at 700 kg-mlmin (p < 0.05)
(Fig. 4).
Discussion
Effects of beta-adrenergic blocking drugs on exercise
performance. The improvement in exercise performance
with aerobic conditioning is the result of changes occurring
Figure 4. Effects of exercise conditioning on calf vascular resistance. Control subjects had a significant increase in vascular resistance at the higher work load. Propranolol-treated subjects had no
change in resistance at either load. * p < 0.05 between groups
after training.
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Figure 3. Effects of exercise conditioning on calf blood flow.
Control subjects had a significant decrease in flow at both work
loads of subrnaximal exercise, while those receiving propranolol
did not change. * p < 0.05 between groups after training.
Exercise Duration
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961
HIATI ET AL.
BETA-BLOCKERS AND PERIPHERAL CIRCULATION
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962
lACC Vol. 4 . No .5
November 1984:958-6 ~
HIATI ET AL.
BETA-BLOCKERS AND PERIPH ERAL CI RC ULATIO N
in the heart, peripheral circulation and skeletal muscle (17,18).
Previous work (19,20) has shown that both short and longterm dosing of subjects with beta-adrenergic blocking agents
doe s not impair or only minimally decreases the ability to
perform short-term maximal or subrnaximal exertion. Also ,
these drug s do not decrease blood flow to the exercising
limb (21-23) . However, high and low dose nonselective
beta-adrenergic blockade has been shown (11 ,16) to markedly diminish the improvement in maximal oxygen consumption (V0 2 max) and exercise duration that occurs with
aerobic conditioning in normal subjects , as this study confirms . Ewy et al. (24) noted an increase in V0 2 max in a
group of subjects conditioned while taking the betaadrenergic blocking agent sotalol, but the changes in both
placebo and drug groups were small. Thus, the acute responses to exercise are not diminished in normal subjects
receiving beta-adrenergic blocking agents , but the ability to
condition aerobically is impaired. The mechanism by which
this impairment occurs has not been investigated.
Mechanisms of conditioning. An important effect of
aerobic conditioning is an increase in oxidative enzymes in
trained skeletal muscle (5,7) . In addition, conditioning is
associated with increases in capillary density and the number
of mitochondria (6 ,25) . These cellul ar changes permit more
efficient utilization of oxygen and metabolic substrates as
indicated by a widening of the arteriovenous oxygen difference (18).
In patients with peripheral vascular disease who have a
fixed and limited leg muscle oxygen supply, exercise conditioning can still result in an impressive increase in walking
distance (26). Conditioning occurs in these patients primarily as a result of adaptations in skeletal muscle, especially increases in oxidative enzymes (27). These results
further substantiate the important role that peripheral metabolic changes play in the conditioning process.
Aerobic training in normal subjects results in a decrease
in skeletal muscle blood flow at submaximal work loads,
presumably by autoregulation to meet local oxygen requirements (7-9). Thus, the more efficient metabolic environment established through training requires less oxygen to
maintain muscular activity. In the control group, calf blood
flow decreased significantly at both 300 and 700 kg-rn/min
of exertion as the result of training . Vascular resistance
increa sed at both work loads, but was significant only at
700 kg-m/rnin, possibly as a result of the small number of
subjects studied.
The attenuation of conditioning in propranolol-treated
subjects may have been related to lower absolute exercise
heart rates. However, the intensity of training was equivalent in both groups as confirmed by the V0 2 calculated
from the average heart rates during the supervised sessions .
Propranolol-treated subjects did not demonstrate the expected post-training changes in blood flow or vascular resistance. These results are not due to drug effect at the time
of testing, because 72 hours is sufficient to clear propranolol
from the blood and for changes in beta --adrenergic receptors
to return to basal conditions (15). After 72 hours, heart rate
and blood pressure respon ses to exercise have returned to
pretreatment values as well (28). In this study , propranololtreated subjects obtained the same maximal exercise heart
rate after training and drug washout as did the control subjects, confirming an absence of drug effect at exit testing.
Mechanism of propranolol's effect. The mechanism by
which propranolol prevent s the change in skeletal muscle
vascular tone normally resulting from aerobic conditioning
may be attributed to failure to increase capillary density or
oxidative enzymes in trained muscle . Rats given propranolol
during training do not demonstrate the expected increase in
skeletal muscle oxidative enzymes (10). If similar events
occur in human beings, then the usual improvements in
peripheral oxygen extraction associated with conditioning
may not occur. Therefore , to meet oxygen demand , skeletal
muscle blood flow would remain unchanged after conditioning . Changes in calf blood flow and vascular resistance
may then serve as indicators of the cellular adaptations that
result from conditioning.
We are grateful for the techni cal support provided by Arlene Niccoli. RN.
Barbara Morgan . RPT . Sandra Stoll. OTR. Jean Parks and Sam Kelly
(electronics specialist).
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