J.
Phy8iol.
(1970),
207,
429-448
429
WVith
8
text-ftgureM
Printed
in
Great
Britain
THE
EFFECT
OF
ADRENALINE
ON
THE
CONTRACTION
OF
HUMAN
MUSCLE
BY
C.
D.
MARSDEN*
AND
J.
C.
MEADOWSt
From
the
Departments
of
Medicine
and
Neurology,
St
Thomas'
Hospital,
London,
S.E.
1,
and
the
Physiological
Laboratory,
University
of
Cambridge
(Received
11
September
1969)
SUMMARY
1.
Infusions
of
adrenaline
in
physiological
amounts
alter
human
muscle
contractions
evoked
by
nerve
stimulation.
2.
Adrenaline
shortens
the
duration
of
the
slow
calf
muscle
twitch,
but
has
no
effect
on
the
fast
twitch
of
adductor
pollicis.
3.
Adrenaline
decreases
unfused
tetanic
tension
and
increases
the
oscillation
of
tension
in
10/sec
tetani
of
calf
muscle
and
adductor
pollicis.
The
usual
rise
of
tension
and
decrease
in
oscillation
in
unfused
tetani
('ramp'
phenomenon)
is
abolished.
4.
Adrenaline
has
no
effect
on
maximal
tetanic
tension
or
maximal
rate
of
rise
of
tension
in
a
fused
tetanus
of
adductor
pollicis.
5.
The
effects
of
adrenaline
on
human
muscle
are
due
to
stimulation
of
,f-adrenotropic
receptors,
for
they
are
abolished
by
the
f-adrenotropic
antagonist
DL-propranolol
(but
not
by
D-propranolol),
and
are
mimicked
by
isoprenaline
but
not
by
noradrenaline.
6.
The
effect
of
adrenaline
on
adductor
pollicis
is
abolished
by
local
fl-blockade
of
one
arm
with
intra-arterial
DL-propranolol,
indicating
that
the
responsible
fl-receptors
lie
peripherally.
7.
The
changes
in
muscle
contraction
observed
cannot
be
explained
by
altered
muscle
temperature,
for
this
falls
during
adrenaline
infusion;
nor
are
they
due
to
an
action
on
neuromuscular
transmission,
for
these
small
doses
of
adrenaline
do
not
affect
the
muscle
action
potential.
The
evidence
points
to
a
direct
action
of
adrenaline
on
muscle.
*
Present
address:
The
National
Hospital
for
Nervous
Diseases,
Queen
Square,
London,
W.C.
1.
t
Present
address:
The
Middlesex
Hospital,
London,
W.
1.
C.
D.
MARSDEN
AND
J.
C.
MEADOWS
INTRODUCTION
It
is
a
commonplace
that
fright
causes
people
to
shake,
and
there
is
good
reason
to
suppose
that
this
is
due
to
liberation
of
adrenaline,
for
injection
of
adrenaline
brings
on
a
similar
state
of
tremor.
Recently,
Marsden,
Foley,
Owen
&
McAllister
(1967)
established
that
adrenaline
tremor
is
not
a
central
effect
but
is
due
to
stimulation
of
peripheral
adrenotropic
,-recep-
tors,
for
they
found
that
the
increase
in
the
amplitude
of
the
normal
tremor
of
the
outstretched
fingers
during
intravenous
infusion
of
adrenaline
in
healthy
subjects
could
be
prevented
in
an
arm,
and
in
that
arm
alone,
by
injection
of
a
small
dose
of
DL-propranolol
(an
adrenotropic
f8-blocking
agent)
into
the
brachial
artery.
Of
the
numerous
known
effects
of
adrenaline
on
the
peripheral
neuro-
muscular
apparatus
the
two
that
appear
most
likely
to
be
relevant
in
explaining
adrenaline
tremor
are
the
abbreviation
of
the
twitch
of
the
cat
soleus
muscle
by
physiological
doses
of
adrenaline,
discovered
by
Bowman
&
Zaimis
(1958),
and
the
sensitization
of
muscle
spindles
to
stretch
by
adrenaline,
investigated
by
Calma
&
Kidd
(1962).
Bowman
&
Zaimis
them-
selves
suggested
that
their
effect
might
be
responsible
for
human
adrenaline
tremor
and
their
case
was
strengthened
by
the
observation
of
Marsden,
Meadows,
Lange
&
Watson
(1967)
that
adrenaline
still
accentuated
hand
tremor
in
an
arm
that
had
been
surgically
deafferented
by
section
of
dorsal
roots
C5-T2,
thus
ruling
out
all
reflex
effects,
in
particular
those
from
muscle
spindles.
A
direct
effect
of
adrenaline
on
the
parameters
of
contrac-
tion
seemed
the
only
explanation.
The
present
paper
brings
forward
further
evidence
for
the
suggestion
of
Bowman
&
Zaimis
(based
on
their
results
on
cat
muscle),
by
showing
that
adrenaline
speeds
up
contraction
of
human
muscle
too.
It
should
be
made
clear
at
the
outset,
however,
that
the
matter
may
be
more
complicated
than
Bowman
&
Zaimis
originally
thought,
for
in
the
deafferented
patient
investigated
by
Marsden
et
al.
(1967)
adrenaline
and
isoprenaline
increased
tremor
considerably
more
in
the
normal
arm
than
in
the
deafferented
arm.
Sensitization
of
the
stretch
reflex
by
adrena-
line
(Hodgson,
Marsden
&
Meadows,
1969)
by
an
effect
on
muscle
spindles
(or
some
other
different
reflex
effect)
may,
therefore,
contribute
to
adrenaline
tremor,
but
we
offer
no
further
evidence
as
yet
on
this
possi-
bility.
(That
peripheral
factors,
acting
reflexly,
may
influence
or
determine
the
frequency
of
tremor
was
shown
by
Robson
(1959)
and
has
recently
been
emphasized
by
Lippold
(1969)
with
new
experimental
support.)
Some
of
our
results
presented
here
have
already
been
communicated
to
the
Physiological
Society
(Marsden
&
Meadows,
1968).
430
ADRENALINE
AND
MUSCLE
CONTRACTION
431
METHODS
The
subjects
studied
were
ourselves
or
colleagues.
The
effect
of
intravenous
adrena-
line
on
the
contraction
of
triceps
surae
and
adductor
pollicis
was
investigated.
Two
methods
were
used
for
recording
contraction
of
the
calf
muscles.
In
the
main
series
of
experiments
the
subject
lay
face
downward
on
a
bed
with
his
feet
clear
of
the
end.
One
foot
was
securely
strapped
to
a
rigid
footplate,
at
right
angles
to
the
leg,
through
which
the
tension
developed
during
contraction
of
triceps
surae
under
approximately
isometric
conditions
was
transmitted
as
a
bending
movement
to
a
stiff
aluminium
bar
incorporating
two
silicon
strain
gauges
(Ether
Ltd.,
type
2A-
IA-350P).
The
latter
formed
two
arms
of
a
bridge
circuit,
the
output
of
which
was
displayed
on
a
Tektronix
502A
oscilloscope.
The
contraction
of
triceps
surae
was
expressed
in
terms
of
the
pressure
exerted
on
the
footplate
under
the
ball
of
the
foot
(the
level
of
the
first
metatarsophalangeal
joint),
the
system
being
calibrated
by
placing
weights
at
this
position
on
the
footplate
with
the
footplate
horizontal.
The
output
was
linear
up
to
15
kg.
A
few
later
experiments
on
the
calf
muscles
were
done
at
the
Physiological
Laboratory,
Cambridge,
with
Dr
P.
A.
Merton.
In
these
experiments
the
subject
sat
on
a
chair
with
his
thigh
horizontal
and
his
knee
bent
to
a
right
angle.
The
foot
was
again
strapped
to
a
footplate,
force
being
recorded
by
a
strain
gauge
of
small
com-
pliance
and
referred,
as
before,
to
the
pressure
exerted
at
the
ball
of
the
foot.
The
footplate
was
designed
to
swivel
about
the
same
axis
as
the
ankle
joint,
the
align-
ment
of
the
axes being
finally
secured
by
careful
adjustment
of the
fore
and
aft
position
of
the
foot
on
the
footplate
and
of
the
height
of
the
foot
(by
placing
packing
pieces
between
it
and
the
footplate)
until
both
contraction
of
the
extensors
of
the
knee
and
resting
a
20
kg
weight
upon
the
knee
gave
no
output
from
the
strain
gauge.
The
20
kg
weight
was
then
left
in
position
on
the
knee
to
prevent
the
heel
from
lifting
off
the
footplate
during
contraction
of
the
calf
muscles.
With
both
recording
arrangements
single
twitches
and
incomplete
(i.e.
unfused)
tetani
of
the
calf
muscles
were
evoked
by
supramaximal
cathodal
stimulation
of
the
medial
popliteal
nerve
in
the
popliteal
fossa
with
brief
shocks
delivered
via
a
fixed
silver
surface
electrode
about
1
cm
in
diameter.
The
tension
developed
must
have
been
mainly
due
to
contraction
of
soleus
and
gastrocnemius
(triceps
surae),
with
inevitable
smaller
contributions
from
plantaris,
tibialis
posterior,
flexor
digitorum
longus
and
flexor
hallucis
longus.
In
some
experiments
the
first
differential
of
the
tension
sigrial,
corresponding
to
velocity
of
contraction,
was
also
recorded.
In
other
experiments
the
muscle
action
potential
was
led
off
by
two
surface
electrodes
strapped
approximately
4
cm
apart
on
the
belly
of
the
muscle.
With
either
type
of
recording
arrangement
single
maximal
twitches
of
the
calf
muscles
are
not
smooth
but
exhibit
one
or
more
bumps
on
the
rising
phase,
e.g.
Fig.
8.
(The
records
chosen
for
the
Figures
are,
of
course,
the
smoothest.)
After
taking
great
care
with
both
types
of
apparatus
to
exclude
free
play,
sideways
move-
ments
and
similar
mechanical
troubles
that
can
undoubtedly
cause
the
appearance
of
bumps
on
twitch
records,
we
are
left
with
the
strong
impression
that
some
of
the
bumps
seen
are
not
artefactual
and
probably
reflect
the
different
rat6s
of
contrac-
tion
in
different
muscles
participating,
e.g.
slow
soleus
and
fast
gastrocnemius.
The
experiments
on
the
hand
muscle,
adductor
pollicis,
were
carried
out
in
Cambridge,
using
a
modified
form
of
the
equipment
described
by
Merton
(1951).
The
main
difference
was
that
action
potentials
were
recorded
by
surface
electrodes,
one
on
the
palm
about
2
cm
medial
to
the
first
metacarpophalangeal
joint
and
the
other
on
the
fourth
finger.
The
ulnar
nerve
was
stimulated
at
the
wrist
and
muscle
tension
recorded
by
a
strain
gauge
and
direct-coupled
amplifier.
C.
D.
MARSDEN
AND
J.
C.
MEADOWS
Other
neurophysiological
techniques
employed
are
described
in
the
Results.
The
delivery
of
nerve
stimuli
was
programmed
by
a
Devices
Instruments
Ltd
Digitimer
and
supplementary
Logic
Unit
3080,
both
designed
by
Mr
H.
B.
Morton
of
the
National
Hospital,
Queen
Square.
Intravenous
infusions
were
administered
via
a
needle
inserted
in
an
antecubital
vein
at
rates
varying
from
2-4
ml./min,
by
a
constant-rate
infusion
pump.
Solutions
of
catecholamines
were
diluted
in
isotonic
saline
to
which
0-03
%
ascorbic
acid
was
added
to
prevent
oxidation.
The
dosages
of
adrenaline
(1-adrenaline
bitartrate)
and
of
noradrenaline
(1-noradrenaline
bitartrate)
are
given
in
terms
of
the
base,
but
of
isoprenaline
(isopropylnoradrenaline
sulphate)
as
the
salt.
Blockade
of
fl-adreno-
tropic
receptors
was
produced
by
intravenous
or
intra-arterial
DL-propranolol
(Inderal,
I.C.I.).
In
a
few
control
experiments
D-propranolol
(I.C.I.
47,319)
was
given.
In
all
experiments
the
effects
of
infused
catecholamine
were
compared
with
control
values
obtained
during
prior
infusion
of
isotonic
saline
alone,
usually
for
many
minutes.
With
few
exceptions,
which
are
referred
to
specifically,
all
observations
on
the
effects
of
catecholamines
were
made
between
the
third
and
sixth
minute
of
in-
fusion.
Statistical
analysis
was
by
Student's
t
test
on
paired
samples.
RESULTS
The
effect
of
adrenaline
on
the
calf
muscle
twitch
Adrenaline
consistently
altered
the
shape
of
the
isometric
twitch
of
tri-
ceps
surae
evoked
by
supramaximal
nerve
stimulation.
The
experiment
illustrated
in
Fig.
1
is
taken
from
the
main
series
of
experiments
in
which
the
dose
of
adrenaline
was
always
10
,ug/min.
Control
twitches
during
the
initial
saline
infusion
are
compared
with
twitches
recorded
during
the
fifth
minute
of
a
subsequent
intravenous
infusion
of
adrenaline.
Adrenaline
in-
creased
the
peak
tension
developed
by
2-7
%;
decreased
the
time
taken
to
develop
peak
tension
from
95
to
87
msec;
and
decreased
the
time
taken
to
reach
half-relaxation
from
184
to
155
msec.
Table
1
gives
the
results
obtained
in
this
and
eight
similar
experiments
on
five
subjects.
Adrenaline
always
reduced
the
duration
of
the
twitch.
The
time
to
half-relaxation
decreased
by
a
mean
of
28-7
msec
(S.E.
of
mean
+
2-6
msec;
P
<
0-001).
Adrenaline
also
appeared
to
decrease
the
time
to
peak
tension
as
measured
from
the
twitch
records,
by
a
mean
of
7-5
msec
(s.E.
of
mean
+
1-26
msec;
P
<
0.005).
It
was
often
difficult
to
determine
the
exact
point
at
which
peak
tension
was
achieved
in
twitch
records,
but
records
of
the
first
differ-
ential
of
the
twitch
confirmed
that
it
was
reached
earlier
during
adrenaline.
Adrenaline
always
shortened
relaxation
time
much
more
than
contraction
time.
Maximum
tension
was
variably
affected;
it
was
decreased
in
six
experiments,
increased
in
two,
and
unchanged
in
one.
Adrenaline
had
similar
effects
on
triceps
surae
twitches
evoked
by
constant
submaximal
nerve
shocks.
After
adrenaline
infusions
the
twitch
returned
to
its
previous
shape
within
about
30
min.
Sufficient
observations
were
made
at
these
late
432
ADRENALINE
AND
MUSCLE
CONTRACTION
intervals
to
establish
this
point,
but
the
long
duration
of
the
adrenaline
action
explains
why
its
effects
were
normally
only
compared
with
control
records
taken
immediately
beforehand.
Observations
were
later
made
both
on
calf
twitch
and
on
calf
tremor
with
much
smaller
doses
of
adrenaline,
using
the
Cambridge
equipment.
The
standard
dose
of
adrenaline,
10
ltg/min,
may
increase
tremor
in
the
R
5
kg
L--.vJ
100
msec
Fig.
1.
The
effect
of
adrenaline
(10
l,g/min
intravenously)
on
calf
muscle
twitch.
(A)
Six
superimposed
twitches
during
prior
infusion
of
saline,
(B)
six
twitches
during
adrenaline
superimposed
on
six
twitches
during
saline,
(C)
six
twitches
during
adrenaline.
In
this
and
some
subsequent
Figures,
rapid
transients
in
the
signal
photographed
have
been
retouched
for
the
sake
of
clarity.
TABLE
1.
Effect
of
adrenaline
(10
jug/min
intravenously)
on
(A)
peak
tension,
(B)
time
to
peak
tension,
(C)
time
to
half-relaxation
of
calf
muscle
twitch
in
nine
experiments
on
five
subjects
(A)
Peak
tension
(kg)
Subject
Saline*
Adrenalinet
1
5*96
5-78
5-26
5.79
6*82
7-00
6*14
5-92
2
7*31
7-31
7*91
6-37
3
6*11
6-00
4
3.55
3.45
5
4*70
4*60
(B)
Time
to
peak
tension
(msec)
Saline*
Adrenalinet
91
84
100
93
95
87
106
104
100
89
107
93
61
62
136
129
118
109
(C)
Time
to
half-relaxation
(msec)
Saline*
Adrenalinet
160
185
184
197
175
207
162
225
178
136
106
155
160
142
164
140
198
160
*
Mean
values
during
3
min
prior
saline
infusion.
t
Mean
values
during
fifth
min
of
adrenaline
infusion.
calf
so
much
that
in
some
subjects
the
muscles
break
into
violent
clonus.
As
it
seemed
implausible
that
such
a
striking
oscillation
could
be
precipi-
tated
merely
by
a
change
in
muscle
dynamics
of
the
degree
just
demon-
strated,
smaller
doses
of
adrenaline
were
tried
to
see
whether
an
increase
in
tremor
could
be
produced
without
detectable
abbreviation
of
the
A
433
4.
D.
MARSDEN
AND
J.
C.
MEADOWS
muscle
twitch.
Tremor-recording
runs
at
a
demanded
force
of
5
kg
(to
be
described
in
detail
in
a
subsequent
paper)
were
alternated
with
records
of
maximal
twitches
during
adrenaline
infusion.
Somewhat
to
our
surprise
the
smallest
doses
of
adrenaline
that
increased
tremor
also
distinctly
abbreviated
the
twitch.
Thus,
in
three
experiments,
adrenaline
(only
1-25
,tg/min)
decreased
the
time
taken
to
reach
half-relaxation
from
a
mean
of
218
msec
to
a
mean
of
204
msec,
a
change
of
14
msec.
The
effect
of
adrenaline
on
the
adductor
pollicis
twitch
The
adductor
pollicis
twitch
was
of
shorter
duration
than
that
of
the
calf
muscles.
For
the
adductor
pollicis,
time
to
half-relaxation
averaged
112
msec
calculated
from
the
figures
in
Table
2;
for
calf
muscles,
time
to
TABLE
2.
Effect
of
adrenaline
(10
jig/min
intravenously)
on
(A)
peak
tension,
(B)
time
to
peak
tension,
(C)
time
to
half-relaxation
of
adductor
pollicis
twitch
in
eight
experiments
on
three
subjects
(B)
Time
to
peak
(C)
Time
to
(A)
Peak
tension
tension
half-relaxation
(kg)
(msec)
(msec)
Subject
Saline*
Adrenalinet
Saline*
Adrenalinet
Saline*
Adrenalinet
1
0-80
0-87
60
60
122
122
1-02
1X02
55
56 114
112
0-99
0-98
53
62
115
116
0-75
0-76
58
61
97
106
2
0-90
0-90
63
63
127
126
1-04
1-01
69
71
122
124
1-03
1-03
63
63
113
120
3
1-05
1-00
46
48
90
90
*
Mean
values
during
3
min
prior
saline
infusion.
t
Mean
values
during
fifth
min
of
adrenaline
infusion.
half-relaxation
averaged
186
msec
(Table
1)
when
the
knee
was
extended,
and
218
msec
when
the
knee
was
flexed
to
900.
In
contrast
to
its
effect
on
the
calf
muscle
twitch,
intravenous
adrenaline
had
no
detectable
effect
on
the
peak
tension
or
the
duration
of
the
adductor
pollicis
twitch
(Table
2).
The
effect
of
adrenaline
on
incomplete
tetani
of
the
calf
muscles
As
was
expected
from
the
results
obtained
with
single
twitches,
adrenaline
had
marked
effects
on
the
tension
developed
by
triceps
surae
during
stimulation
of
the
medial
popliteal
nerve
at
10/sec.
This
rate
of
stimulation
was
chosen
because
grouping
of
muscle
action
potentials
at
about
10
c/s
is
seen
during
contraction
of
human
calf
muscle
(Lippold,
434
ADRENALINE
AND
MUSCLE
CONTRACTION
Redfearn
&
Vuco,
1957)
and
has
been
held
to
be
responsible
for
the
peak
at
about
10
c/s
which
is
conspicuous
in
the
spectrum
of
physiological
tremor.
An
increased
oscillatory
response
to
a
10/sec
tetanic
stimulation
would
lead
one
to
expect
an
increased
response
to
action
potentials
grouped
at
10/sec
and
could
therefore
help
to
explain
the
elevation
of
the
10
c/s
peak
in
adrenaline
tremor.
Figure
2A
illustrates
such
an
experiment.
Before
infusion
of
adrenaline,
10/sec
supramaximal
stimulation
produced
a
peak
tension
of
13-3
kg
at
the
end
of
2
sec.
The
tetanus
was
unfused
and
the
peak-to-trough
oscilla-
tion
in
tension
at
the
end
of
2
sec
amounted
to
about
0-67
kg,
or
5
0
%
of
A
5
kg
Saline
Saline
Adrenaline
Adrenaline
0
2
sec
Fig.
2.
The
effect
of
adrenaline
(10
gg/min
intravenously)
on
calf
muscle
tetani
at
10/sec
(A)
before,
and
(B)
after,
5
mg
DL-propranolol
intra-
venously.
In
both
A
and
B
the
base
line
was
lowered
during
the
adrenaline
infusion.
the
peak
tension
developed.
During
the
fifth
minute
of
intravenous
infusion
of
adrenaline
at
a
rate
of
10
,ug/min,
the
peak
tension
fell
to
11-2
kg
and
the
oscillation
increased
to
about
2-72
or
24-3
%
of
peak
tension.
The
results
of
a
series
of
six
similar
experiments
on
two
subjects
are
summarized
in
Table
3
A.
The
tension
developed
during
the
final
second
of
a
2
sec
tetanus
at
10/sec
decreased,
while
the
peak-to-trough
oscillation
in
tension
in-
creased
during
adrenaline
infusion.
Such
experiments
are
painful
and
the
difficulty
of
ensuring
complete
voluntary
relaxation
leads
to
some
irregularity
in
the
records,
which
do
not,
however,
conceal
the
main
phenomena,
although
the
'ramp'
(see
below)
is
less
convincingly
seen
than
in
adductor
pollicis.
Higher
fre-
quencies
of
stimulation
proved
impracticable,
so
we
are
unable
to
say
what
the
effect
of
adrenaline
is
on
the
maximal
tetanic
tension
of
triceps
surae.
435
C.
D.
MARSDEN
AND
J.
C.
MEADOWS
The
effect
of
adrenaline
on
incomplete
tetani
of
the
adductor
pollici8
Although
adrenaline
did
not
alter
the
single
twitch
of
adductor
pollicis,
it
did
change
the
response
to
repetitive
stimulation.
In
the
experiment
illustrated
in
Fig.
3A
supramaximal
shocks
at
10/sec
were
delivered
to
the
ulnar
nerve
for
periods
of
4
sec.
(Each
tetanus
was
preceded
and
followed
by
isolated
single
twitches.)
In
the
control
tetanus
the
tension
rises
pro-
gressively
and
the
peak-to-trough
oscillation
of
tension
diminishes,
both
TABI,E
3.
Effect
of
adrenaline
(10
ug/min
intravenously)
on
10/sec
tetani
of
(A)
calf
muscle
(mean
of
six
experiments)
and
(B)
adductor
pollicis
(mean
of
ten
experiments)
(A)
Calf
muscle
Median
tension*
during
final
second
of
2
sec
tetanus
Peak-to-trough
oscillation
(kg)
as
%
of
peak
tension
Ir
_
-
r
A
_ _
_i
n
Saline
Adrenaline
Saline
Adrenaline
6
10-91
8-58
15.1
29-2
t
=
3-5,P
<
0-02
t=
9*3,P
<
0-001
(B)
Adductor
pollicis
Median
tension*
during
final
second
of
4
sec
tetanus
Peak-to-trough
oscillation
(kg)
as
%
of
peak
tension
f
A
A
.
n
Saline
Adrenaline
Saline
Adrenaline
10
2-27
1-41
40-2
60-1
t
=
4-9,P
<
0-001
t
=
6-2,P
<
0-001
*
Calculated
as
the
midpoint
between
the
peak
and
the
trough
of
oscillations.
absolutely
and
relatively.
This
conjunction
of
a
rising
tetanic
tension
with
a
diminishing
oscillation
is
here
called
the
'ramp'
phenomenon.
It
can
also
be
seen
in
calf
muscles
in
the
control
record
in
Fig.
2A
and
in
both
records
in
Fig.
2B.
During
longer
periods
of
stimulation
of
adductor
pollicis
at
10/sec
the
ramp
continued,
the
oscillation
gradually
fading
until
the
tetanus
was
almost
fused
at
a
tension
some
two
to
three
times
that
achieved
during
the
initial
second
of
stimulation.
The
relation
of
the
ramp
to
the
classical
post-tetanic
potentiation
of
the
twitch
is
uncertain.
The
latter
is
attributable
to
an
initial
increase
in
the
response
of
the
contractile
material
itself,
followed
by
prolongation
of
the
duration
of
the
active
state
of
the
contractile
mechanism
of
the
muscle
(Ritchie
&
Wilkie,
1955;
Close
&
Hoh,
1968).
Adrenaline
did
not
alter
the
initial
twitch
of
a
10/sec
tetanus
but,
as
can
be
seen
in
Fig.
3A,
it
changed
subsequent
events
by
preventing
the
rise
in
tension
and
fall
in
oscillation.
Before
adrenaline,
the
peak
tension
achieved
436
ADRENALINE
AND
MUSCLE
CONTRACTION
after
4
sec
of
stimulation
was
3*34
kg
and
the
peak-to-trough
oscillation
in
tension
was
0
77
kg
or
23-0
%
of
peak
tension.
During
the
fifth
minute
of
adrenaline
infusion
the
peak
tension
was
1P42
kg
and
peak-to-trough
oscillation
was
0W91
kg
or
64-0
%
of
peak
tension.
The
results
of
a
series
of
ten
such
experiments
on
three
subjects
are
summarized
in
Table
3B.
Adrenaline
consistently
reduced
or
abolished
both
components
of
the
ramp
phenomenon
on
repetitive
stimulation
of
adductor
pollicis
and
the
same
was
true
of
the
calf
muscles.
Saline
Adrenaline
A
Fig.
3.
The
effect
of
adrenaline
(10
fig/min
intravenously)
on
adductor
pollicis
tetani
at
10/sec.
Below
the
tension
trace
in
each
record
is
the
first
differential
of
the
tension
signal.
(A)
Before
propranolol
and
(B)
after
injection
of
propranolol
(0-5
mg)
into
the
brachial
artery
of
the
same
subject.
Single
twitches
before
and
after
each
tetanus
are
also
shown.
The
effect
of
adrenaline
on
tetani
of
adductor
pollicis
evoked
by
greater
rates
of
stimulation
was
also
studied
in
three
subjects.
Single
twitches
and
3
sec
periods
of
stimulation
at
10/sec,
12/see,
15/sec,
20/sec
andl
50/sec
in
a
programmed
sequence
once
every
2
min
were
given
before
and
during
adrenaline
infusion
at
the
usual
dose
of
10
fig/min.
Sample
records
are
shown
in
Fig.
4
and
the
mean
values
for
the
three
subjects
are
plotted
in
Fig.
5.
437
C.
D.
MARSDEN
AND
J.
C.
MEADOWS
The
peak
tension
of
a
single
twitch
was,
as
already
stated,
unaltered
by
adrenaline.
The
mean
tension
achieved
after
3
sec
tetani
at
10,
12,
15,
and
20/sec
was
decreased
by
adrenaline,
the
effect
becoming
less
marked
the
greater
the
rate
of
stimulation.
Adrenaline
increased
the
relative
peak-to-
trough
oscillation
of
tension
after
3
sec
stimulation,
the
effect
again
be-
coming
less
obvious
as
stimulation
frequency
increased.
At
50/sec,
the
10/sec
12/sec
15/sec
20/sec
A
.
-.........
_...._.........._._
-_-_---------------
~
~
~
.
...
.
.....
C
-.--
-zrz..
--m-
C
..........
.
............
....
---
D.______
_V
-__
.
m...
3
sec
Fig.
4.
The
effect
of
adrenaline
(10
g/min
intravenously)
on
adductor
pollicis
tetani
at
10,
12,
15
and
20/sec.
Below
the
tension
trace
in
each
record
is
the
first
differential
of
the
tension
signal.
(A)
and
(B)
recorded
at
an
interval
of
7
min
during
prior
saline
infusion,
(C)
during
adrena-
line,
and
(D)
25
min
after
adrenaline
infusion.
tetanus
appeared
fused
and
adrenaline
had
no
effect
on
the
tension
achieved.
Higher
rates
of
stimulation
were
also
studied,
and
it
was
con-
cluded
that
adrenaline
had
no
effect
on
the
maximum
tetanic
tension
of
adductor
pollicis
(which
appears
to
be
achieved
at
a
frequency
of
100/sec).
Measurement
of
the
rate
of
rise
of
tension
using
the
differentiated
tension
signal
indicated
that
adrenaline
did
not
alter
the
maximum
velocity
of
contraction
of
adductor
pollicis
at
the
start
of
a
fused
tetanus,
at
50/sec
or
100/sec.
438
ADRENALINE
AND
MUSCLE
CONTRACTION
439
The
type
and
site
of
the
adrenotropic
receptors
responsible
for
the
effect
of
adrenaline
The
criteria
for
identification
of
a
,-adrenotropic
action
are
that
the
effect
of
adrenaline
should
be
mimicked
by
isoprenaline
but
not
by
noradrenaline,
and
prevented
by
DL-propranolol
but
not
by
D-propranolol.
Howe
&
Shanks
(1966)
have
shown
that
D-propranolol
has
only
about
one
sixtieth
of
the
fl-blocking
activity
of
the
racemic
mixture,
although
it
retains
the
latter's
local
anaesthetic
and
cardiac
anti-arrhythmic
properties.
10
_
8
@
0
C
00
0
Single
10
12
15
20
50/sec
Frequency
of
stimulation
Fig.
5.
The
effect
of
adrenaline
(10
,tg/min
intravenously)
on
adductor
pollicis
tetani
at
10,
12,
15,
20
and
50/sec.
Median
tension
after
3
sec
of
stimulation
before
(ifilled
circles)
and
during
adrenaline
(open
circles)
is
shown,
as
well
as
peak
tension
in
a
single
twitch.
The
peak-to-trough
oscillation
in
tension
after
3
sec
of
stimulation
is
shown
before
(continuous
lines)
and
during
adrenaline
(interrupted
lines).
The
results
shown
com-
prise
the
mean
of
those
obtained
in
three
subjects.
All
these
criteria
are
satisfied
for
the
effect
of
adrenaline
on
the
calf
muscle
twitch.
Isoprenaline,
in
doses
of
5-10
/tg/min
intravenously,
caused
a
characteristic
decrease
in
twitch
duration,
whereas
10
Itg/min
of
nor-
adrenaline
intravenously
did
not
(Fig.
6).
The
effects
of
adrenaline
and
of
isoprenaline
were
both
abolished
by
prior
fl-blockade
with
51mg
DL-
propranolol
intravenously,
but
not
by
51mg
of
D-propranolol
intravenously.
440
C.
D.
MARSDEN
AND
J.
C.
MEADOWS
In
addition
Fig.
2B
shows
that
the
effect
of
adrenaline
on
a
10/sec
tetanus
of
the
calf
muscles
was
abolished
by
DL-propranolol,
thus
confirming
that
the
change
in
the
ramp
phenomenon
after
adrenaline
is
also
due
to
stimula-
tion
of
f8-adrenotropic
receptors.
In
the
arm,
intra-arterial
propranolol
was
used
to
show
that
the
relevant
fl-receptors
are
in
the
periphery.
In
one
subject
a
dose
of
0-5
mg
DL-pro-
pranolol,
intended
as
a
control,
was
injected
intravenously,
but
it
appeared
Before
After
propranolol
DL-
DL-
D-
0,
+20
*4°
E0
.0
'4
0
e
-20
0~~~
u
-40~
A
0
C
D
E
F
(ADR)
(ISO)
(NOR)
(ADR)
(ISO)
(ADR)
Fig.
6.
Change
in
time
to
half-relaxation
of
calf
muscle
twitch
produced
by
intravenous
infusion
of
(A)
adrenaline
(10
,ug/min),
(B)
isoprenaline
(5
,ug/min,
squares;
10
/c6g/min,
circles),
(C)
noradrenaline
(10,ug/min),
(D)
adrenaline
(lO,uzg/min)
after
DL-propranolol
(5
mg
i.v.),
(E)
isOprenaline
(10,ug/min)
after
DL-propranolol
(5
mg
i.v.),
(F)
adrenaline
(lO
#cg/min)
after
D
-propranolol
(5
mg
I.V.).
to
cause
some
reduction
in
the
effect
of
adrenaline
on
the
10/sec
tetanus
of
adductor
pollicis.
The
following
day
0-25
mg
intravenously
was
without
detectable
blocking
action,
so,
after
another
24
hr
interval,
this
dose
was
given
into
the
brachial
artery
of
the
arm
from
which
records
were
being
taken.
The
effect
of
adrenaline
on
the
10/sec
tetanus
of
the
adductor
was
then
found
to
be
abolished.
As
the
same
dose
had
been
without
effect
intravenously
this
experiment
indicates
that
the
responsible
,8-receptors
lie
in
the
distribution
of
the
brachial
artery;
thus
they
are
of
the
same
type
and
in
the
same
location
as
those
responsible
for
the
increase
of
tremor
after
adrenaline.
Previous
experiments
on
two
other
subjects
had
shown
ADRENALINE
AND
MUSCLE
CONTRACTION
that
0
5
mg
intra-brachial
DL-propranolol
completely
blocked
the
effect
of
adrenaline
on
the
10/sec
tetanus
of the
adductor
pollicis.
One
of
these
experiments
is
illustrated
in
Fig.
3B.
Precisely
in
what
structures
these
peripheral
fl-receptors
lie
we
have
not
established,
but
the
likelihood
is
that
they
are
in
the
muscle
fibres
them-
selves.
The
experiments
that
follow
attempt
to
support
this
view
by
offering
evidence
to
exclude
other
possible
sites
and
modes
of
action.
Control
observations
on
various
factors
that
alter
the
muscle
twitch
Muscle
temperature.
Adrenaline
has
complex
effects
on
muscle
blood
flow,
but
it
is
difficult
to
see
how
these
could
be
relevant
to
the
present
phenomenon
except
by
altering
muscle
temperature.
Bowman
&
Zaimis
(1958)
did,
indeed,
find
that
the
effect
of
adrenaline
on
the
cat
soleus
was
independent
of
concomitant
changes
in
blood
flow.
In
a
number
of
experi-
ments
we
measured
muscle
temperature
by
means
of
a
needle
thermo-
couple
thrust
into
the
first
dorsal
interosseus
muscle
for
about
1
cm
towards
the
adductor
pollicis.
During
the
intravenous
infusion
of
adrena-
line
muscle
temperature
consistently
fell
by
0
3
to
0.90
C
and
remained
low
at
a
time
when
records
were
taken
showing
an
abolition
of
the
ramp
phenomen.
To
explain
the
decreased
degree
of
tetanic
fusion
during
adrenaline
the
temperature
would
have
to
rise,
not
fall
(we
have
checked
this
assertion).
Hence
it
appears
that
temperature
changes
cannot
account
for
the
effects
of
adrenaline
we
observe.
Changes
in
resting
length
and
tension.
As
discussed
by
Buller
&
Lewis
(1963)
changes
in
the
initial
length
or
tension
in
a
muscle
can
alter
the
shape
of
the
recorded
twitch.
There
were
no
changes
in
initial
length
of
the
calf
muscles
during
the
adrenaline
infusion,
nor
were
changes
in
resting
tension
observed.
Furthermore,
during
adrenaline
infusions,
alterations
in
the
tension
applied
to
the
footplate
by
making
a
small
voluntary
con-
traction,
or
alterations
in
the
angle
of
the
foot
relative
to the
footplate,
did
not
restore
the
twitch
to
its
pre-adrenaline
shape;
nor
did
such
manoeuvres
reproduce
the
effects
of
adrenaline.
The
Muscle
action
potential.
Although
adrenaline
lowers
the
electrical
threshold
of
nerve
(Bulbring
&
Whitteridge,
1941;
Goffart
&
Holmes,
1962)
and
has
complex
effects
on
neuromuscular
transmission
(Bowman
&
Raper,
1966,
1967),
it
is
difficult
to
see
how
these
actions
can
be
involved
in
the
changes
in
mechanical
response
described
above.
We
have,
however,
confirmed
(Fig.
7)
that,
at
a
time
when
the
usual
abbreviation
of
the
triceps
surae
twitch
had
occurred,
during
adrenaline
infusion
there
was
no
alteration
in
the
maximal
action
potential
recorded
from
the
calf
with
surface
electrodes.
Furthermore,
in
a
series
of
experiments
on
five
subjects,
adrenaline
did
not
alter
consistently
either
the
action
potential
recorded
441
C.
D.
MARSDEN
AND
J.
C.
MEADOWS
from
abductor
pollicis
brevis
on
supramaximal
stimulation
of
the
median
nerve
or
individual
motor
unit
action
potentials
recorded
with
concentric
needle
electrodes
from
the
thenar
muscles
on
minimum
voluntary
effort.
Motor
nerve
conduction
velocity
in
the
median
nerve
between
the
elbow
and
wrist,
measured
by
conventional
techniques,
was
not
affected
by
adrenaline.
The
'back
response'
of
muscle.
Elimination
of
the
back
response
of
the
muscle
during
a
mechanical
twitch,
discovered
by
Merton
(1954)
and
analysed
by
Brown
&
Matthews
(1960),
produces
changes
in
twitch
shape
A
B
100
msec
5
kg
5
my
l l
l
l
I
1
0
50
msec.
Fig.
7.
Effect
of
adrenaline
(10
,ug/min
intravenously)
on
triceps
surae
twitch
(above)
and
evoked
electromyographic
action
potential
(below).
Six
superimposed
traces
during
(A)
saline
and
(B)
adrenaline.
In
(C)
siX
action
potentials
during
saline
are
superimposed
on
those
during
adrena-
line
at
a
faster
sweep
speed.
Despite
the
usual
changes
in
the
twitch,
the
muscle
action
potential
was
unaltered
by
adrenaline.
similar
to
those
caused
by
adrenaline.
Although,
as
already
mentioned,
adrenaline
lowers
the
threshold
of
nerve,
and
would
therefore
be
expected
to
augment
the
back
response
rather
than
abolish
it,
we
confirmed
by
experiment
that
adrenaline
has
its
usual
effect
when
the
muscle
is
stimu-
lated
in
such
a
way
that
back
responses
are
prevented.
This
experiment
depends
on
the
observation
that
the
back
response
may
be
abolished
by
applying
a
second
maximal
nerve
stimulus
at
an
interval
less
than
the
absolute
refractory
period
of
the
muscle
fibres
(Brown
&
Matthews,
1960).
The
second
volley
has
no
effect
on
the
muscle,
but
renders
the
intra-
442
ADRENALINE
AND
MUSCLE
CONTRACTION
muscular
nerve
fibres
refractory
to
a
'back
response'
restimulation
by
the
muscle
action
potential.
Accordingly,
the
effect
of
adrenaline
on
twitches
elicited
by
paired
stimuli
of
200
,tsec
duration
was
compared
with
that
on
twitches
elicited
by
a
single
shock.
When
the
two
stimuli
were
separated
by
an
interval
of
2
msec
or
more,
the
resulting
twitch
was
larger
than
that
produced
by
a
single
stimulus.
The
twitch
evoked
by
stimuli
separated
by
500
/ssec
to
1
msec
was
smaller
and
briefer,
suggesting
that
at
these
intervals
a
double
shock
was
occluding
a
'back
response'.
Adrenaline
shortened
the
time
to
half-relaxation
of
twitches
evoked
by
a
single
stimulus,
and
of
the
twitches
evoked
by
paired
stimuli
separated
by
intervals
of
500
,sec
to
4
msec.
The
extent
of
the
twitch
shortening
was
proportionately
the
same
irrespective
of
whether
a
single
or
double
stimulus
was
used,
or
of
the
interval
between
two
stimuli.
While
it
cannot
be
claimed
as
certain
that
any
'back
response'
in
the
muscle
has
been
wholly
occluded
by
the
paired
stimuli
used,
this
experiment
makes
it
most
unlikely
that
adrenaline
is
exerting
its
action
on
the
twitch
by
inhibiting
the
'back
response'.
The
H
reflex
and
the
F
wave.
Both
the
H
reflex
(Magladery
&
McDougal,
1950)
and
the
F
wave
(Dawson
&
Merton,
1956;
McLeod
&
Wray,
1966)
are
spinal
responses
elicited
by
nerve
stimulation
in
intact
subjects
and
could
both
result
in
distortion
of
the
twitch
by
delayed
activation
of
motor
units.
The
H
reflex
is
antidromically
blocked
by
maximal
motor
nerve
stimulation,
and
ought
therefore
to
have
been
absent
in
our
experi-
ments.
We
demonstrated
on
one
subject
that
when
the
H
reflex
was
elicited
by
suitably
chosen
submaximal
stimuli,
it
was
not
altered
in
latency,
duration
or
amplitude
by
adrenaline.
The
F
wave
is
not
blocked
by
supramaximal
stimuli,
but
it
is
always
small
and
inconstant
and
has
not
been
observed
to
change
during
adrenaline
infusion
(see
Fig.
7).
A
control
experiment
with
nerve
block.
In
one
subject,
to
obtain
a
true
uncontaminated
twitch,
the
H
and
F
responses
were
prevented
by
pressure
block
of
the
sciatic
nerve,
as
described
by
Brindley
(1962),
while
back
responses
were
eliminated
by
paired
stimulation.
The
experiment
is
illustrated
in
Fig.
8.
The
subject
sat
on
a
metal
bar
positioned
under
his
sciatic
nerve
with
the
leg
extended
parallel
to
the
ground,
and
the
foot
strapped
to
the
footplate,
which
for
this
experiment
was
inverted.
After
50
min,
voluntary
power
in
the
calf
muscles
had
almost
disappeared
and
the
leg
felt
numb
in
the
distribution
of
the
sciatic
nerve.
Total
nerve
block
could
not
be
achieved,
for
slight
power
remained
in
the
peronei
and
cutaneous
sensation
was
not
wholly
abolished.
The
triceps
surae
twitch
was
then
elicited
by
supramaximal
stimulation
of
the
medial
popliteal
nerve
in
the
popliteal
fossa
with
paired
pulses
separated
by
500
/,sec.
Such
a
double
stimulus
had
previously
been
shown
to
reduce
twitch duration
443
C.
D.
MARSDEN
AND
J.
C.
MEADOWS
by
4
msec
when
compared
with
a
single
shock
in
this
subject,
which
we
interpret
as
occlusion
of
the
'back
response'.
The
shape
of
the
muscle
twitch
so
produced
did
not
change
significantly
during
the
period
of
sciatic
nerve
pressure,
but
was
somewhat
shorter
than
that
usually
re-
corded
in
this
subject,
probably
as
a
result
of
the
change
in
mechanical
arrangements
necessary
to
record
the
twitch
in
the
sitting
position.
The
twitch
elicited
after
50
min
of
sciatic
nerve
pressure
was
speeded
up
by
adrenaline
in
the
usual
manner,
the
time
to
half-relaxation
falling
by
A
B
-
5
kg
100
msec
Fig.
8.
The
effect
of
adrenaline
(10
,ug/min
intravenously)
on
calf
muscle
after
prolonged
sciatic
nerve
pressure.
(A)
Six
superimposed
twitches
before
adrenaline,
(B)
six
twitches
during
adrenaline.
15
msec
from
115
msec,
a
change
of
13
%.
In
two
previous
experiments
on
this
subject
using
the
standard
procedure,
adrenaline
in
the
same
dose
shortened
the
time
to
half-relaxation
by
about
19
%.
The
smaller
effect
of
adrenaline
during
nerve
block
is
still
well
within
the
range
obtained
in
the
group
of
subjects
studied.
DISCUSSION
The
effects
of
adrenaline
in
speeding
up
the
contraction
of
human
muscle
are
very
similar
to
those
observed
by
Bowman
&
Zaimis
(1958)
on
cat
soleus
muscle,
but
less
marked.
In
both
cases
the
effects
are
,8-adreno-
tropic.
The
chief
difference
is
that
adrenaline
causes
a
substantial
reduction
in
twitch
tension
in
cat
soleus,
but
no
unequivocal
change
in
the
human
calf.
Their
doses
(single
intravenous
injections
of
0
06-0*5
5,g/kg)
were
similar
to
ours
(10
/tg/min,
equivalent
to
roughly
0.15
,tg/kg.min).
Using
doses
some
fifty
times
larger
(3-10
#tg/kg),
Bowman
&
Zaimis
(1958)
found
that
the
effect
of
adrenaline
on
tibialis
anterior
was
to
in-
crease
both
the
tension
and
the
duration
of
the
twitch.
(A
similar
effect
in
the
rat
diaphragm
was
described
by
Goffart
&
Ritchie
(1952)
but
their
dosage,
10-
w/v
in
the
bathing
fluid,
was
three
orders
of
magnitude
larger
than
ours.)
In
the
cat,
soleus
is
a
slow
(red)
muscle
and
tibialis
anterior
a
fast
(pale)
muscle.
Bowman
&
Zaimis
hence
concluded
that
adrenaline
has
opposite
effects
on
slow
and
fast
muscle.
In
man
the
distinction
between
fast
and
slow
muscles
is
less
definite
than
in
lower
animals,
and
information
about
the
speed
of
contraction
of
different
muscles
is
not
easily
to
be
found
in
the
literature.
The
question
as
to
444
ADRENALINE
AND
MUSCLE
CONTRACTION
whether
human
muscles
contain
a
mixture
of
slow
and
fast
motor
units,
as
do
animal
muscles,
is
still
unanswered.
We
have
found
that
the
adductor
pollicis
twitch
is
only
about
two
thirds
of
the
duration
of
the
calf
muscle
twitch,
and
when
the
knee
is
bent
so
as
to
decrease
the
contribution
of
gastrocnemius
to
the
calf
twitch
the
resulting
'soleus'
twitch
is
longer
than
the
twitch
obtained
with
the
knee
straight.
The
faster
calf
twitch
produced
by
adrenaline
could
be
accounted
for
if
adrenaline
decreased
the
contribution
from
slow
soleus
and
increased
that
from
fast
gastro-
cnemius.
This
seems
unlikely
as
adrenaline
shortened
the
calf
twitch
obtained
both
with
the
knee
straight
and
with
it
bent.
In
our
experiments
adrenaline
did
not
have
opposite
effects
on
calf
muscle
and
adductor
pollicis,
but
the
differences
we
observed
in
their
responses
to
adrenaline
are
at
any
rate
in
the
direction
to
be
expected
from
the
results
of
Bowman
&
Zaimis.
Adrenaline
did
not
actually
lengthen
the
contraction
of the
faster
muscle,
adductor
pollicis,
but
its
action
in
speeding
up
contraction
was
much
smaller
than
in
the
slow
calf
muscles.
Thus
the
single
twitch
of
adductor
was
unchanged
by
adrenaline,
while
its
effect
in
abolishing
the
ramp
phenomenon
may
mean
merely
that
adrena-
line
prevents
that
prolongation
of
the
mechanical
responses
to
successive
volleys
in
a
tetanus
that
appears
to
cause
the
ramp,
rather
than
that
it
actually
shortens
these
responses.
There
may,
of
course,
be
fast
muscles
in
the
human
other
than
adductor
pollicis
whose
contraction
would
be
prolonged
by
adrenaline.
However,
in
four
experiments
(not
mentioned
in
Results)
the
twitch
of
the
human
anterior
tibial
muscles
elicited
by
stimulation
of
the
common
peroneal
nerve
was
slightly
shortened
by
adrenaline
in
doses
of
10
,g/min;
doses
comparable
with
those
found
by
Bowman
&
Zaimis
to
lengthen
the
twitch
of
this
muscle
in
the
cat
would
be
unphysiological
and
unsafe
in
humans.
Our
experiments
do
not
conflict
with
the
plausible
view
that
the
fl-receptors
responsible
for
the
effects
of
adrenaline
are
in
the
muscle
fibres
themselves.
Sutherland
and
his
colleagues
(Robison,
Butcher
&
Sutherland,
1967)
have
provided
cogent
reasons
for
believing
that
the
enzyme
adenyl
cyclase
is
itself
the
fl-receptor.
Stimulation
of
the
,8-receptor
increases
the
concentration
of
adenyl
cyclase,
which
catalyses
the
conversion
of
ATP
to
adenosine
3',5'-cyclic
monophosphate
(cyclic
3',
5'-AMP).
Adrenaline
increases
the
amount
of
cyclic
3',5'-AMP
in
skeletal
muscle,
and
this
substance
activates
the
enzymes
necessary
for
break-down
of
muscle
glycogen
(Posner,
Stern
&
Krebs,
1962,
1965).
Independently
of
this
particular
theory,
infusion
of
adrenaline
into
the
human
brachial
artery
has
been
shown
to
increase
glycogenolytic
activity
in
forearm
muscles
in
man
(De
la
Lande,
Manson,
Parks,
Sandison,
Skinner
&
Whelan,
1961).
The
time
course
of
this
effect
was
similar
to
the
time
445
C.
D.
MARSDEN
AND
J.
C.
MEADOWS
course
of
the
effect
of
adrenaline
on
contraction
that
we
have
observed.
It
is
not
improbable
that
the
two
effects
may
be
causally
related.
It
is
planned
to
test
this
hypothesis
in
two
ways,
first
by
studying
the
effects
of
cyclic
3',5'-AMP
on
human
muscle
dynamics,
and,
secondly,
by
looking
at
the
effect
of
adrenaline
in
cases
of
McArdle's
syndrome,
in
which
muscle
glycogenolysis
is
effectively
non-existent
owing
to
a
congenital
absence
of
striated
muscle
phosphorylase
(McArdle,
1951).
As
regards
the
changes
brought
about
in
the
contractile
mechanism
itself,
our
results,
showing
a
reduction
of
the
time
to
half-relaxation
of
the
twitch,
are
consistent
with
the
view
that
adrenaline
shortens
the
duration
of
the
active
state
in
the
calf
muscles.
This
of
itself,
as
discussed
by
Close
(1965),
would
lead
to
a
decrease
in
twitch
tension
as
well
as
in
twitch
duration,
but,
in
the
human
subject,
we
found
that
the
height
of
the
calf
muscle
twitch
was
often
not
reduced.
To
explain
this
would
require
some
other
parameter
to
change
as
well
as
the
active
state
duration.
One
possibility
is
an
increase
in
the
intrinsic
speed
of
shortening.
Close
(1965)
has
presented
evidence
that,
in
muscles
in
general,
speed
of
shortening
increases
as
the
duration
of
the
active
state
gets
shorter.
Our
results
would
be
accounted
for
if
a
reciprocal
change
of
this
nature
was
induced
in
the
calf
muscles
by
adrenaline.
Following
from
what
was
said
above,
the
lesser
effect
of
adrenaline
on
adductor
pollicis
may
merely
be
to
prevent
or
delay
a
change
of
these
parameters
in
the
opposite
direction
during
a
tetanus.
The
consequences
of
the
effect
of
adrenaline
on
the
twitch
and
tetanus
of
triceps
surae
and
similar
muscles
in
man
were
discussed
by
Bowman
&
Zaimis
(1958).
They
pointed
out
that
the
tension
developed
by
such
muscles
for
a
given
rate
of
firing
of
the
anterior
horn
cells
must
be
decreased
by
circulating
adrenaline,
an
effect
that
might
account
for
the
well
known
feeling
of
weakness
in
the
limbs
experienced
during
fright
and
during
adrenaline
infusion
in
man.
The
increase
in
tremor
of
the
limbs
and
particu-
larly
of
the
outstretched
hands
in
similar
circumstances,
which
is
also
a
peripheral
,8-adrenotropic
effect
(Marsden
et
al.
1967),
may,
in
part,
have
a
similar
explanation.
Thus,
we
have
shown
that
adrenaline
increases
the
oscillatory
component
of
tension
during
a
10/sec
tetanus.
If
the
peak
in
the
tremor
spectrum
near
10
c/s
is
due
to
bursts
of
motor
impulses
at
10/sec
(as
claimed
by
Lippold
et
al.
1957)
then
it
seems
clear
that
adrena-
line
would
tend
to
increase
the
amplitude
of
tremor
oscillations
near
10
c/s
by
its
direct
action
on
the
muscle.
This,
or
something
closely
similar,
would
seem
to
be
the
only
possible
explanation
for
the
increase
of
tremor
after
adrenaline
in
the
deafferented
arm
of
the
patient
studied
by
Marsden
et
al.
(1967).
It
would
not
be
the
only
instance
of
a
relation
between
tremor
and
muscle
dynamics,
for
C.
D.
Marsden,
J.
C.
Meadows,
G.
W.
Lange
&
R.
S.
Watson
(in
preparation)
have
found
that
the
amplitude
of
finger
446
ADRENALINE
AND
MUSCLE
CONTRACTION
tremor
is
directly
related
to
the
duration
of
the
muscle
twitch
in
patients
with
thyroid
disease.
However,
for
reasons
given
in
the
Introduction,
it
is
not
likely
that
adrenaline
tremor
of
healthy
subjects
can
be
wholly
accounted
for
by
the
effect
of
adrenaline
on
muscle
dynamics.
Some
peripheral
action
of
adrenaline
working
reflexly
to
accentuate
tremor
seems
to
be
required.
The
most
likely
candidate
is
the
stretch
reflex,
see
e.g.
the
vibration
experiments
of
Hodgson
et
al.
(1969).
In
view
of
the
demonstrable
action
of
adrenaline
on
the
main
contractile
(extrafusal)
fibres
it
is
interest-
ing
to
speculate
on
the
possibility
that
adrenaline
modifies
the
stretch
reflex
by
some
similar
action
on
the
contraction
dynamics
of
the
intrafusal
fibres
of
the
muscle
spindles.
This
work
was
supported
by
a
grant
to
Dr
C.
D.
Marsden
from
the
National
Fund
for
Research
into
Crippling
Diseases
and
by
a
grant
to
Dr
P.
A.
Merton
from
the
Ministry
of
Technology.
We
are
grateful
to
Professor
W.
I.
Cranston
for
his
con-
tinued
encouragement,
and
to
Sir
Bryan
Matthews
for
allowing
us
to
work
at
the
Physiological
Laboratory
at
Cambridge.
It
is
our
pleasure
to
thank
Dr
P.
A.
Merton,
with
whom
much
of
this
work
was
carried
out,
for
his
hospitality
and
help.
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