THE
PHYSIOLOGICAL
ACTION
OF
PHYSOSTIGMINE
AND
ITS
ACTION
ON
DENERVATED
SKELETAL
MUSCLE.
BY
J.
N.
LANGLEY
AND
TOYOJIRO
KATO.
(From
the
Physiological
Laboratory,
Cambridge.)
IN
the
previous
observations
by
one
of
us
it
has
been
shown
that
in
the
denervated
muscle
of
the
fowl(l)
and
frog(2),
a
low
concentration
of
nicotine
causes
tonic
contraction,
and
that
this
tonic
contraction
is
antagonised
in
the
normal
manner
by
curari.
Thus
the
effect
of
these
alkaloids
as
regards
the
tonic
contraction
is
not
on
the
nerve
endings.
Results
essentially
similar
were
obtained
in
the
fowl
by
Edmunds
and
Roth,
using
both
nicotine
and
physostigmine(3)
(cp.
also
(1o),
p.
104).
The
observations
which
have
been
made
on
the
muscular
twitchings
caused
by
nicotine
and
by
physostigmine
after
nerve
section
are
less
conclusive.
Some
experiments
were
made
by
one
of
us
((2),
p.
288)
in
the
frog,
but
recently
it
has
been
shown(4)
that
twitchings
may
be
produced
by
slight
variations
in
the
salt
content
of
the
fluid
in
which
the
muscle
is
placed
so
that
a
repetition
of
the
experiments
is
desirable.
Magnus(5)
has
made
observations
on
the
effect
of
physostigmine
on
the
denervated
muscle
of
the
rabbit.
He
found
that
the
muscular
twitchings
caused
by
the
drug
were
rather
greater
than
normal
up
to
the
18th
day
after
nerve
section,
but
were
not
obtained
from
the
27th
to
the
34th
days.
He
concluded
that
physostigmine
acts
on
nerve
endings.
But
it
has
been
shown
that
the
nerve
endings
break
up
into
fragments
in
about
three
days.
If
twitchings
occur
on
the
18th
day,
it
is
unlikely
that
they
are
caused
by
an
action
on
nerve
endings;
and
it
is
a
more
natutal
conclusion
that
the
twitchings
are
caused
by
an
action
on
the
muscle,
and
cease
to
be
obtainable
when
the
atrophic
changes
in
the
muscle
have
reached
a
certain
extent.
In
view
of
this
position
of
the
question
we
have
re-investigated
the
action
of
physostigmine
on
denervated
rabbit's
muscle,
and
have
also
made
some
observations
on
the
action
of
physostigmine.
ACTION
OF
PHYSOSTIGMINE.
OBSERVATIONS
ON
THE
ACTION
OF
PHYSOSTIGMINE.
Method.
Most
of
our
experiments
were
made
on
half-grown
rabbits
of
about
14
kilos.
weight;
a
few
were
made
on
adult
rabbits
and
on
cats.
The
animals
were
anaesthetised
first
with
ether
or
chloroform
under
a
bell
jar.
Tracheotomy
was
performed
and
ansesthesia
main-
tained
by
A.C.E.
Usually
also
about
*75
to
2-5
grms.
of
urethane
was
injected
into
a
vein,
or
into
the
carotid
artery
peripherally.
When
it
was
necessary
to
inject
curari,
the
animal
was
first
decerebrated
by
injection
of
starch
grains
(10%
suspension
in
Ringer's
fluid)
into
the
carotid
peripherally.
The
whole
of
the
brain
(including
the
spinal
bulb)
was
put
out
of
action
so
that the
blood-pressure
was
low.
The
circulation
was
sufficient
to
maintain
peripheral
effects,
but
the
reflexes
from
the
spinal
cord
progressively
decreased.
The
physostigmine
used
was
the
eserine
salicylate
of
Merck,
the
solution
being
made
up
at
short
intervals
as
required.
The
atropine
used
was
atropine
sulphate
also
prepared
by
Merck.
A
considerable
difficulty
in
the
investigation
we
found
to
be
the
tendency
in
the
rabbit
of
small
amounts
of
physostigmine
(1-4
migms.)
either
to
stop
the
ventricular
beat
altogether
or
to
reduce
it
to
such
an
extent
that
there
was
insufficient
circulation.
The
usual
course
of
the
effects
on
the
heart
appeared
to
be,
dilatation
of
the
ventricles,
heart
block,
and
cessation
of
the
ventricular
beat
in
diastole.
The
respiration
generally
stops
after
1-2
mgms.
of
physostigmine.
It
is
known
that
after
physostigmine,
more
than
the
normal
force
of
respira-
tion
is
required
to
distend
the
lungs
but
we
have
not
found
that
rabbits
can
be
kept
alive
by
forcible
artificial
respiration.
As
mentioned
by
Dixon,
the
heart
can
be
revived
by
injecting
adrenalin,
but
the
revival
is
transient,
and
during
the
period
of
increased
blood-pressure,
the
contraction
of
the
small
arteries
interferes
with
the
physostigmine
reactions.
In
some
cases
in
order
to
observe
the
effect
of
physostigmine
on
twitchings
we
have
injected
it
into
the
muscle
instead
of
injecting
into
a
blood
vessel.
A
somewhat
greater
quantity
of
physostigmine
can
thus
be
given
without
stopping
the
heart,
and
the
local
effect
is
somewhat
greater;
the
difference
however
is
insufficient
to
be
of
much
importance,
and
the
unequal
distribution
of
the
drug
in
the
muscle
made
the
local
injection
unsuitable
for
most
of
our
experiments.
A
considerably
larger
amount
of
physostigmine
can
be
given
to
a
cat
without
causing
death.
Fas8ceular
twitchings.
As
is
known,
the
twitchings
caused
in
411
J.
N.
LANGLEY
AND
T.
KATO.
decentralised
muscle
by
physostigmine
are
fascicular.
Each
twitch
is
a
more
or
less
powerful
contraction
of
a
considerable
number
of
muscle
fibres,
though
the
number
of
fibres
involved
varies
widely.
With
a
minimal
amount
of
physostigmine,
only
one
or
two
twitchings
in
a
minute
occur
in
the
muscle;
as
the
amount
of
physostigmine
increases,
the
frequency
of
the
twitches
greatly
increases,
but
there
is
always
an
interval
easily
appreciable
to
the
eye
between
the
twitches
in
any
one
part
of
the
muscle.
The
amount
of
physostigmine
required
to
cause
lively
twitches
varied
a
good
deal
in
our
experiments,
and
this
seemed
to
depend
upon
the
amount
of
the
anaesthetics
administered.
Physostigmine
above
a
certain
dose
decreases
the
twitchings
caused
by
a
small
dose,
and
in
sufficient
quantity
abolishes
them.
This
we
shall
refer
to
in
speaking
of
the
experiments
in
which
large
doses
were
given.
Fascicular
twitchings
and
fibrillation
caused
by
nerve
stimulation.
A
point
which
seemed
worth
determining
was
the
effect
on
the
physo-
stigmine
twitches
of
applying
tetanising
currents
to
the
nerve.
When
the
circulation
is
good,
the
earlier
stimulations-lasting
for
about
half-a-
minute-produce
the
normal
effect,
but
the
fascicular
contractions
do
not
begin
again
for
some
time
after
the
stimulation
has
ceased.
After
a
variable
number
of
such
stimuli,
small
fascicular
contractions
occur
towards
the
end
of
the
period
of
stimulation.
On-further
repetition,
the
twitchings
affect
fewer
fibres
and
become
weaker.
Further
a
certain
number
of
the
fibres
enter
into
a
state
of
rapid
rhythmic
contraction
-fibrillation.
In
some
cases
the
fibrillation
continues,
and
it
may
become
more
obvious,
after
the
stimulation
has
ceased.
The
fibrilla-
tion
is
most
easily
obtained
when
the
circulation
is
feeble
towards
the
end
of
an
experiment.
In
one
such
case
in
which
the
fascicular
con-
tractions
had
stopped,
and
in
which
the
tetanus
caused
by
stimulation
was
weak,
fibrillation
began
almost
at
once
in
parts
of
the
muscle
and
lasted
for
a
minute
or
more
after
the
end
of
the
stimulation.
Even
after
death
fibrillation
may
be
obtained.
The
phenomena
are
no
doubt
due
to
an
accumulation
of
metabolites
acting
on
some
abnormally
excitable
structure.
It
may
be
recalled
that
Winterberg(6)
found
that
fibrillation
of
the
auricle
could
sometimes
be
produced
by
stimulating
the
vagus
after
giving
physostigmine.
Since
in
this
case
an
inhibitory
nerve
is
stimulated,
the
genesis
of
the
fibrillation
is
probably
different
from
that
which
we
have
described
in
striated
muscle.
Action
of
atropine
on
the
twitchings.
Rothberger
((7),
p.
139)
412
A
CTION
OF
PHYSOSTIGMINE.
413
states
that
the
fascicular
contractions
caused
by
physostigmine
are
at
once
abolished
by
a
small
dose
of
atropine
(apparently
2-3
mgms.),
and
that
when
so
abolished
they
cannot
again
be
produced
even
by
a
large
dose
of
physostigmine.
On
general
grounds
it
seemed
to
us
improbable
that
atropine
sbould
affect
striated
muscle
or
its
peripheral
nervous
mechanism
in
this
way,
and
on
testing
the
matter
in
rabbits
and
cats
we
found
that,
in
fact,
it
did
not.
A
fairly
large
dose
of
atropine
(as
20-30
mgms.)
has
no
appreciable
effect
on
the
fascicular
contractions
caused
by
a
small
dose
of
physostigmine
(1-2
mgms.)
in
muscle
the
nerve
supply
of
which
has
been
severed,
and
even
after
60
mgms.
of
atropine,
peripheral
muscular
twitchings
are
at
once
set
up
by
a
small
dose
of
physostigmine.
We
give
an
abstract
of
two
experiments,
one
on
a
rabbit
and
the
other
on
a
cat
in
illustration.
Exp.
1.
Rabbit,
3100
grms.
Ether.
Tracheotomy.
Urethane
and
A.C.E.
The
injections
were
made
into
the
jugular
vein.
Left
gastrocnemius
muscle
exposed
and
left
sciatic
cut.
11.45.
10
mgms.
atropine.
11.52.
5
mgms.
physostigmine.
Lively
fascicular
contractions
in
gastrocnemius
and
elsewhere.
No
defaecation
nor
salivation.
12.20.
10
mgms.
atropine.
Contractions
as
before.
12.25.
10
mgms.
atropine.
,,
11.32.
10
mgms.
atropine.
p,
12.40.
20
mgms.
atropine.
Still
good
fascicular
contractions.
Exp.
2.
Cat,
4300
grms.
Preparation
as
in
Exp.
1,
but
A.C.E.
used
instead
of
urethane
and
A.c.E.
Left
sciatic
cut
and
left
gastrocnemius
exposed.
4.3.
5
mgms.
physostigmine.
Lively
twitching
of
gastrocnemius,
and
some
limb
movements
apparently
of
central
origin.
Peristalsis,
salivation,
lachrymation,
nystag-
mus.
Defacation.
Vagus-pulse.
4.9.
10
mgms.
atropine.
4.11.
Twitching
as
before;
peristalsis
nearly
ceased,
other
effects
stopped.
4.15.
5
mgms.
atropine.
Twitching
as
before.
4.20.
5
mgms.
atropine.
..
..
4.25.
5
mgms.
atropine.
..
.,
4.31.
10
mgms.
atropine.
Twitching
rather
less.
4.36.
10
mgms.
atropine.
4.41.
15
mgms.
atropine.
4.43.
Twitchings
few.
4.49.
15
mgms.
atropine.
4.49.
One
or
two
twitchings
a
minute.
4.51.
10
mgms.
atropine.
No
twitching
in
two
minutes.
4.55.
5
mgms.
physostigmine.
Fairly
good
twitchings.
No
salivation
or
lachry.
mation.
It
will
be
noticed
that
in
the
second
experiment
there
was
a
gradual
decrease
of
the
twitchings
and
that
about
three
quarters
of
an
hour
PH.
XLIX.
2'7
J.
N.
LANGLEY
AND
T.
KATO.
after
injecting
5
mgms.
of
physostigmine,
during
which
85
mgms.
of
atropine
were
injected,
the
twitchings
stopped
or
nearly
stopped.
Whether
this
indicates
a
quickening
of
the
normal
rate
of
decrease
of
the
twitchings
we
have
not
determined,
but
it
is
clear
that
the
atropine
had
no
special
antagonistic
action
on
the
twitchings,
since
after
85
mgms.
of
atropine,
5
mgms.
of
phvsostigmine
caused
twitchings
as
good
as
could
be
expected
with
the
decreased
circulation.
The
statement,
then,
that
atropine
readily
antagonises
the
action
of
physostigmine
on
muscle
is
erroneous.
Nevertheless
there
could
be
little
doubt
that the
statement
must
have
had
some
basis.
And
Dixon(s)
has
given
a
tracing
showing
that
the
contractions
of
the
quadriceps
cruris
muscle
caused
by
2
mgms.
of
physostigmine
are
stopped
by
1
mg.
of
atropine.
The
explanation
of
the
apparent
contra-
diction
lies
in
the
action
of
atropine
on
the
central
nervous
system.
It
is
known
that
physostigmine
besides
causing
muscular
twitchings
mav
cause
also
irregular
contractions
and
trembling
of
the
limbs.
A
certain
increase
in
the
depth
of
intoxication
with
anvesthetics
abolishes
both.
They
are
of
central
origin,
for
when
they
occur
in
a
limb
they
at
once
cease
on
severing
its
nerve
supply.
Some
of
the
muscular
twitchings
are
also
of
central
origin;
with
a
small
dose
of
physostigmine
(1-2
mgms.),
these
are
for
the
most
part
at
any
rate
the
weaker
con-
tractions.
All
these
muscular
effects
of
central
origin
are
in
a
certain
stage
of
anesthesia
more
or
less
readily
stopped
by
a
small
dose
of
atropine.
Atropine
in
these
cases
appears
to
act
on
the
central
nervous
system
partly
by
deepening
the
ansesthesia
and
partly
as
a
specific
antagonist
of
physostigmine.
In
the
course
of
our
observations
we
noticed
that
a
small
dose
of
physostigmine
causes
twitching
of
the
eyelids,
and
twitching
of
the
eye-ball-nystagmus.
In
the
rabbit
the
nystagmus
was
often
a
very
slight,
rapid
and
regular
vibration,
the
movement
being
usually
forward
and
downward,
occasionally
slightly
rotatory;
sometimes
it
was
slower
and
more
extensive.
In
the
cat,
the
slower
movement
only
was
observed,
and
it
was
lateral
either
to
the
right
or
left.
With
progressive
increase
in
the
amount
of
anesthetic,
both
twitching
of
the
eyelids
and
nystagmus
occur
for
a
time
after
the
corneal
reflex
and
the
irregular
body
contractions
have
ceased;
later
they
also
cease.
Occasionally
in
the
cat
the
nystagmus
is
synchronous
on
the
two
sides,
i.e.
is
undoubtedly
of
central
origin.
Both
movements
are
stopped
by
a
small
amount
of
atropine
(2-5
mgms.),
the
nystagmus
much
more
readily
than
the
eyelid
movement.
Subsequent
injection
414
ACTION
OF
PHYSOSTIGMINE.
of
physostigmine
may
cause
a
brief
return
of
the
eyelid
movement
and
of
the
slow
nystagmus;
we
have
not
observed
any
return
of
the
quick
vibratory
nystagmus
of
the
rabbit.
The
antagonistic
action
of
atropine
to
physostigmine
in
the
central
nervous
system
is
at
its
maximum
in
the
case
of
nystagmus.
A
small
dose
of
atropine
has
been
said
by
Edmunds
and
Roth(3)
to
stop
physostigmine
twitchings
in
the
fowl.
It
was
advisable,
then,
to
determine
whether
the
reaction
to
the
drugs
in
the
fowl
was
the
same
as,
or
different
from,
that
in
the
mammal,
and
we
made
a
few
experiments
on
this
question.
Chloroform
followed
by
A.C.E.
mixture
were
used
for
ancesthetics,
and
in
one
case
*25
grm.
of
urethane
was
in
addition
injected
intravenously.
The
injection
of
1-2
mgms.
of
physostigmine
causes
irregular
muscular
movements;
there
may
be
brief
flapping
of
the
wings,
trem-
bling
of
the
legs,
rhythmic
movements
of
the
tail
feathers
and
a
few
fascicular
twitchings.
Excess
of
ancesthetics
greatly
reduces
these
movements.
They
are
accompanied
by
movements
of
the
cesophagus,
and
mucous
fluid
may
pour
from
the
mouth.
The
eye
opens
for
a
short
time
and
the
pupil
dilates.
The
respiration
usually
stops
and
the
heart
beat
becomes
feeble
so
that
artificial
respiration
is
necessary.
Soon
after
the
injection
there
is
defaecation.
There
is
some
nystagmus
with
rhythmic
movements
of
the
nictitating
membrane
and
iris;
in
two
cases
it
was
noticed
that
the
sweeping
of
the
membrane
across
the
eye
and
the
contraction
of
the
iris
were
synchronous
and
were
also
synchronous
on
the
two
sides.
The
general
muscular
movements
are
brief,
but
the
eye
movements
and
especially
those
of
the
nictitating
membrane
and
iris
continue.
There
are
few
twitchings
in
the
muscles
of
any
part
of
the
body
and
none
in
the
gastrocnemius
after
section
of
the
tibial
nerve.
There
is
slight
tonic
contraction,
but
with
the
dose
we
are
considering-I
to
2
mgms.-it
is
slight
only.
All
of
these
effects
except
the
tonic
contraction
are
stopped,
or
greatly
reduced,
by
i
few
milligrams
of
atropine.
As
we
have
said,
the
movements
of
the
nictitating
membrane
and
iris
go
on
for
some
time
after
body
move-
ment
has
ceased;
these
movements
stop
20
to
30
seconds
after
injecting
atropine.
When
5
to
10
mgms.
of
atropine
have
been
ad-
ministered,
10
mgms.
of
physostigmine
may
be
injected
with
little
or
no
effect;
the
degree
of
effect
depending
on
the
depth
of
anaesthesia.
A
striking
difference
in
the
action
of
1-2
mgms.
of
physostigmine
in
the
fowl
and
in
the
mammal
is,
that
in
the
former
this
dose
causes
no
fascicular
twitchings
in
the
decentralised
gastrocnemius.
We
tried
27-2
4110
J.
N.
LANGLEY
AND
T.
KATO.
the
effect
of
injecting
larger
doses,
but
these
killed
the
animal
by
stopping
the
heart,
so
that
we
have
resorted
to
local
injection
to
see
whether
physostigmine
in
larger
quantity
causes
twitchings.
After
cutting
the
tibial
nerve,
S
c.c.
of
5
0/0
physostigmine
was
injected
into
the
muscle;
this
caused
a
couple
of
twitchings
just
after
the
injection
and
then
the
muscle
remained
perfectly
quiescent.
Though
atropine
does
not
affect
the
peripheral
physostigmine
twitchings
in
the
mammal,
it
cannot
be
said
with
certainty
that
it
might
not
do
so
in
the
fowl.
But
it
may
be
mentioned
that
in
one
experiment
after
giving
10
mgms.
of
atropine
we
injected
intravenously
first
10
mgms.
and
then
7*5
mgms.
of
physostigmine
without
causing
any
fascicular
twitchings.
These
doses
however
caused
considerable
tonic
contraction
like
that
caused
by
nicotine,
and
the
legs,
both
that
with
the
sciatic
cut,
and
that
with
the
nerves
intact,
were
in
strong
extension;
a
result
which
is
in
agreement
with
Edmunds
and
Roth's
results.
The
tone
decreased
after
injecting
*3
grm.
CaC12,
and
disap-
peared
after
injecting
an
additional
*15
grm.
We
have
seen
that
in
the
rabbit,
tetanic
nerve
stimulation
after
administration
of
physostigmine
may
cause
fibriDlar
tNitching
for
a
short
time
after
the
cessation
of
the
stimulus.
In
the
one
case
in
which
we
repeated
the
experiment
in
the
fowl,
the
result
was
very
different.
The
muscle
remained
nearly
fully
contracted
for
i
to
j
a
minute
after
the
end
of
the
stimulation,
and
complete
relaxation
did
not
occur
for
a
further
period
of
about
a
minute.
These
experiments
show
(1)
that
the
muscular
contractions
caused
by
physostigmine
in
the
ancesthetised
fowl
are
due
to
impulses
coming
from
the
central
nervous
system
and
that
they
are
prevented
by
atropine.
In
this
respect
the
reaction
is
the
same
in
the
fowl
as
in
the
mammal;
(2)
that
phy3ostigmine
causes
in
the
fowl
few
or
no
twitchings
of
peri-
pheral
origin.
In
this
respect
the
reaction
is
similar
to
that
in
amphibia.
Since
atropine
does
not
affect
the
peripheral
action
of
physostigmine
on
muscle,
it
is
an
advantage
to
give
atropine
as
a
preliminary
to
an
investigation
of
the
twitchings.
As
is
known,
atropine
antagonises
the
parasympathetic
effects
of
physostigmine,
so
that
defaecation
and
tracheal
secretion
are
avoided.
Further
by
preventing
the
action
of
physostigmine
on
the
lungs,
and
in
part
at
any
rate
on
the
heart,
a
larger
amount
of
physostigmine
can
be
given
without
causing
death.
The
dose
of
atropine
required
is
about
10
mgms.;
5
mgms.
is
insufficient
to
stop
the
effect
on
the
intestines.
After
10
mgms.
of
atropine
a
very
large
amount
of
physostigmine
can
be
given
to
the
cat
without
causing
416
ACTION
OF
PHYSOSTIGMINE.
death;
in
one
case
we
injected
intravenously
(in
successive
doses)
176
mgms.
In
the
rabbit
though
the
amount
of
physostigmine
can
be
increased
we
have
not
found
that
any
large
quantity
can
be
given;
usually
the
heart
stopped
after
6-10
mgms.;
and
in
decerebrate
rabbits,
in
which
the
circulation
is
much
below
normal,
4
to
6
mgms.
was
usually
fatal.
The
fascicular
contractions
are
said
by
Loewi(9)
to
be
readily
stopped
by
CaCI2
injected
intravenously.
We
have
made
three
experi-
ments
on
this
point,
but
we
have
not
found
that
the
salt
has
much
effect
until
a
considerable
amount
is
given.
In
one
of
the
experiments,
after
injecting
2-5
mgms.
of
physostigmine
into
a
small
rabbit,
successive
doses
of
CaCl2
amounting
in
all
to
16
c.c.
of
a
1
%
solution
were
injected
intravenously
in
the
course
of
half-an-hour;
the
twitchings
of
the
gastrocnemius
persisted
although
they
became
weak.
In
another
experiment,
a
short
account
of
which
we
give
(Exp.
3),
the
twitchings
caused
by
2
mgms.
of
physostigmine
were
stopped
by
450
mgms.
of
CaCl2,
but
appeared
again
on
injecting
another
2
mgms.
of
physostig-
mine.
ExP.
3.
Rabbit,
1]45
kilos.
Chloroform.
Tracheotomy.
A.C.E.
Right
tibial
nerve
cut,
and
gastrocnemius
exposed.
The
threshold
(th.)
for
a
tetanising
current
is
indicated
by
the
distance
in
cms.
of
the
secondary
coil
from
the
primary.
The
solutions
were
injected
into
the
jugular
vein;
the
CaCl2
solution
was
5
0/0.
0
mins.
Th.-sec.
coil
=
89.
3
,,
10
mgms.
atropine.
8
,,
Th.-sec.
coil
-
88.
13
,,
2
mgms.
physostigmine.
Muscle
twitchings.
No
nystagmus.
No
visible
autonomic
effect.
17
,,
Th.-sec.
coil
=
104.
23
,,
Th.-sec.
coil
=
105.
24
,,
*2grm.
CaCl2.
Twitchings
less.
30
,,
*15
grm.
CaCd2
.
37
,,
Twitchings
infrequient.
Th.-sec.
coil
=
29.
38
,,
05
grm
CaCl2.
After
5
mins.
are
still
a
few
twitchings.
44
,,
*05
grm.
CaC12.
Twitchings
ceased.
Th.-sec.
coil
=
21.
49
,,
2
mgms.
physostigmine.
55
,,
Th.-sec.
coil
=
24.
A
few
twitches.
57
,,
2
mgms.
physostigmine.
Twitchings
more
frequent.
Th.-sec.
coil
=
45.
62
,,
*25
grm.
CaCl2.-heart
stops.
It
will
be
noticed
in
this
experiment
that
atropine
did
not
prevent
the
normal
increase
in
nerve
irritability
caused
by
physostigmine.
The
asserted
paralysis
of
motor
nerves
by
physostigmine.
It
is
generally
held
that
a
large
dose
of
physostigmine
paralyses
the
motor
nerve
endings
in
skeletal
muscle.
Dixon
(8)
gives
the
amount
which
prevents,
417
J.
N.
LANGLEY
AND
T.
KATO.
in
the
cat
and
rabbit,
the
strongest
nerve
stimulation
from
causing
muscular
contraction
as
40
to
50
mgms.
In
the
rabbit
we
have
not
been
able
to
give
anything
approaching
this
amount
without
causing
death.
In
the
cat
we
have
given
up
to
33
mgms.
in
successive
doses
of
2
to
5
mgms.,
the
last
dose
stopping
the
heart.
The
tibial
nerve
was
cut
and
stimulated
with
the
interrupted
current.
The
threshold
stimulus
before
injecting
physostigmine
was
with
the
secondary
coil
at
90
cm.
At
the
end
of
the
experiment
the
threshold
stimulus
was
with
the
secondary
coil
at
84
cm.,
a
difference
which
is
not
outside
the
range
which
might
be
expected
from
the
continued
anaesthesia
and
the
fall
of
blood-pressure
during
the
experiment.
We
have
seen
that
atropine
does
not
prevent
the
action
of
physo-
stigmine
in
producing
muscular
twitchings.
And
atropine
does
not
prevent
the
increase
of
nerve
irritability
caused
by
physostigmine.
This
affords
fairly
conclusive
evidence
that
atropine
does
not
antagonise
at
all
the
effect
of
physostigmine
on
the
skeletal
neuro-muscular
apparatus.
We
therefore
injected
intravenously
10
mgms.
of
atropine
in
an
experiment
on
a
cat
before
injecting
physostigmine.
In
this
case
the
threshold
stimulus
of
the
tibial
nerve
with
tetanising
currents
was
with
the
sec.
coil
at
62.
After
injecting
6
mgms.
of
physostigmine
the
threshold
stimulus
was
with
the
sec.
coil
at
75.
With
further
injec-
tions,
it
slowly
declined
but
after
the
enormous
dose
of
176
mgms.
contraction
was
obtained
with
the
sec.
coil
at
60;
i.e.
the
threshold
stimulus
was
practically
the
same
as
at
the
beginning
of
the
experiment.
So
far
then
as
our
experiments
go,
physostigmine
has
no
paralysing
action
on
the
motor
nerves
to
skeletal
muscle.
In
these
experiments
another
unexpected
result
was
obtained.
In
the
first,
in
which
atropine
was
not
given,
the
twitchings
began
to
decrease
after
10
mgms.
of
physostigmine
had
been
given,
they
became
infrequent
after
14
mgms.,
and
they
occurred
only
at
rather
long
intervals
after
24
mgms.
In
this
experiment
J
c.c.
of
*01
%
adrenalin
was
given
after
each
injection
of
physostigmine
in
order
to
keep
up
the
blood-pressure,
and
the
consequent
contraction
of
the
arteries
supplying
the
muscle
may
have
aided
in
reducing
the
twitching.
But
in
the
second
experiment
in
which
atropine
was
administered,
no
adrenalin
was
given;
a
similar
result
was
obtained
but
of
a
more
striking
character
since
a
larger
quantity
of
physostigmine
could
be
given.
The
twitchings
decreased
after
18
mgms.,
became
infrequent
after
26
mgms.,
nearlv
stopped
after
49
mgms.,
and
stopped
after
69
mgms.
During
the
rest
of
the
experiment,
during
which
107
mgms.
of
physostigmine
were
418
ACTION
OF
PHYSOSTIGMINE.
injected,
there
was
no
twitching,
notwithstanding
that
nerve
stimulation
readily
caused
contraction.
The
antagonism
of
curari
and
physostigmine
as
regards
mus8cular
twitchings
and
indirect
irritability.
It
has
been
shown
by
one
of
us(lo)
that
in
the
frog
the
effect
of
curari
in
preventing
the
tonic
contraction
of
muscle
normally
caused
by
nicotine
depends
upon
the
relative
concentration
of
the
two
substances,
but
that
the
effect
of
curari
in
preventing
the
twitchings
normally
caused
by
nicotine
follows
a
different
rule
and
depends
chiefly
upon
the
absolute
concentration
of
the
curari.
It
is
obviously
desirable
to
determine
the
rules
which
govern
antagonism
in
other
cases.
We
have
ih
consequence
made
some
observations
on
the
antagonism
of
physostigmine
to
curari
as
regards
muscular
twitchings
and
the
restoration
of
nerve
irritability.
Certain
facts
bearing
on
the
question
are
already
known.
Pal(1i)
and
Rothberger(7)
have
shown
that
after
curari
has
been
given
in
a
quantity
just
sufficient
to
paralyse
the
motor
nerves,
the
irritability
is
rapidly
restored
by
a
small
amount
of
physostigmine.
Rot
hberger
however
found
that
when
the
dose
of
curari
was
several
times
the
minimal
paralysing
dose,
physostigmine
in
many
cases
caused
no
return
of
nerve
irritability.
As
regards
the
twitchings,
it
has
been
noticed
by
several
observers
that
when
physostigmine
is
given
after
curari,
twitchings
do
not
occur
at
the
time
nerve
irritability
returns.
The
limitation
in
the
antagonism
of
physostigmine
to
curari
was
considered
by
Rothberger
to
be
due
to
physostigmine
when
given
beyond
a
certain
amount
paralysing
the
motor
nerve
endings
on
its
own
account.
We
have
seen
above
(p.
418)
that
physostigmine
in
very
large
dose
does
not
paralyse
the
nerves,
so
that
Rothberger's
explanation
of
the
absence
of
antagonistic
action
falls
to
the
ground.
The
following
experiment
will
serve
to
show
how
limited
the
antagonism
is.
A
cat
was
anaesthetised
by
chloroform
and
A.C.E.,
the
left
tibial
nerve
cut,
the
left
gastrocnemius
exposed
and
the
animal
decerebrated
by
injecting
3
c.c.
100%
starch
suspension
into
the
peripheral
end
of
the
carotid.
The
threshold
stimulus
(tetanising
current)
was
with
sec.
coil
at
90
cm.
Successive
doses
of
I
c.c.
of
1
%
curari1
were
then
given
intravenouslv,
after
3*5
c.c.
of
curari
had
been
given,
strong
stimulation
of
the
nerve
had
no
effect.
Two
mgms.
of
physostigmine
partly
restored
the
irritability
(T.S.=
sec.
coil
at
125
cm.).
Then
twice
the
original
dose
of
curari
was
given
(7
c.c.
10%
solution);
the
1
The
solution
of
curari
used
in
this
instance
had
been
made
up
for
a
considerable
time
and
was
only
i-1
the
effeetiveness
of
a
freshly
made
solution.
419
J.
N.
LANGLEY
AND
T.
KAITO.
nerve
effect
was
rapidly
abolished.
Thereupon
twice
the
original
dose
of
physostigmine
was
given.
This
caused
no
return
of
irritability.
Suiccessive
injections
of
physostigmine
were
made.and
the
nerve
stimu-
lated
after
each
injection.
After
32
mgms.-in
addition
to
that
previously
administered-had
been
injected,
during
which
there
was
no
return
of
nerve
irritability,
the
heart
beat
was
much
weakened.
With
subsequent
injections
the
heart
beat
became
feebler
and
slower,
but
it
was
still
beating
after
an
additional
105
mgms.
had
been
given.
There
was
no
restoration
of
nerve
irritability,
and
no
muscle
twitchings
at
anv
time.
In
this
experiment
2
mgms.
of
physostigmine
partially
restored
nerve
irritability
after
3-5
c.c.
of
curari;
but
no
dose
of
physostigmine
up
to
132
mgms.
restored
nerve
irritability
after
7
c.c.
of
curari,
nor
did
the
physostigmine
at
any
time
cause
twitchings.
In
similar
experiments
on
the
rabbit
we
have
only
succeeded
in
one
case
in
giving
physos-
tigmine
much
above
the
equivalent
quantity.
In
this,
18
mgms.
of
physostigmine
were
given
in
addition
to
that
theoretically
required
to
antagonise
the
curari.
No
return
of
irritability
occurred
in
the
tibial
nerve,
nor
were
there
any
twitchings.
We
conclude
then
that
the
antagonism
of
physostigmine
and
curari
as
regards
muscle
twitchings
and
nerve
irritability
is
of
the
type
of
that
of
nicotine
and
curari
on
the
muscle
twitchings,
and
not
of
the
type
of
nicotine
and
curari
in
the
production
of
tonic
contraction.
The
change
which
stops
the
passage
of
the
nerve
impulse
from
nerve
to
muscle
is
in
some
respects
at
any
rate
different
from
that
which
stops
the
twitchings.
Where
curari
is
given
after
physostigmine,
the
twitchings
are
stopped
before
nerve
irritability
is
abolished.
We
should
in
consequence
expect
that
when
physostigmine
is
given
after
curari
some
restoration
of
nerve
irritability
would
occur
before
twitchings
are
produced,
but
if
the
same
change
is
responsible
both
for
the
effect
on
nerve
irritability
and
on
the
twitchings,
we
should
also
expect
the
twitchings
to
begin
during
recovery
at
the
stage
of
irritability
at
which
it
disappears
when
curari
is
given
after
physostigmine.
This
is
not
the
case.
Our
experiments
on
this
point
have
been
made
on
the
rabbit.
After
paralysis
of
the
nerve
by
curari
we
have
obtained
with
physostigmine
not
only
a
restoration
of
irritability
but
an
increase
above
the
normal,
without
obtaining
twitchings.
And
we
have
seen
above
(p.
418)
that
a
large
dose
of
physostigmine
stops
the
twitchings
without
blocking
the
passage
of
nerve
impulses
to
the
muscle.
Exciting
action
of
physostigmine
on
the
central
nervous
system.
The
420
ACTION
OF
PHIYSOSTIGMINE.
general
statements
that
at
present
can
be
made
with
regard
to
the
action
of
physostigmine
are
few.
One
which
has
been
more
or
less
widely
accepted
is
that
the
direct
action
on
the
central
nervous
system
is
in
the
main
a
paralysing
one
(Harnack
and
Witkowski(12)).
This
was
based
on
the
effects
of
physostigmine
on
voluntary
and
reflex
movements.
Rothberger
has
pointed
out
that
the
primary
effect
on
unaniesthetised
animals
is
to
cause
movement;
he
concludes
that
in
small
doses
physostigmine
excites
some
part
of
the
central
nervous
system,
probably
the
cerebral
cortex,
and
in
larger
doses
paralyses
it.
But
2-3
mgms.
of
physostigmine
are
sufficient
to
produce
the
lack
of
voluntary
control,
and
this
amount
in
other
physostigmine
action
would
be
considered
as
a
very
moderate
dose.
Whether
this
amount
has
a
paralysing
action
or
no
on
the
higher
centres
of
the
brain,
it
has
no
obvious
paralysing
action
on
the
central
nervous
sygtem
in
general,
since
many
of
the
peripheral
phenomena
are
to
a
large
extent
produced
by
impulses
passing
from
the
central
nervous
system.
That
this
is
the
case
is
shown
by
their
decrease
or
cessation
when
the
nerves
are
severed.
It
has
been
shown
by
Heidenhain
for
the
salivary
glands,
and
by
Schultz
for
the
sphincter
iridis.
The
degree
of
central
action
in
the
secretion
of
sweat
has
so
far
as
we
know
not
been
determined;
we
have
in
consequence
made
a
couple
of
experiments
on.
the
secretion
in
the
hind
foot
of
the
cat.
In
one
experiment
the
sciatic
nerve
was
cut
on
one
side,
in
the
other
the
sciatic
and
the
crural
nerves.
Injection
of
physostigmine
caused
a
free
secretion
in
the
pad
and
toes
on
the
intact
side,
and
very
little
on
the
side
with
severed
nerves;
the
secretion
which
occurred
was
confined
to
the
outer
part
of
the
foot.
Thus
the
secretion
of
sweat
caused
by
2
to
3
mgms.
of
physostigmine
is
mainly
due
to
impulses
coming
from
the
central
nervous
system.
We
found
however
that
injection
of
.50/0
physostigmine
under
the
skin
of
the
pad
after
section
of
both
sciatic
and
crural
nerves
caused
a
fairly
free
secretion,
so
that
in
suffi-
cient
dose
there
was
apparently
a
peripheral
stimulating
action.
But
whilst
the
evidence
is
against
the
primary
effect
of
physostigmine
being
a
paralysing
one,
the
question
of
how
far
the
primary
effect
is
one
of
excitation
requires
consideration.
Loewi
and
Mansfeld(13)
have
attributed
all
the
peripheral
effects
caused
by
physostigmine
to
increased
nerve
irritability;
the
normal
'tonic
imptulses
from
nerve
cells
or
nerve
endings
have
then
an
increased
effect
or
rise
above
the
threshold
and
so
produce
an
effect.
It
is
unnecessary
for
us
to
discuss
this
theory
except
so
far
as
it
might
be
applied
to
the
decrease
421
J.
N.
LANGLEY
AND
T.
KATO.
of
physostigmine
effects
on
nerve
section.
It
seems
to
us
clear
that
the
theory
will
not
account
for
the
effects
of
a
small
dose
of
physostigmine
on
striated
muscle,
and
that
in
some
way
physostigmine
causes
new
im-
pulses-
to
be
sent
out
from
the
central
nervous
system
to
the
muscles:
(a)
The
general
muscular
movements
are
as
we
have
said
of
short
duration,
the
increase
in
peripheral
nerve
irritability
is
not.
(b)
An
increase
in
effectiveness
of
the
tonic
impulses
sent
out
by
the
central
nervous
system
to
striated
muscle
should
only
cause
an
increase
in
the
muscular
tone.
This
is
not
what
occurs.
The
contractions
of
the
skeletal
muscles,
of
the
eye
muscles
and
of
the
bird's
iris
are
clonic
with
either
irregular
or
regular
rhythm.
(c)
A
small
dose
of
atropine
does
not
appreciably
diminish
tonic
impulses
to
muscle,
or
prevent
physostigmine
from
causing
an
increase
in
nerve
irritability,
yet
a
small
amount
decreases
or
stops
the
muscular
contractions
of
central
origin
caused
by
physostigmine.
If,
as
we
conclude,
physostigmine
causes
new
impulses
to
pass
to
striated
muscle,
it
establishes
a
probability
that
the
effect
on
secretory
glands,
unstriated
and
cardiac
muscle,
is
in
part
produced
in
the
same
way
and
this
certainly
seems
to
be
the
simplest
explanation
of
the
sweat
secretion.
The
setting
up
of
new
nerve
impulses
is
in
ordinary
usage
spoken
of
as
an
excitation.
Using
the
term
in
this
manner
we
conclude
that
a
small
dose
of
physostigmine
has
as
its
primary
effect
an
excitation
of
a
number
of
centres
in
the
central
nervous
system.
This
leaves
open
the
question
whether
the
new
nervous
impulses
are
due
in
part
or
wholly
to
increase
of
irritability
of
the
central
synapses.
Increase
of
nerve
excitability
and
excitation.
Cushny
(14)
regards
the
increase
of
nerve
irritability
caused
by
physostigmine
as
the
first
stage
of
stimulation.
Whilst
this
view
seems
probable
on
general
grounds
it
presents
one
difficulty
which
has
not
been
noticed.
Physostigmine,
as
is
known,
causes
few
or
no
twitchings
in
frog's
muscle.
We
sbould
expect
then
that
physostigmine
would
either
not
increase
the
excita-
bility
of
the
motor
nerves
of
skeletal
muscle
in
the
frog,
or
would
only
do
so
in
large
doses.
We
made
two
experiments
on
this
point
and
in
both
a
small
doge
of
physostigmine
lowered
the
threshold
of
excitation
to
single
break
induction
shocks.
Thus
in
one
experiment
on
a
Hungarian
frog
weighing
42
grms.,
1
mgm.
of
physostigmine
injected
into
the
abdominal
vein
after
decerebration
lowered
the
threshold
of
the
sciatic
from
sec.
coil
at
26
to
sec.
coil
at
28;
after
another
mgm.
the
threshold
was
at
31;
after
successive
doses
up
to
13
mgms.
in
all,
the
422
ACTION
OF
PHYSOSTIGMINE.
threshold
was
still
at
31,
but
there
were
no
twitchings
at
any
time.
Similarly
we
found
that
in
the
fowl
1
mgm.
of
physostigmine
lowered
the
threshold
of
the
tibial
nerve
to
single
break
induction
shocks
from
sec.
coil
at
22
to
sec.
coil
at
29,
and
as
we
have
said
above
we
have
not
obtained
twitchings
in
the
fowl
on
injecting
*5
0/0
physostigmine
directly
into
the
muscle.
It
may
be
mentioned
that
we
have
not
found
that
soaking
the
trunk
of
the
sciatic
nerve
in
physostigmine
increases
its
excitability.
In
one
experiment
the
tibial
nerve
of
a
rabbit
was
passed
through
an
indiarubber
tube,
the
lower
end
stopped
with
China
clay
and
the
tube
filled
with
.1
and
50/0
physostigmine.
The
threshold
of
stimulation
of
the
nerve
above
the
tube
remained
unaltered.
Sympathetic
system.
The
most
striking
actions
of
physostigmine
are,
as
has
been
pointed
out
by
Meyer
and
Gottlieb(15)
and
by
Loewi
and
Mansfeld(13),
on
tissues
innervated
by
the
parasympathetic
system.
But
a
number
of
examples
have
been
brought
forward
of
an
action
of
physostigmine
like
that
which
is
produced
by
the
sympathetic.
So
far
as
our
observations
go
we
are
inclined
to
think
that
a
small
dose
of
physostigmine
(1-3
mgms.)
has
little
if
any
effect
on
peripheral
sympathetic
nerves.
The
chief
examples
of
sympathetic
action
which
have
been
described
are
secretion
of
sweat,
contraction
of
the
uterus
and
contraction
of
small
arteries.
The
secretion
of
sweat
we
have
dealt
with
above
(p.
421).
Contraction
of
the
uterus
has
been
found
by
Kurdimowski
(in
the
rabbit)
and
by
Cushny
(in
the
cat)
to
be
produced
by
physostig-
mine.
We
made
three
experiments
on
the
rabbit.
The
abdominal
wall
was
opened,
the
hypogastric
nerve
cut
on
one
side
and
the
lower
part
of
the
animal
immersed
in
warm
Ringer's
fluid.
The
injection
of
1-2
mgms.
of
physostigmine
had
no
definite
effect
on
the
uterus,
though
there
was
strong
contraction
of
the
intestine.
Adrenalin
caused
very
obvious
uterine
contraction.
We
conclude
that
a
small
dose
of
physostigmine
has
little
or
no
peripheral
effect
on
the
uterus;
the
central
effect,
if
any,
may
have
been
prevented
by
the
anmsthetic.
It
is
known
that
physostigmine
causes
a
brief
rise
of
blood-pressure
of
40-60
mms.
of
Hg
and
that
this
is
not
prevented
by
injecting
atropine.
We
find
that
the
rise
of
blood-pressure
is
much
less
in
the
spinal
atropinised
animal.
The
result
suggests
that
the
rise
with
intact
nervous
system
is
chiefly
a
central
action.
Whether
this
is
the
case
or
no,
the
result
shows
that
a
dose
of
physostigmine
sufficient
to
cause
strong
effects
in
the
oro-anal
system
causes
but
a
minimal
423
J.
N.
LANGLEY
AND
T.
KATO.
contraction
of
the
blood
vessels,
and
it
is
to
be
noted
that
according
to
Dixon
(8)
physostigmine
causes
contraction
in
perfused
vessels
which
have
no
sympathetic
innervation.
With
regard
to
the
sympathetic
ganglia,
Dixon(s)
mentions
that
physostigmine
applied
locally
to
the
superior
cervical
ganglion,
or
to
the
ganglia
of
the
solar
plexus,
has
no
distinct
effect.
We
have
tried
the
experiment
upon
the
superior
cervical
ganglion
of
the
cat
and
rabbit
and
can
confirm
this
statement.
Physostigmine
*5
to
1%
brushed
freely
on
the
ganglion
had
no
trace
of
effect
on
the
eye,
pupil,
nictitating
membrane
or
eyelids;
stimulation
of
the
cervical
sympathetic
had
its
usual
effect,
and
so
also
had
5
0/0
nicotine
applied
locally
to
the
ganglion.
THE
EFFECT
OF
PHYSOSTIGMINE
ON
DENERVATED
MUSCLE.
Our
starting
point
in
these
experiments
was
the
statement
of
Magnus(5)
that
the
physostigmine
twitchings
cease
to
be
obtainable
between
the
18th
and
27th
days.
If
the
disappearance
of
the
reaction
were
due
to
the
atrophy
of
the
muscle,
it
seemed
possible
that
the
period
during
which
the
reaction
is
obtained
would
depend
upon
the
nutritive
condition
of
the
muscle.
In
Magnus's
experiments
both
the
sciatic
and
crural
nerves
were
cut;
so
that
the
limb
was
nearly
immobilised.
The
gastrocnemius
muscle
receives
nerve
fibres
from
the
tibial
nerve
and
from
this
only;
after
section
of
the
tibial
nerve,
there
is
considerable
-power
of
movement
of
the
leg,
and
consequent
passive
movement
of
the
denervated
gastrocnemius.
Hence,
then,
we
severed
the
tibial
nerve,
excising
i
to
1
cm.
Half-grown
animals
were
taken,
since
it
was
possible
(though
by
no
means
certain)
that
the
gastrocnemius
would
have
greater
vitality
in
them
than
in
full-grown
animals.
In
some
cases
the
muscle
was
massaged
or
electrically
stimulated,
but
as
we
found
no
essential
difference
in
the
behaviour
of
the
muscles
treated
in
this
way,
it
is
unnecessary
to
give
the
details.
The
tine
allowed
in
the
first
three
experiments
was
18,
25
and
28
days.
In
these
animals
the
tibial
nerve
was
cut
aseptically
on
both
sides
under
ether
(the
small
wound
in
this
and
other
cases
healed
rapidly).
After
the
lapse
of
the
given
number
of
days,
the
procedure
was
as
described
above
under
"Methods"
(p.
411).
The
gastrocnemius
was
exposed,
physostigmine
administered
and
the
muscle
closely
examined
with
the
naked
eye
and
by
the
aid
of
a
lens.
In
none
of
the
cases
was
there
any
fascicular
contraction
in
the
gastrocnemius,
but
in
its
place
there
was
fibrillar
'424
ACTION
OF
PHYSOSTIGMINE.
contraction.
The
fibrillar
contraction
was
rapid,
giving
a
shimmering
appearance
to
the
surface
of
the
muscle,
but
it
caused
no
movement
of
the
muscle
as
a
whole.
Some
characters
of
the
fibrillation
we
shall
give
later.
These
experiments
so
far
as
they
went
tended
to
show
that
physostigmine
causes
muscular
contraction
at
all
times
after
nerve
section,
but
that
the
contractions
are
changed
in
character.
Thus
the
next
point
to
determine
was
the
time
after
nerve
section
at
which
the
fascicular
contractions
changed
to
fibrillar
contractions.
Observations
were
then
made
at
successively
decreasing
periods
of
degeneration.
The
contractions
after
injection
of
physostigmine
were
fibrillar
after
fourteen
days'
denervation,
and
they
were
still
fibrillar
but
weaker
after
seven
days'
denervation.
On
testing
after
four
days'
denervation,
we
found
no
effect
at
all
in
the
greater
part
of
the
muscle;
there
was
slight
quivering
at
one
point
under
the
artery.
Two
days
after
denervation,
injection
of
physostigmine
had
no
effect.
This
series
of
experiments
placed
the
problem
in
quite
a
new
light.
The
fascicular
contractions
did
not
gradually
change
into
fibrillar
in
the
course
of
two
or
three
weeks,
but
the
fascicular
contractions
ceased
to
be
obtainable
in
a
couple
of
days;
after
an
interval,
fibrillar
con-
tractions
occurred
and
these
increased
in
intensity
up
to
about
a
fortnight
after
denervation.
So
far
we
had
paid
no
special
attention
to
the
gastrocnemius
until
physostigmine
had
been
injected;
the
muscle
was
viewed
from
different
angles
after
the
injection
until
the
fibrillation
was
clearly
seen.
It
was
best
seen
when
the
muscle
was
looked
at
from
the
side
opposite
the
source
of
light,
so
that
light
was
reflected
from
the
surface
of
the
muscle.
In
the
experiment
seven
days
after
denervation
we
noticed
that
the
fibrillation
was
not
visible
from
certain
points
of
view,
and
that
its
visibility
depended
greatly
on
the
angle
of
illumination.
This
suggested
that
in
the
other
cases
in
which
we
h#d
observed
fibrillation
after
physostigmine,
the
fibrillation
might
have
been
present
before
physostigmine
was
injected
but
had
escaped
notice
because
in
exposing
the
muscle
it
had
been
looked
at
from
the
wrong
angle.
Further
experiments
were
therefore
made
to
determine
whether
denervation
led
to
spontaneous
fibrillation
or
no.
In
these
some
other
points
were
investigated,
and
we
need
not
consider
them
in
the
order
in
which
they
were
made.
The
times
allowed
for
degeneration
in
these
further
experiments
were
1,
1-,
2,
3,
5,
8,
10,
12,
14,
30,
35,
36
and
71
days.
In
the
last
experiment
the
peroneal
nerve
was
cut
and
the
tibialis
anticus
muscle
examined.
425
J.
N.
LANGLEY
AND
T.
KATO.
On
the
fifth
day
and
on
all
the
later
days,
spontaneous
fibrillation
was
found,
and
it
was
of
the
same
character
as
that
which
we
had
previously
observed
after
injecting
physostigmine.
In
order
to
see
it,
it
is
necessary
to
look
at
the
muscle
from
a
certain
angle;
the
surface
has
then
the
appearance
of
being
in
continuous
slight
movement;
this
is
made
more
obvious
by
moistening
the
surface
of
the
muscle
with
warm
Ringer's
fluid.
In
close
examination
it
is
seen
that
the
contraction
in
any
one
spot-as
a
rule
at
any
rate-has
a
perfectly
regular
rhythm,
and
that
the
apparently
continuous
movement
of
the
surface
as
a
whole
is
mainly
due
to
the
rhythm
in
adjoining
fibres
being
different.
The
rate
of
rhythm
and
apparently
the
intensity
of
the
contraction
vary
consider-
ably
in
different
parts
of
the
surface
of
the
muscle;
we
have
not
observed
any
constant
difference
in
rate
in
the
gastrocnemius
(white)
and
in
the
soleus
(red).
When
the
surface
of
the
muscle
is
only
slightly
moistened
the
contractions
usually
cause
slight
depressions
in
the
surface
*5
to
1
mm.
in
length,
as
if
they
occurred
in
a
-small
region
of
the
fibre
and
spread
out
very
little
from
this
region.
When
the
foot
is
bent
to
form
about
a
right
angle
with
the
lower
leg,
so
as
to
stretch
the
gastrocnemius,
the
fibrillation
is
no
longer
seen.
The
fibrillation
continues
for
a
few
minutes
after
death,
but
stops
before
the
indirect
irritability
of
the
normal
muscles.
Its
rapidity
is
lessened
by
feeble
circulation;
adrenalin
causes
great
pallor
of
the
gastrocnemius,
and
by
lessening
the
circulation
decreases
the
fibrillation
and
in
certain
circumstances
may
we!
think
stop
it.
The
following
experiment
shows
we
think
that
if
the
blood
flow
through
the
muscles
is
stopped
for
10
to
15
minutes,
fibrillation
on
restoration
of
the
blood
flow
is
greatly
diminished
or
absent.
In
a
rabbit,
the
left
tibial
nerve
of
which
had
been
cut
nine
days
previously,
the
heart
stopped
during
the
administration
of
chloroform.
Artificial
respiration
and
other
mani-
pulation
were
kept
up
for
about
10
minutes
without
effect.
A
cannula
was
then
placed
in
the
jugular
vein,
and
a
strong
dose
of
adrenalin
injected
(.75
c.c.
of
1
%
solution)
and
this
was
driven
into
the
heart
by
injecting
5
c.c.
of
warm
Ringer's
fluid.
The
heart
began
beating
strongly
almost
at
once,
and
continued
to
beat
for
a
couple
of
hours.
The
denervated
gastrocnemius
was
examined
at
intervals
for
half-an-
hour
after
the
re-establishment
of
the
circulation;
there
was
no
fibrilla-
tion
at
any
time.
Atropine
(10
mgms.)
was
injected
and
then
1
mgm.
of
physostigmine,
followed
by
other
doses
until
10
mgms.
had
been
given,
and
the
heart
stopped.
At
no
time
was
there
fibrillation
in
the
denervated
gastrocnemiuis.
Fibrillation
was
noticed
in
the
plantaris
426
ACTION
OF
PHYSOSTIGMINE.
after
the
first
dose
of
physostigmine;
this
mav
have
been
present
earlier;
it
continued
throughout.
The
prolonged
absence
of
circulation
had
also
an
effect
on
the
other
muscles.
The
twitchings
were
very
much
less
than
usual,
and
those
in
the
right
gastrocnemius
involved
in
most
cases
but
a
small
bundle
of
fibres.
Further
in
parts
of
the
muscle
there
were
fibrillar
twitchings.
The
fibrillation
is
no
doubt
of
the
same
nature
as
the
well-known
fibrillation
described
by
Schiff
and
others,
which
occurs
in
the
tongue
muscles
a
few
days
after
section
of
the
hypoglossal
nlerve.
The
spontaneous
fibrillation
is
not
stopped
by
curari.
The
most
complete
observations
on
this
point
were
made
in
the
experiment
in
which
10
days
were
allowed
for
degeneration.
The
rabbit
weighed
only
1-2
kilos.;
curari
was
given
in
successive
doses
up
to
7
c.c.
of
a
1
%
solution,
and
the
fibrillation
was
still
lively.
The
curari
solution
was
made
fresh
from
a
purified
curari
extract,
and
was
very
active;
1
c.c.
of
it
paralysed
the
motor
nerves
in
another
rabbit
weighing
1-25
kilos.
Nicotine
also,
in
much
larger
dose
than
is
required
to
paralyse
motor
nerves,
does
not
stop
the
fibrillation;
in
the
experiment
just
mentioned
50
mgms.
of
nicotine
were
injected
after
the
curari
and
had
very
little
effect
on
the
fibrillation.
In
the
experiments
two
and
three
days
after
denervation,
we
found,
as
in
the
previous
experiment
of
two
days'
denervation,
that
there
was
no
spontaneous
fibrillation,
and
that
fibrillation
was
not
produced
by
injecting
physostigmine.
Stimulation
of
the
tibial
nerve
caused
no
muscular
contraction.
Two
experiments
were
made
on
the
day
following
nerve
section,
one
25
and
the
other
29
hours
after
the
operation,
the
experiments
themselves
lasting
2-3
hours.
In
neither
case
was
there
anv
spontaneous
contraction
in
the
gastrocnemius
or
soleus
of
the
cut
side.
The
injection
of
physostigmine
gave
rise
to
a
mixture
of
fascicular
and
fibrillar
con-
tractions,
the
fibrillar
contractions
in
places
being
marked
by
small
depressions
about
a
millimetre
in
length
like
those
often
seen
with
the
spontaneous
fibrillation.
Stimulation
of
the
cut
tibial
nerve
caused
some
contraction,
but
much
less
than
normal,
especially
in
the
second
experiment.
The
fibrillar
twitching
as
well
as
the
fascicular
was
stopped
by
curari.
In
the
second
experiment
(the
rabbit
weighing
1-25
kilos.)
1
c.c.
of
1
%
curari
was
sufficient
to
stop
the
twitching
and
this
paralysed
both
peroneal
and
tibial
nerves.
Injection
of
5
mgms.
of
physostigmine
restored
some
irritabilitv
to
the
peroneal
nerve,
427
J.
1N.
LANGLEY
AND
T.
KATO.
but
none
to
the
tibial
nerve
which
had
been
cut
on
the
previous
day.
The
coincidence
of
the
time
at
which
nerve
irritability
disappears
with
the
time
at
which
physostigmine
ceases
to
produce
twitchings
is
strong
evidence
that
physostigmine
causes
muscular
twitchinas
by
acting
on
the
nerve
endings,
but
this
by
itself
is
not
quite
conclusive.
In
frog's
muscle,
guanidine
twitches
are
prevented
by
a
small
increase
in
the
calcium
percentage
of
the
fluid
bathing
the
muscle,
and
both
guanidine
and
nicotine
twitches
are
often
not
obtainable
if
the
frog
has
been
kept
in
activity.
We
have
seen
(p.
418)
that
in
mammalian
muscle,
the
nerve
may
cause
strong
contraction
after
physostigmine
has
ceased
to
cause
twitchings.
It
is,
then,
conceivable
that
pbysostigmine
acts
on
the
neural
region
of
the
muscle,
and
that
after
nerve
section
its
effect
is
stopped
for
a
time
by
the
action
on
the
neural
region
of
the
metabolic
products
of
the
degenerating
nerve
endings.
If
this
occurs
we
should
expect
that
as
the
metabolic
products
are
absorbed,
fibrilla-
tion
should
be
increased
in
rate
by
injecting
physostigmine
and
reduced
to
its
original
rate
by
injecting
curari.
The
determination
of
this
point
is
unfortunately
beset
with
considerable
difficulties,
the
chief
of
which
is
the
varying
distinctness
of
the
fibrillation
as
it
is
viewed
at
slightly
varying
angles
and
with
different
amounts
of
fluid
on
the
surface
of
the
muscle.
In
the
considerable
number
of
observations
we
have
made
on
this
point,
we
did
not
find
any
striking
increase
in
fibrillation
on
giving
physostigmine,
or
similar
decrease
on
giving
curari
after
physostigmine.
Some
effect
appeared
in
nearly
all
cases
to
be
produced,
but
in
view
of
the
difficulties
of
observation
we
have
mentioned,
we
feel
no
certainty
that
the
appearance
was
not
illusory.
It
may
be
noted
that
if
substances
which
cause
twitchings
stimulate
nerve
endings,
the
fascicular
character
of
the
twitchings
would
probably
be
due
in
part
to
axon
reflexes;
these
would
afford
some
explanation,
though
not
a
wholly
satisfactory
one,
of
the
production
of
fibrillar
twitching
bv
physostigmine
on
the
dav
after
nerve
section.
SUMMARY.
In
an
anesthetised
rabbit
or
cat,
physostigmine
in
addition
to
causing
the
irregular
muscular
movements
which
are
already
known,
causes
nystagmus
and
rhythmic
movements
of
the
nictitating
membrane.
In
the
rabbit
the
nystagmus
may
take
the
form
of
a
slight
rapid
regular
movement.
All
these
movements,
and
fo
a
slight
extent
the
fascicular
428
ACTION
OF
PHYSOSTIGMINE.4
muscular
twitchings
also,
are
of
central
origin.
All
the
contractions
in
striated
muscle
which
are
of
central
origin
are
(in
the
anasthetised
animal)
decreased
or
stopped
by
a
few
milligrams
of
atropine.
The
effect
of
atropine
appears
to
be
partly
due
to
an
anaesthetic
action
and
partly
to
a
direct
antagonism
to
physostigmine.
Atropine
has
no
effect
on
the
muscular
twitchings
caused
by
physos-
tigmine
so
far
as
they
are
of
peripheral
origin.
CaCl2
must
be
given
in
large
amount
in
order
to
abolish
the
twitchings.
The
peripheral
twitchings
caused
by
a
small
dose
of
physostigmine
cease
when
a
sufficiently
large
dose
is
given.
After
physostigmine
has
been
given,
tetanic
nerve
stimulation
gives
rise
in
certain
circumstances
to
fibrillar
twitchings
which
may
continue
for
a
short
time
after
the
stimulus
has
ceased.
The
secretion
of
sweat
in
the
foot
of
the
cat
caused
by
a
small
dose
of
physostigmine
is
greatly
decreased
or
stopped
by
section
of
the
sciatic
and
crural
nerves.
In
this
and
a
number
of
other
cases
the
primary
effect
of
physostigmine
appears
to
be
an
excitation
of
centres
in
the
central
nervous
system.
When
curari
is
given
in
dose
just
sufficient
to
paralvse
the
motor
nerves,
the
nerve
irritability
can
be
raised
by
physostigmine
above
the
normal
level
without
causing
twitcbings.
We
conclude
that
conditions
which
allow
the
production
of
twitchings
are
to
some
extent
different
in
character
from
those
which
allow
the
passage
of
impulses
from
nerve
to
muscle.
When
curari
is
given
in
dose
two
to
three
times
as
great
as
that
just
sufficient
to
paralyse
the
motor
nerves,
physostigmine
in
large
amount
neither
restores
nerve
irritability
nor
causes
twitchings.
The
absence
of
effect
is
not
due
to
curari
paralysis
being
replaced
by
physos-
tigmine
paralysis,
since
physostigmine
in
very
large
amount
does
not
paralyse
motor
nerves.
Thus
the
power
of
physostigmine
to
antagonise
curari
depends
in
this
case
chiefly
on
the
concentration
of
curari
and
not
upon
the
relative
concentration
of
physostigmine
and
curari.
Physostigmine
in
doses
sufficient
to
have
a
strong
effect
on
the
oro-anal
nervous
system
has
so
far
as
we
have
seen
no
definite
effect
on
the
peripheral
sympathetic
system.
In
the
fowl
the
effects
of
physostigmine
are
in
general
similar
to
those
in
the
mammal,
except
that
there
is
rhythmic
contraction
of
the
iris,
the
muscular
twitchings
of
central
origin
are
few,
and
there
are
no-or
very
few-twitchings
of
peripheral
origin.
A
few
milligrams
of
atropine
stop
the
effects
of
central
origin.
Tetanic
stimulation
after
PEI.
XLIX.
A
429
J.
N.
LANGLEY
AND
T.
KATO.
physostigmine
was
tried
in
one
experiment;
in
this
there
was
a
steady
contraction
which
lasted
for
a
minute
or
more
after
the
end
of
the
stimu-
lation.
The
tonic
contraction
shown
by
Edmunds
and
Roth
to
be
caused
by
physostigmine
was
abolished
by
large
doses
of
calcium
salt
in
the
two
experiments
made.
Although
a
large
dose
of
physostigmine
causes
few
or
no
twitchings
of
peripheral
origin
in
the
frog
and
the
fowl,
a
small
dose
(1
mgm.)
lowers
the
threshold
of
nerve
excitation.
On
the
day
following
section
of
the
tibial
nerve,
stimulation
of
the
nerve
still
causes
muscular
contraction
but
the
contraction
is
weaker
than
normal.
Physostigmine
causes
twitchings
which
are
partly
fascicular
and
partly
fibrillar.
Both
are
readily
stopped
by
curari.
About
two
days
after
nerve
section,
the
nerve
ceases
to
be
capable
of
causing
contraction.
On
the
second
and
third
days
there
are
no
spontaneous
twitchings,
and
physostigmine
has
no
effect.
On
the
fourth
or
fifth
day
spontaneous
fibrillar
twitchings
begin;
they
increase
in
rate
and
extent
for
about
a
fortnight
and
continue
up
to
71
days,
the
longest
period
observed.
The
degree
of
fibrillation
varies
in
different
parts
of
the
denervated
muscle;
it
occurs
both
in
white
and
in
red
muscle.
When
well
developed
the
muscle
presents
a
continuously
quivering
surface;
this
is
best
seen
when
the
surface
is
well
moistened
with
warm
Ringer's
fluid.
When
there
is
but
little
fluid,
the
fibrillation
appears
as
short
depressions,
occurring
now
here,
now
there,
on
the
surface.
The
contractions
of
any
one
fibre
have
a
regular
rhythm.
The
fibrillation
is
only
seen
when
the
muscle
is
looked
at
from
certain
angles,
and
its
distinctness
varies
with
the
angle.
Curari
(7
c.c.
1
/0
solution)
and
nicotine
(50
mgms.)
have
little
or
no
effect
on
the
fibrillation.
Physostigmine
does
not
cause
any
marked
increase
in
the
spontaneous
fibrillation,
and
curari
after
physostigmine
does'not
cause
any
marked
decrease.
We
were
however
not
certain
that
these
drugs
had
no
effect.
As
has
been
remarked
at
the
beginning
of
this
paper,
the
lack
of
coincidence
between
the
time
after
nerve
section
at
which
the
nerve
endings
show
granular
degeneration
(2-3
days)
and
the
time
during
which
physostigmine
was
said
still
to
cause
twitchings
(18
days),
rendered
the
theory
of
the
action
of
physostigmine
on
nerve
endings
extremely
improbable.
The
results
given
in
this
paper
have
justified
the
argument,
but
at
the
same
time
by
showing
that
the
physostigmine
reaction
is
not
obtainable
on
the
second
and
third
day
after
nerve
section,
they
430
A
OTION
OF
PHYSOSTIGMINB
431
give
strong
support
to
the
theory.
The
facts
now
fall
in
line
with
those
obtained
by
Anderson(l6)
on
the
pupil;
he
found
that
two
days
after
section
of
the
post-ganglionic
ciliary
nerves,
physostigmine
ceased
to
cause
contraction
of
the
sphincter
of
the
iris.
Whilst
the
balance
of
evidence
is
now
in
favour
of
physostigmine
having
an
action
both
on
the
neural
region
of
the
muscle
causing
tonic
contraction,
and
on
the
nerve
endings
causing
twitching,
there
are
in
our
view
some
points
still
to
be
settled
before
the
action
on
the
nerve
endings
can
be
considered
to
be
definitely
proved.
REFERENCES.
(1)
Langley.
This
Journal,
xxxm.
p.
374.
1905;
xxxviI.
p.
285.
1908.
(2)
Langley.
Ibid.
xxxvia.
p.
285.
1908.
(3)
Edmunds
and
Roth.
Amer.
Journ.
Physiol.
xxm.
p.
28.
1908.
(4)
Langley.
Proc.
Physiol.
Soc.
p.
xxix.
1915.
(This
Journal.
XLIX.)
(5)
Magnus.
Arch.
f.
d.
ges.
Physiol.
cxxm.
p.
99.
1908.
(6)
Winterberg.
Ztschr.
f.
exp.
Path.
u.
Ther.
Iv.
p.
636.
1907.
(7)
Rothberger.
Arch.
f.
d.
ges.
Physiol.
LXXXVU.
p.
117.
1901.
(8)
Dixon.
Article
Hdb.
d.
exp.
Pharmak.
1913.
(Dr
Dixon
was
kind
enough
to
send
us
a
proof
of
this
article;
whether
it
has
been
published
we
do
not
know.)
(9)
Loewi.
Quoted
from
Meyer
and
Gottlieb
(15),
p.
147.
(10)
Langley.
This
Journal,
xLvm.
p.
73.
1914.
(11)
Pal.
Centrlb.
f.
Physiol.
p.
255.
1900.
(12)
Harnack
and
Witkowski.
Arch.
f.
exp.
Path.
u.
Pharm.
v. p.
401.
1876.
(13)
Loewi
and
Mansfeld.
Arch.
f.
exp.
Path.
u.
Pharm.
LXII.
p.
180
1910.
(14)
Cushny.
This
Journal,
xIi.
p.
244.
1910.
(15)
Meyer
and
Gottlieb.
Exper.
Pharmak.
3ยข
Auf
Wien.
1914.
(16)
Anderson.
This
Journal,
xxxiII.
p.
414.
1905.
