The effects of acute or chronic ingestion of propranolol or metoprolol on the metabolic and hormonal responses to prolonged submaximal exercise in hypertensive men


Macdonald, I.A.; Bennett, T.; Brown, A.M.; Wilcox, R.G.; Skene, A.M.

British Journal of Clinical Pharmacology 17(3): 283-294

1984


The effects of single oral doses of, and of 28 days treatment with, placebo, propranolol or metoprolol, on the metabolic and hormonal responses to prolonged exercise in hypertensive men were studied. Blood glucose levels fell during exercise on all occasions. No additional effects of the .beta.-adrenoceptor antagonists, compared to placebo, were observed. The exercise-induced increase in plasma K was enhanced after a single dose of propranolol or metoprolol, and also after chronic treatment with propranolol. Chronic treatment with either drug led to an increase in plasma K levels at rest. The growth hormone response to exercise was potentiated by a single dose of metoprolol or propranolol, and after chronic treatment with the drugs. A single dose of propranolol (but not metoprolol) was associated with a marked increase in plasma cortisol and adrenaline [epinephrine] levels durng exercise. After chronic treatment no such increase occurred. In both the acute and chronic phases of the study, blood lactate levels were higher during exercise in the presence of either propranolol or metoprolol compared to placebo, whereas non-esterified fatty acid levels were lower. A single dose of metoprolol produced a significantly greater reduction in blood glycerol levels during exercise than a single dose of propranolol. After chronic treatment, both propranolol and metoprolol produced similar reductions in blood glycerol levels during exercise. After a single dose, both drugs significantly augmented the increase in plasma noradrenaline levels during exercise. A similar effect was seen after chronic treatment.

Br.
J.
dim
Pharmac.
(1984),
17,283-293
The
effects
of
acute
or
chronic
ingestion
of
propranolol
or
metoprolol
on
the
metabolic
and
hormonal
responses
to
prolonged,
submaximal
exercise
in
hypertensive
men
I.
A.
MACDONALD',
T.
BENNETT',
A.
M.
BROWN',
R.
G.
WILCOX'
&
A.
M.
SKENE"
'Departments
of
Physiology
and
Pharmacology,
'Medicine
and
"Mathematics,
University
of
Nottingham,
Nottingham
1
We
have
studied
the
effects
of
single
oral
doses
of,
and
of
28
days
treatment
with,
placebo,
propranolol
or
metoprolol,
on
the
metabolic
and
hormonal
responses
to
pro-
longed
exercise
in
hypertensive
men.
2
Blood
glucose
levels
fell
during
exercise
on
all
occasions.
No
additional
effects
of
the
/3-adrenoceptor
antagonists,
compared
to
placebo,
were
observed.
3
The
exercise-induced
increase
in
plasma
potassium
was
enhanced
after
a
single
dose
of
propranolol
or
metoprolol,
and
also
after
chronic
treatment
with
propranolol.
Chronic
treatment
with
either
drug
led
to
an
increase
in
plasma
potassium
levels
at
rest.
The
growth
hormone
response
to
exercise
was
potentiated
by
a
single
dose
of
metoprolol or
pro-
pranolol,
and
after
chronic
treatment
with
the
drugs.
4
A
single
dose
of
propranolol
(but
not
metoprolol)
was
associated
with
a
marked
increase
in
plasma
cortisol
and
adrenaline
levels
during
exercise.
After
chronic
treatment
no
such
increase
occurred.
5
In
both
the
acute
and
chronic
phases
of
the
study,
blood
lactate
levels
were
higher
during
exercise
in
the
presence
of
either
propranolol
or
metoprolol
compared
to
placebo,
whereas
non-esterified
fatty
acid
levels
were
lower.
6
A
single
dose
of
metoprolol
produced
a
significantly
greater
reduction
in
blood
glycerol
levels
during
exercise
than
a
single
dose
of
propranolol.
After
chronic
treatment,
both
propranolol
and
metoprolol
produced
similar
reductions
in
blood
glycerol
levels
during
exercise.
7
After
a
single
dose,
both
drugs
significantly
augmented
the
increase
in
plasma
nor-
adrenaline
levels
during
exercise.
A
similar
effect
was
seen
after
chronic
treatment.
Keywords
propranolol
metoprolol
exercise
hypertension
hormonal
response
Introduction
In
a
previous
paper
(Wilcox
et
al.,
1984)
we
presented
data
concerning
the
cardiorespiratory
responses
to
exercise
and
the
perception
of
the
exercise
severity
after
acute
or
chronic
ingestion
of
propranolol
or
metoprolol.
In
addition
to
their
effects
on
the
cardiovascular
system,
it
is
well
established
that
f3-adrenoceptor
antagonists
influence
catecholamine-mediated
metabolic
processes
such
as
lipolysis
and
glycogenolysis.
The
present
investigation
was
designed
to
estab-
lish
the
effects
of
propranolol
or
metoprolol
on
the
metabolic
and
hormonal
responses
to
pro-
longed
submaximal
exercise.
These
responses
were
evaluated
both
after
acute
and
after
chronic
ingestion
of
the
/3-adrenoceptor
antagonists
(or
placebo)
in
a
group
of
patients
with
uncompli-
cated,
essential
hypertension.
283
284
I.
A.
Macdonald
et
al.
Methods
Ten
men
with
uncomplicated
essential
hyper-
tension
took
part
in
the
study
which
was
approved
by
the
ethical
committee
of
the
University
Hospital,
Nottingham.
The
detailed
experimental
protocol
and
data
concerning
body
weight
and
resting
lung
function
prior
to
each
exercise
test
are
given
in
the
preceding
paper
(Wilcox
et
al.,
1984).
Briefly,
each
patient
attended
for
a
preliminary
visit
during
which
he
walked
on
a
treadmill
(10%
slope)
at
a
speed
which
was
sufficient
to
raise
his
heart
rate
to
approximately
120
beats/min
(in
the
untreated
state).
The
treadmill
speed
was
then
noted
and
used
for
the
patient
on
each
subsequent
visit.
Each
patient
then
attended
on
six
further
occasions;
the
first
three
visits
were
1
week
apart
(acute
phase).
and
the
final
three
visits
were
4
weeks
apart
(chronic
phase).
In
the
acute
phase
the
patients
reported
to
the
laboratory
1.5
h
after
ingesting
a
single
tablet
of
metoprolol
(100
mg)
or
propranolol
(80
mg)
or
placebo.
In
the
chronic
phase,
following
the
twice
daily
in-
gestion
of
metoprolol
(100
mg)
or
propranolol
(80
mg)
or
placebo
for
28
days,
the
patients
attended
the
laboratory
1.5
h
after
taking
the
final
tablet.
The
patients
had
abstained
from
food,
cigarettes,
tea
or
coffee
for
at
least
8
h
before
each
visit.
Each
visit
commenced
with
a
30
min
baseline
period,
resting
supine,
followed
by
5
min
stand-
ing,
after
which
the
patient
started
to
exercise
(approximately
2
h
after
ingesting
the
tablet).
Exercise
consisted
of
walking
on
the
treadmill
(at
10%
slope
and
at
the
pre-determined
speed)
for
5
periods
of
10
min,
separated
by
3
min
rest
sitting
on
a
chair
on
the
treadmill.
After
the
fifth
period
of
exercise
the
patient
sat
on
a
chair
during
a
30
min
recovery
period.
Blood
samples
were
taken
via
a
cannula
which
was
placed
in
a
forearm
vein
at
the
start
of
the
initial
baseline
period
and
which
was
maintained
patent
by
the
continuous
infusion
of
154
mmol
NaC1/1
(0.3
ml/min).
Two
blood
samples
were
withdrawn
after
10
and
20
min
of
the
baseline
period
and
another
sample
after
5
min
standing.
Further
samples
were
taken
after
9
min
of
each
exercise
period,
after
2
min
of
each
rest
period
and
after
15
and
30
min
of
the
post-exercise
recovery
period.
For
the
measurement
of
metabolite
concen-
trations
(glucose,
glycerol,
lactate
and
pyruvate)
3
ml
of
whole
blood
was
placed
in
tubes
contain-
ing
3
ml
1
M
perchloric
acid,
mixed
and
centri-
fuged,
and
the
deproteinised
supernatant
snap
frozen
and
stored
at
—80°C
until
analysis
(Lloyd
et
al.,
1978).
The
remaining
blood
was
centri-
fuged,
the
plasma
separated,
snap
frozen
where
necessary,
and
stored
at
—80°C.
Analysis
of
this
plasma
for
potassium,
cortisol,
growth
hormone
(somatotropin)
and
insulin
was
by
standard
clinical
laboratory
methods,
plasma
non-esteri-
fied
acids
were
measured
according
to
the
method
of
Elphick
(1975),
and
plasma
catechol-
amines
using
high
performance
liquid
chromato-
graphy
with
electrochemical
detection
(Green
&
Macdonald,
1981).
Statistical
analysis
Treatment
and
exercise
effects
were
assessed
using
standard
analysis-of-variance
methods.
Variability
in
the
data
due
to
differences
be-
tween
subjects
was
controlled
by
including
sub-
ject
identity
as
a
blocking
factor
in
the
analysis.
Where
F
tests
revealed
differential
treatment
or
exercise/rest
effects,
the
precise
nature
of
these
differences
was
identified
using
t-tests
on
con-
trasts
in
the
group
means.
The
bulk
of
the
calcu-
lations
was
carried
out
using
the
facilities
for
the
analysis
of
designed
experiments
provided
by
the
statistical
package
GENSTAT
(1980).
Results
All
10
patients
completed
the
study.
However,
subsequent
determination
of
the
plasma
pro-
pranolol
or
metoprolol
levels
revealed
one
patient
who
had
not
completed
the
chronic
treat-
ment
with
metoprolol.
In
addition,
we
had
some
difficulty
in
obtaining
blood
samples
from
one
patient
during
exercise
so
the
results
presented
are
for
eight
subjects.
Unless
otherwise
stated
the
resting
values
were
not
significantly
affected
by
either
acute
or
chronic
administration
of
pro-
pranolol
or
metoprolol.
For
each
variable,
data
are
presented
for
the
acute
phase
of
the
study
and
then
the
chronic
phase,
mean
values
±
s.e.
mean
are
given.
(i)
Potassium
(Figure
1)
Acute
phase
Plasma
potassium
levels
increased
with
each
exercise
period;
the
increase
was
signi-
ficantly
greater
after
propranolol
or
metoprolol
than
after
placebo
(mean
maximum
increase
after
placebo
0.95
mmol
1;
after
propranolol
1.36
mmol
/1;
after
metoprolol
1.42
mmol'l;
P
<
0.01).
Thirty
minutes
after
exercise,
plasma
potassium
levels
were
highest
following
the
ingestion
of
propranolol.
Chronic
phase
Plasma
potassium
levels
during
the
baseline
period
were
slightly
higher
following
chronic
ingestion
of
placebo
(4.14
mmol/1)
than
13-adrenoceptor
blockade
and
exercise
metabolism
_
Chronic
study
/
285
P
lasm
a
p
o
tass
iu
m
(m
mo
1/
11
6.0
5.6
5.
2
4.8
4.4
4.0
3.6
_
Acute
study
-
r
1
1
10
20
Pre
-
exercise
rest
(min)
1
1
I
I
I
1
3
5
15
30
Exercise
periods
Post
-
exercise
(min)
1
1
10
20
Pre
-
exercise
rest
(min)
I I
1
1
3
5
Exercise
periods
1
15
30
Post
-
exercise
(min)
Figure
1
Plasma
potassium
levels
before,
during
and
after
exercise
following
ingestion
of
placebo
(0),
propranolol
(0)
or
metoprolol
(
0
)
in
both the
acute
(left
panel)
and
chronic
(right
panel)
phases
of
the
study.
Values
are
mean
±
s.e.
mean,
n
=
8.
after
placebo
in
the
acute
phase
(3.83
mmol/1;
P
<
0.01).
Chronic
ingestion
of
propranolol
or
metoprolol
produced
increases
in
baseline
plasma
potassium
levels
(metoprolol
4.37,
pro-
pranolol
4.35
mmo1/1;
P
<
0.05
compared
to
chronic
placebo).
During
exercise
in
the
chronic
phase
of
the
study,
plasma
potassium
rose
by
1.17
mmo1/1
after
placebo,
by
1.33
mmo1/1
after
metoprolol,
and
by
1.42
mmo111
after
proprano-
lol.
The
increase
in
potassium
seen
after
pro-
pranolol
was
greater
than
after
placebo,
but
the
difference
was
not
significant
(P
<
0.10).
During
the
first
15
min
of
the
post-exercise
recovery
period,
plasma
potassium
appeared
to
fall
by
a
Acute
study
5.8
5.6
5.4
5.2
5.0
4.8
4.6
4.4
4.
2
greater
amount
after
placebo
or
metoprolol
than
after
propranolol.
(ii)
Glucose
(Figure
2)
Acute
phase
Blood
glucose
levels
decreased
gradually
but
significantly
during
exercise
in
the
presence
of
placebo
(P
<
0.05).
Similar,
signi-
ficant
reductions
in
blood
glucose
occurred
during
exercise
in
the
presence
of
either
pro-
pranolol
or
metoprolol
(mean
fall
after
placebo,
0.44
mmol/l;
after
propranolol
0.70
mmo1/1,
after
metoprolol
0.61
mmo1/1).
The
absolute
blood
glucose
concentrations
were
significantly
Chronic
study
B
loo
d
g
lu
c
os
e
Im
mo
l
/
ll
1
1
10
20
Pre-
exercise
rest
(min)
1
1
1
1
1
1
1
1
2
3
4
5
15
30
Exercise
periods
Post-exercise
(min)
1
1
10
20
Pre-
exercise
rest
(min)
1
1
1 1
I
1
1
2
3
4
5
15
30
Exercise
periods
Post
-exercise
(min)
Figure
2
Blood
glucose
levels
before,
during
and
after
exercise
following
ingestion
of
placebo
(•),
propranolol
(0)
or
metoprolol
(
0
)
in
both
the
acute
(left
panel)
and
chronic
(right
panel)
phases
of
the
study.
Values
are
mean
s.e.
mean,
n
=
8.
I
1
I
I
1
1
I
10
20
1
2
3
4
5
Pre
-
Exercise
periods
exercise
rest
(min)
1
15
30
Post
-
-exercise
(min)
I
10
20
1
Pre
-
exercise
rest
(min)
_1
1
1
1
1
2
3
4
5
15
30
E
xercise
periods
Post
-
exercise
(min)
286
I.
A.
Macdonald
et
al.
150
Acute
study
Chronic
study
B
loo
d
g
ly
c
ero
l
Il
i
mo
l
/
I)
100
50
Figure
3
Blood
glycerol
levels
before,
during
and
after
exercise
following
ingestion
of
placebo
(0),
propranolol
(0)
or
metoprolol
(0)
in
both
the
acute
(left
panel)
and
chronic
(right
panel)
phases
of
the
study.
Values
are
mean
±
s.e.
mean,
n
=
8.
lower
during
the
later
stages
of
exercise
in
the
presence
of
metoprolol
(exercise
periods
4
and
5)
or
propranolol
(exercise
periods
3
and
4)
than
placebo.
Blood
glucose
was
rapidly
restored
during
the
post-exercise
recovery
period
after
all
three
treatments.
Chronic
phase
After
the
chronic
ingestion
of
propranolol
or
metoprolol
(but
not
placebo)
there
were
small,
but
significant,
increases
in
blood
glucose
levels
in
the
baseline
period
com-
pared
to
those
seen
after
acute
treatment
(pro-
pranolol
5.68
mmo1/1
(chronic),
5.13
(acute);
metoprolol
5.48
(chronic),
5.07
(acute)).
During
1500
Acute
study
1300
1100
E
a
900
E
ffl
exercise
in
the
chronic
phase,
blood
glucose
levels
fell
by
similar
amounts
after
all
three
treat-
ments
(placebo
—0.58
mmol,'1;
propranolol
—0.74
mmo1/1;
metoprolol
—0.78
mmo1/1).
Glucose
levels
increased
towards
baseline
levels
during
the
post-exercise
recovery
period.
(iii)
Glycerol
and
non-esterified
fatty
acids
(NEFA)
(Figures
3
and
4)
Acute
phase
Blood
glycerol
levels
increased
significantly
during
exercise
after
placebo
(P
<
Chronic
study
700
1
1
10
20
Pre-
exercise
rest
(min)
/
1
I
1
1
1
1
2
3
4
5
Exercise
periods
1
15
30
Post
-
exercise
(min)
1
10
20
Pre-
exercise
rest
(min)
iIII1
1
2
3
4
5
Exercise
periods
1
1
15
30
Post
-
exercise
(min)
500
300
Figure
4
Plasma
non-esterified
fatty
acid
(NEFA)
levels
before,
during
and
after
exercise
following
ingestion
of
placebo
(0),
propranolol
(0)
or
metoprolol
(0)
in
both
the
acute
(left
panel)
and
chronic
(right
panel)
phases
of
the
study.
Values
are
mean
±
s.e.
mean,
n
=
8.
1
3-adrenoceptor
blockade
and
exercise
metabolism
287
0.001);
this
effect
was
apparent
in
the
second
exercise
period.
In
the
presence
of
either
pro-
pranolol
or
metoprolol,
glycerol
levels
fell
during
the
first
exercise
period
and
then
in-
creased
during
the
later
exercise
periods.
The
glycerol
levels
in
the
fifth
exercise
period
were
significantly
less
with
metoprolol
than
either
propranolol
or
placebo
(P
<
0.001).
During
the
early
exercise
periods
there
was
little
change
in
NEFA
levels
after
placebo.
However,
during
the
last
two
exercise
periods
NEFA
levels
rose
slightly.
In
contrast,
after
either
propranolol
or
metoprolol,
NEFA
levels
fell
during
the
first
period
of
exercise
and
re-
mained
significantly
less
than
placebo
through-
out
(P
<
0.001),
with
the
levels
after
metoprolol
being
lower
than
those
after
propranolol.
During
the
recovery
period,
NEFA
levels
increased
markedly
and
by
similar
amounts
on
all
three
occasions,
although
to
a
significantly
higher
peak
after
placebo
than
after
either
/3-adrenoceptor
antagonist
(P
<
0.001).
Chronic
phase
After
chronic
ingestion
of
placebo,
a
larger
increase
in
glycerol
levels
was
seen
during
exercise
than
in
the
acute study.
After
chronic
ingestion
of
propranolol
or
meto-
prolol,
a
decrease
in
glycerol
levels
was
seen
during
the
early
periods
of
exercise,
followed
by
an
increase
above
baseline
levels
in
the
later
exercise
periods.
Blood
glycerol
levels
in
the
fifth
exercise
period
were
significantly
lower
after
propranolol
or
metoprolol
than
after
placebo
(P
<
0.001);
most
of
this
difference
can
be
accounted
for
by
the
failure
to
increase
glycerol
levels
at
the
beginning
of
exercise.
The
changes
in
NEFA
levels
during
both
exer-
cise
and
the
post-exercise
recovery
period
after
chronic
treatment
were
similar
to
the
acute
phase,
except
that
there
were
no
differences
between
the
effects
of
propranolol
and
meto-
prolol.
(iv)
Lactate
(Figure
5)
Acute
phase
Blood
lactate
levels
during
the
baseline
period
were
lower
after
placebo
than
after
propranolol
or
metoprolol,
but
the only
significant
difference
was
between
placebo
and
metoprolol
treatments
after
20
min
of
the
pre-
exercise
rest
period
(P
<
0.05).
During
exercise
there
was
a
significant
increase
in
lactate
levels
after
all
three
treatments
(P
<
0.01),
but
the
absolute
levels
in
the
presence
of
propranolol
or
metoprolol
were
significantly
higher
than
after
placebo
(P
<
0.05).
During
each
of
the
inter-
exercise
rest
periods,
blood
lactate
levels
fell
abruptly;
the
oscillations
in
lactate
level
after
propranolol
or
metoprolol
were
significantly
greater
than
after
placebo
(P
<
0.05).
Lactate
levels
fell
back
towards
baseline
values
during
the
post-exercise
recovery
period.
Chronic
phase
The
blood
lactate
levels
during
the
baseline
period
were
similar
after
all
three
treatments,
but
all
values
were
significantly
higher
than
in
the
acute
phase
of
the
study.
The
pattern
of
change
in
blood
lactate
during
exer-
1800
_
Acute
study
_
Chronic
study
1600
1400
E
1200
1000
800
600
/
V
I I
10
20
Pre-
exercise
rest
(min)
III
I
I
1
2
3
4
5
15
20
Exercise
periods
Post-exercise
(min)
I
10
20
Pre-
exercise
rest
(min)
III
I
1
2
3
4
5
15
30
Exercise
periods
Post
-exercise
(min)
Figure
5
Blood
lactate
levels
before,
during
and
after
exercise
following
ingestion
of
placebo
(
0),
propranolol
(0)
or
metoprolol
(0)
in
both
the
acute
(left
panel)
and
chronic
(right
panel)
phases
of
the
study.
Values
are
mean
±
s.e.
mean,
n
=
8.
P
las
ma
c
or
t
iso
l
(n
mo
1/
1)
900
800
700
600
500
400
300
Acute
study
-
n.
1
I
1
I
I
10
20
1
3
5
Pre-
Exercise
periods
exercise
rest
(min)
1
15
30
Post
-
exercise
(min)
1
I
I
I
10
20
1
3
5
Pre-
Exercise
periods
exercise
rest
(min)
1
15
30
Post-
exercise
tmin)
288
1.
A.
Macdonald
et
al.
cise
after
chronic
ingestion
of
placebo
was
similar
to
that
observed
after
placebo
in
the
acute
phase.
Significantly
higher
blood
lactate
levels
were
seen
during
some
of
the
exercise
periods
after
either
/3-adrenoceptor
antagonist
compared
to
placebo
(P
<
0.05),
but
the
differ-
ences
were
not
as
marked
as
in
the
acute
phase
of
the
study.
Furthermore,
blood
lactate
levels
did
not
fall
abruptly
during
the
inter-exercise
rest
periods
after
chronic
ingestion
of
propranolol
or
metoprolol.
(v)
Insulin
Acute
phase
Plasma
insulin
levels
were
low
in
the
baseline
period
after
all
three
treatments
(placebo
7.0
±
1.2
munits/1,
propranolol
5.7
±
1.8,
metoprolol
7.0
±
1.9)
and
fell
to
less
than
5
munits/1
during
exercise,
there
being
no
signifi-
cant
differences
between
placebo,
propranolol
or
metoprolol.
Chronic
phase
The
plasma
insulin
values
re-
corded
during
the
baseline
period
were
higher
than
those
recorded
in
the
acute
phase
of
the
study
(placebo
9.4
±
2.1
munits/1,
propranolol
11.4
±
1.5,
metoprolol
10.4
±
2.7).
Plasma
in-
sulin
concentrations
fell
during
exercise
(to
about
5.0
munits11)
and
then
increased
slightly
during
recovery,
there
being
no
differences
between
the
treatments.
(vi)
Cortisol
and
growth
hormone
(Figures
6
and
7)
Acute
phase
In
the
presence
of
placebo,
plasma
cortisol
levels
fell
during
exercise,
whereas
in
the
presence
of
metoprolol
a
slight
increase
of
corti-
sol
levels
was
observed
during
exercise,
with
a
further
increase
in
the
post-exercise
recovery
period.
After
the
acute
ingestion
of
propranolol,
plasma
cortisol
levels
at
the
end
of
exercise
and
during
the
recovery
period
were
the
highest
observed
(P
<
0.001).
Growth
hormone
levels
increased
during
exer-
cise
in
the
presence
of
placebo;
significantly
higher
levels
were
observed
in
the
presence
of
propranolol
or
metoprolol
(P
<
0.01).
There
were
no
significant
differences
between
the
levels
recorded
after
the
two
/3-adrenoceptor
antagonists.
Chronic
phase
After
the
chronic
ingestion
of
placebo,
cortisol
levels
fell
during
exercise.
Following
the
chronic
ingestion
of
metoprolol
there
was
a
slight
increase
in
plasma
cortisol
concentration
during
exercise,
whilst
the
chronic
ingestion
of
propranolol
was
associated
with
a
maintenance
of
cortisol
levels
during
exercise.
These
changes
were
such
that
significantly
higher
cortisol
levels
were
recorded
at
the
end
of
exer-
cise
after
metoprolol
than
after
propranolol
(P
<
0.05),
and
the
levels
after
propranolol
were
higher
than
after
placebo
(P
<
0.05).
The
exercise-induced
rise
in
plasma
growth
hormone
levels
was
potentiated
by
the
chronic
/
c
L
Sb
Chronic
study
/
Figure
6
Plasma
cortisol
levels
before,
during
and
after
exercise
following
ingestion
of
placebo
(0),
propranolol
(0)
or
metoprolol
(
0)
in
both
the
acute
(left
panel)
and
chronic
(right
panel)
phases
of
the
study.
Values
are
mean
±
s.e.
mean,
n
=
8.
1
1
3
5
Pre-
Exercise
periods
exercise
rest
(min)
1
15
30
Post
-
exercise
(min)
10
20
Pre-
exercise
rest
(min)
1
3
5
Exercise
periods
15
30
Post
-exercise
(min)
Acute
study
=
40
30
*E
20
E
5
10
E
5
E
fp
0.
I
I
10
20
Chronic
study
d
o
1
1
1
1
1
1
1
10
20
2
4
5
15
30
Standing
Pre-
exercise
rest
(mini
Exercise
periods
Post
-
exercise
(mini
I
1
1
1
1
2
4
5
15
30
Post
-
exercise
(mini
-
Pla
s
ma
a
dr
e
n
a
lin
e
in
m
o
1/
1
,
r
1 1
10
20
1
Standing
Pre-
Exercise
periods
exercise
rest
(mini
/3-adrenoceptor
blockade
and
exercise
metabolism
289
Figure
7
Plasma
growth
hormone
levels
(logarithmic
scale)
before,
during
and
after
exercise
following
ingestion
of
placebo
(
0),
propranolol
(0)
or
metoprolol
(D)
in
both
the
acute
(left
panel)
and
chronic
(right
panel)
phases
of
the
study.
Values
are
mean
±
s.e.
mean,
n
=
8.
ingestion
of
propranolol
or
metoprolol
(P
<
0.01),
although
in
contrast
to
the
acute
phase,
the
highest
mean
value
was
recorded
after
meto-
prolol.
(vii)
Catecholamines
(Figure
8)
Acute
phase
Plasma
noradrenaline
levels
in-
creased
on
standing
on
all
three
occasions.
A
further
increase
occurred
during
exercise
in
the
presence
of
placebo,
the
peak
level
being
re-
Acute
study
5
corded
in
the
second
exercise
period.
In
the
presence
of
propranolol
or
metoprolol,
nor-
adrenaline
levels
during
exercise
periods
4
and
5
were
significantly
elevated
compared
to
placebo
(P
<
0.01).
Plasma
adrenaline
levels
increased
slightly
during
exercise
in
the
presence
of
placebo
or
metoprolol.
In
contrast,
a
more
substantial
in-
crease
was
observed
in
the
fifth
exercise
period
in
the
presence
of
propranolol
such
that
the
levels
were
significantly
higher
than
after
placebo
(P
<
0.05).
Chronic
study
Figure
8
Plasma
noradrenaline
(top)
and
adrenaline
(bottom)
levels
before,
during
and
after
exercise
following
ingestion
of
placebo
(10),
propran6lol
(
0)
or
metoprolol
(0)
in
both
the
acute
(left
panel)
and
chronic
(right
panel)
phases
of
the
study.
Values
are
mean
±
s.e.
mean,
n
=
8.
290
1.
A.
Macdonald
et
al.
Chronic
phase
Plasma
noradrenaline
levels
increased
on
standing
and
showed
a
further
increase
during
exercise.
Noradrenaline
levels
were
significantly
higher
during
the
second
and
fourth
periods
of
exercise
in
the
presence
of
metoprolol
or
propranolol
than
placebo
(P
<
0.01),
but
by
the
end
of
exercise
there
were
no
significant
differences.
A
similar
pattern
was
observed
for
plasma
adrenaline
levels
as
in
the
acute
study,
except
that
the
levels
after
chronic
ingestion
of
pro-
pranolol
were
not
different
from
after
placebo.
Discussion
When
an
individual
undertakes
prolonged
exer-
cise
at
a
moderate
intensity
(50-60%
maximum
aerobic
capacity),
then
some
60%
of
the
fuel
requirements
are
met
by
carbohydrate,
the
re-
mainder
coming
from
NEFA
(Felig
&
Wahren,
1975).
In
the
first
few
minutes
of
such
exercise,
the
major
source
of
carbohydrate
is
intramus-
cular
glycogen,
whilst
after
approximately
10
min,
blood
glucose
makes
a
substantial
contri-
bution
(Felig
&
Wahren,
1975).
The
metabolic
responses
to
the
type
of
exercise
employed
in
the
present
study
involve
the
activation
of
lipolysis
and
glycogenolysis,
as
well
as
the
exchange
of
glucose,
lactate,
glycerol
and
NEFA
between
skeletal
muscle,
adipose
tissue
and
the
liver.
However,
the
alteration
of
these
responses
by
/3-adrenoceptor
antagonists
is
not
restricted
to
direct
effects
on
fuel
mobilisation;
alterations
in
muscle
blood
flow
(Trap-Jensen
et
al.,
1976;
Smith
&
Warren,
1982)
and
splanchnic
blood
flow
(Trap-Jensen
et
al.,
1976)
can
indirectly
affect
metabolism
during
exercise.
Thus,
the
changes
recorded
in
the
present
study
in
the
concentrations
of
the
principal
metabolites
in
blood
may
result
from
alterations
in
fuel
mobilisation
and
utilisation,
as
well
as
changes
in
clearance
and
release
from
the
splanchnic
bed.
Potassium
Exercise
of
moderate
to
severe
intensity
leads
to
an
increase
both
in
arterial
(Lim
et
al.,
1981)
and
venous
potassium
levels
(van
Beaumont
et
al.,
1973;
Carlsson
et
al.,
1978),
presumably
resulting
from
a
marked
efflux
of
potassium
from
the
con-
tracting
muscle
(van
Beaumont
et
al.,
1973).
Our
observation
that
the
effect
is
enhanced
by
the
acute
administration
of
propranolol
or
metopro-
lol
to
hypertensive
patients
is
consistent
with
previous
studies
of
normotensive
subjects
(Carlsson
et
al.,
1978;
Lundborg
et
al.,
1981).
The
impaired
recovery
of
plasma
potassium
after
exercise
following
acute
administration
of
pro-
pranolol
has
been
observed
previously
(Leenan
et
al.,
1980;
Lundborg
et
al.,
1981).
It
has
been
claimed
that
this
effect
is
due
to
the
inhibition,
by
propranolol,
of
a
0
2
-adrenoceptor
mediated
stimulation
of
the
Na/K-ATPase
(Wang
&
Clausen,
1976;
Lockwood
&
Lum,
1979;
Carls-
son
et
al.,
1978).
The
chronic
administration
of
metoprolol
or
propranolol
was
accompanied
by
a
significant
increase
in
resting
plasma
potassium
levels,
similar
to
that
previously
reported
for
proprano-
lol
(Biihler
et
al.,
1973)
and
subsequently
for
a
wide
range
of
/3-adrenoceptor
antagonists
(Wilcox,
1978).
The
increases
in
plasma
potas-
sium
during
exercise
in
the
acute
and
the
chronic
phases
of
the
study
were
similar
for
both
/3-
adrenoceptor
antagonists.
This
may
represent
a
persistent
effect
of
the
drugs
on
the
mechanisms
of
potassium
disposition
during
exercise,
but
the
interpretation
is
complicated
by
the
higher
potassium
levels
seen
at
rest
and
during
exercise
after
chronic
ingestion
of
placebo
compared
to
the
acute
phase
of
the
study.
Many
factors
could
have
contributed
to
the
higher
potassium
levels
after
chronic
treatment
with
placebo,
including
a
possible
carryover
of
previous
/3-adrenoceptor
antagonist
therapy
into
the
placebo
period.
It
remains
to
be
established
whether
the
changes
in
plasma
potassium
levels
during
exer-
cise
contribute
to
the
reported
sensations
of
fatigue.
However,
it
is
interesting
to
note
that
with
chronic
ingestion
of
the
drugs,
the
differ-
ences
between
the
three
treatments
in
both
per-
ceived
exertion
and
in
plasma
potassium
were
diminished
compared
to
the
acute
phase
of
the
study.
Glucose
and
lactate
In
the
present
study,
baseline
blood
glucose
levels
were
unaffected
by
the
acute
ingestion
of
propranolol
or
metoprolol,
although
chronic
treatment
led
to
a
significant
increase
of
about
0.5
mmo1/1.
The
significance
of
this
increase
is
unclear,
but
it
is
interesting
to
note
that
it
was
accompanied
by
significant
increases
in
plasma
potassium
and
insulin
levels
and
thus
may
have
reflected
a
small
reduction
in
insulin
sensitivity.
During
exercise
in
both
the
acute
and
chronic
phases
of
the
study,
blood
glucose
fell
by
0.5
to
0.8
mmol/l,
and
neither
metoprolol
nor
pro-
pranolol
significantly
influenced
this
fall,
in
con-
trast
to
previous
studies
in
normotensive
sub-
jects
(Galbo
et
al.,
1976;
Lundborg
et
al.,
1981;
Uusitupa
et
al.,
1982).
Blood
lactate
levels
during
exercise
were
higher
in
the
presence
of
either
metoprolol
or
/3-adrenoceptor
blockade
and
exercise
metabolism
291
propranolol
(compared
to
placebo)
both
after
acute
and
after
chronic
treatment.
These
effects
are
similar
to
those
reported
in
previous
studies
in
normotensive
subjects
(Galbo
et
al.,
1976;
Twentyman
et
al.,
1981;
Dorow
et
al.,
1982),
and
were
probably
due
to
a
marked
reduction
in
the
splanchnic
clearance
of
lactate
(Trap-Jensen
et
al.,
1976).
The
rapid
falls
in
blood
lactate
in
the
inter-exercise
rest
periods
in
the
acute
phase
of
the
present
study
cannot
be
taken
as
evidence
of
effective
splanchnic
clearance
without
measure-
ments
of
lactate
handling
by
other
tissues.
Glycerol
and
NEFA
In
both
the
acute
and
chronic
phases
of
the
pre-
sent
study,
exercise
(after
placebo)
was
accom-
panied
by
an
initial
fall
in
NEFA
levels,
followed
by
an
increase
above
baseline
by
the
end
of
exer-
cise
and
a
further
marked
increase
in
the
post-
exercise
recovery
period.
In
contrast,
glycerol
levels
rose
progressively
throughout
exercise
and
fell
during
recovery.
These
changes
are
similar
to
those
found
in
untreated,
normotensive
subjects
(Galbo
et
al.,
1976;
Jones
et
al.,
1980).
The
dis-
sociation
between
NEFA
and
glycerol
was,
presumably,
the
consequence
of
an
increased
rate
of
NEFA
utilisation
(keeping
NEFA
levels
down)
and,
possibly,
an
impaired
splanchnic
clearance
of
glycerol
(due
to
reduced
splanchnic
blood
flow)
together
with
an
increased
rate
of
lipolysis
(giving
progressively
increasing
glycerol
levels).
A
further
contributory
factor
might
have
been
the
breakdown
of
intramuscular
triglycer-
ide
,
releasing
glycerol
into
the
blood
with
the
NEFA
remaining
in
the
muscle
and
being
oxi-
dised
(Jones
et
al.,
1980).
In
the
presence
of
metoprolol
or
propranolol
both
the
NEFA
and
the
glycerol
levels
during
exercise
were
reduced.
After
acute
treatment
the
effect
was
most
marked
for
metoprolol.
In
both
phases
of
the
study,
the
ingestion
of
meto-
prolol
or
propranolol
was
associated
with
a
re-
duction
in
glycerol
levels
in
the
early
stages
of
exercise,
followed
by
an
increase
above
baseline
levels
after
approximately
20
min.
The
larger
effect
of
acutely
administered
metoprolol
(com-
pared
to
propranolol)
could
be
explained
by
a
predominance
of
13
1
-adrenoceptors
in
the
con-
trol
of
lipolysis,
but
the
situation
is
likely
to
have
been
complicated
by
the
presence
of
higher
plasma
levels
of
the
catecholamines
and
cortisol
(both
of
which
stimulate
lipolysis)
during
exer-
cise
after
the
acute
ingestion
of
propranolol.
This
interpretation
is
supported
by
the
results
of
the
chronic
phase
of
the
study,
where
similar
hor-
mone
levels
occurred
during
exercise
in
the
pre-
sence
of
metoprolol
or
propranolol,
and
the
13-
adrenoceptor
antagonists
produced
similar
re-
ductions
in
blood
glycerol
levels.
Although
we
observed
that
pre-exercise
NEFA
levels
were
unaffected
by
acute
or
chronic
treatment
with
propranolol
or
meto-
prolol,
we
did
not
measure
any
other
plasma
lipids
and,
thus,
cannot
comment
on
any
associa-
tion
between
1
3-adrenoceptor
antagonist
in-
gestion
and
hyperlipidaemia.
Growth
hormone
The
administration
of
propranolol
or
metoprolol
enhances
the
growth
hormone
responses
to
exer-
cise
in
normotensive
subjects
(Maclaren
et
al.,
1975;
Kindermann
et
al.,
(1982).
Our
results
foil
-
hypertensive
patients
during
exercise
are
similar,
and
are
consistent
with
there
being
a
p
r
adreno-
ceptor
in
the
central
nervous
system,
the
stimu-
lation
of
which
leads
to
an
inhibition
of
growth
hormone
secretion.
However,
we
cannot
ex-
clude
an
influence
of
metabolic
changes,
such
as
the
fall
in
glucose
and
NEFA
levels,
on
growth
hormone
secretion.
Cortisol
The
reduction
in
plasma
cortisol
levels
seen
in
both
phases
of
the
study
during
exercise
with
placebo
is
consistent
with
previous
studies
on
normotensive
individuals
and
is
likely
to
have
been
the
result
of
an
increased
clearance
of
corti-
sol
from
the
circulation
(Few,
1974).
Following
acute
treatment
with
metoprolol,
cortisol
levels
rose
slightly
during
exercise,
whereas
following
acute
ingestion
of
propranolol
there
was
a
marked
increase
in
plasma
cortisol
during
and
after
exercise.
One
cannot
determine
from
the
present
data
whether
this
was
mainly
due
to
changes
in
release
or
clearance.
After
chronic
treatment
with
propranolol
or
metoprolol
there
were
small
increases
in
cortisol
levels
during
exercise;
i.e.
the
acute
effect
of
metoprolol
was
sustained
whereas
that
of
propranolol
had
diminished.
The
elevated
cortisol
levels
during
exercise
after
propranolol
or
metoprolol,
com-
pared
to
placebo,
are
likely
to
have
exerted
metabolic
effects,
potentiating
both
adipose
tissue
lipolysis
and
hepatic
gluconeogenesis,
thereby
opposing
some
of
the
metabolic
distur-
bances
produced
by
the
p-adrenoceptor
antago-
nists.
Catecholamines
The
increase
in
plasma
noradrenaline
levels
seen
after
5
min
standing
was
unaffected
by
either
acute
or
chronic
administration
of
propranolol
or
metoprolol.
In
contrast,
the
further
increase
292
1.
A.
Macdonald
et
al.
in
plasma
noradrenaline
levels
during
exercise
was
enhanced
by
both
drugs,
an
effect
seen
pre-
viously
in
normotensive
subjects
undertaking
prolonged
exercise
(Galbo
et
al.,
1977;
Kindermann
et
al.,
1982).
Plasma
adrenaline
levels
showed
similar
moderate
increases
during
exercise
on
all
occa-
sions
except
following
acute
ingestion
of
pro-
pranolol.
The
much
larger
increase
in
adrenaline
levels
during
exercise
after
a
single
dose
of
propranolol
is
similar
to
the
results
reported
for
normotensive
subjects
during
exercise
to
ex-
haustion
(Galbo
et
al.,
1977;
Lundborg
et
al.,
1981).
The
potentiated
adrenaline
response
seen
in
the
present
study
might
have
been
due
to
an
alteration
in
glucose
metabolism
(Galbo
et
al.,
1977)
but
the
fall
in
blood
glucose
during
exer-
cise
after
acute
ingestion
of
propranolol
was
not
significantly
different
from
placebo.
In
addition,
it
is
possible
that
the
elevated
cortisol
levels
may
have
increased
catecholamine
release
from
the
adrenal
medulla
(Critchley
et
al.,
1982).
The
elevated
plasma
catecholamine
levels
seen
during
exercise
after
acute
treatment
with
pro-
pranolol
or
metoprolol
may
have
been
due,
in
part,
to
a
f3-adrenoceptor
antagonist-induced
reduction
in
the
metabolic
clearance
of
the
cate-
cholamines
(Clutter
et
al.,
1980;
Cryer
et
al.,
1980;
Best
&
Halter,
1982).
However,
the
ab-
sence
of
elevated
catecholamine
levels
during
exercise
after
chronic
treatment
indicates
that
either
the
effect
on
clearance
was
diminished
with
chronic
treatment
or
that
increased
cate-
cholamine
release
made
a
significant
contribu-
tion
to
the
effects
seen
with
acute
ingestion
of
propranolol
or
metoprolol.
The
major
finding
of
the
present
study
was
that
acute
treatment
with
metoprolol
or
pro-
pranolol
produced
a
more
severe
disturbance
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all)
of
the
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and
hormonal
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the
0-
adrenoceptor
antagonists
having
impaired
fat
mobilisation
during
exercise,
giving
increased
dependence
on
carbohydrate
as
a
fuel
source.
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the
antilipolytic
effect
of
the
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may
have
been
offset
by
changes
in
the
hormonal
responses
to
exercise,
making
the
overall
inter-
pretation
somewhat
complex.
In
the
previous
paper
we
reported
that
per-
ceived
exertion
during
exercise
was
greater
after
acute
ingestion
of
propranolol
or
metoprolol
than
placebo,
and
that
the
effect
was
predomin-
antly
due
to
an
increase
in
leg
fatigue
and
was
most
marked
for
propranolol
(Wilcox
et
al.,
1984).
These
effects
on
perceived
exertion
may
have
been
due
to
actions
of
the
drugs
in
the
central
nervous
system,
but
some
of
the
meta-
bolic
changes
reported
in
this
paper
may
have
contributed;
in
particular
the
increases
in
potas-
sium
and
lactate
levels.
It
is
interesting
to
note
that
after
chronic
treatment
the
differences
in
perceived
exertion
and
the
magnitude
of
many
of
the
metabolic
and
endocrine
disturbances
seen
after
acute
treatment
were
reduced.
We
are
grateful
to
Professor
John
Wikstrand
and
Dr
Eric
Fellenius
(AB
Hassle,
MOlndal,
Sweden)
for
their
advice
and
encouragement
and
Astra
Pharmaceuti-
cals,
St
Albans,
UK,
for
financial
support.
Some
of
the
metabolite
assays
were
performed
in
collaboration
with
Dr
A.
M.
J.
Woolfson
and
made
possible
by
a
grant
to
him
from
the
Trent
Regional
Health
Author-
ity.
We
thank
Dawn
Lake,
Christine
Lewis
and
Hilary
Green
for
their
excellent
technical
assistance;
the
Department
of
Clinical
Chemistry,
City
Hospital,
Nottingham
for
performing
the
insulin,
cortisol
and
growth
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Worley
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Rosemary
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(Received
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