THE
ACTION
OF
CHOLINE,
CERTAIN
ESTERS
AND
AND
THEIR
RELATION
MUSCARINE
From
Physiological
H.
the Weilcome
Received
H.
ETHERS
TO
OF
DALE
Research
for publication,
Laboratories,
May
He,’ne
Hill
20, 1914
INTRODUCTORY
The investigation
with which this paper deals started
with the
observation,
that
certain
specimens
of ergot
and its extracts
exhibited
a type of action which was clearly
not referabie
to any
of the active
principles
hitherto
described.
The action
in question appeared
to be of the muscarine-type,
and, indeed,
the
search for the principle
responsible
for it was begun in the expectation
that the muscarine
would be found.
The chemical
procedure
leading
to the isolation
of this principle
has already
been
the subject
of a paper
by A. J. Ewins,’
who has described
its
identification
as Acetyl-Choline,
the intense
depressor
activity
of which
was already
known
through
the work
of Hunt
and
Taveau.2
A preliminary
note
on the general
features
of its
action
has also been published
by myself,a
and it is here only
necessary
to fill in the details
of that account.
For chemical
and physiological
comparison
a specimen
of
the so-called
“synthetic
muscarine”
or “pseudomuscarine”
of
Schmiedeberg
and Harnack4
had been prepared,
and the opportunity
was taken
of investigating
this substance,
with the result
that,
as elsewhere
published,
it was proved
to be the choline‘Ewins:
Hunt
2
No.
and
Biochem.
Taveau:
Journ.
Brit.
viii,
Med.
44, 1914.
Journ.,
1906,
ii, 1788.
Hygienic
73, 1911.
Journ.
Pharm.
and Exp. Therap.,
i, 303, 1909.
Dale:
Proc.
Phys.
Soc. iii, Journ.
of Physiol.
xlviii,
1914.
Schmiedeberg
and Harnack:
Arch.
f. exp. Path.
u. Pharm.,
Lab.
Bulletins
vi, 101,
1877.
147
This
One
ILLIII1II1HIII1IllMIIIKIII
RZ44-9D7-61CT
148
H.
H.
DALE
ester of nitrous
acid, HO N(CH3)3
CH2CH2 .0. NO and not, as
supposed
by Schmiedeberg
and Harnack,
an aldehyde.
This observation
led us to consider
the possibility
that
the
true, natural
muscarine,
from Amanita
Muscaria,
might
be also
a choline-ester,
although
the supposition
would involve
a revision
of the formula,
based
by Schmiedeberg
and Harnack
on their
analyses.
To test this idea we examined
several
choline-esters,
and one of these,
the nitric
acid ester,
HO N(CH3)3
CH2CHv
O NO2, was found
to resemble
true muscarine
in action
more
closely
than does the nitrous
acid ester-the
so-called
“pseudomuscarine.”
The difference
was still clearly
marked,
however,
in that nitric,
like the nitrous
acid ester, has an action
of the
nicotine-curare
type on the atropinised
frog, which is not shown
by natural
muscarine.
Meanwhile
experiments
on the stability
to hydrolysing
agents
of the activity
of an Amanita
extract
had considerably
weakened
the probability
of muscarine
being a choline
ester.
Brief boiling
with 1 per cent caustic
alkali affected
the activity
of the extract
hardly
at all.
The more stable ethers of choline
were, therefore,
investigated,
and in the ethyl-ether,
HO. N(CH)3CH2
CH2 .0.
we found a substance
showing
a closer resemblance
to muscanine in action than any other of the whole series of derivatives
as yet examined
from this point of view.
The only point of difference was, again, the possession
by the ethyl-ether
of a nicotinecurare action on the atropinised
frog; but this was quite sufficient
to exclude
its identification
with muscarine.
It seems doubtful
at present
whether
we shall succeed
in getting further
light on the structure
of the true muscarine,
unless
we can procure
a sufficient
supply
of the substance
for a direct
investigation.
Meanwhile
it seems desirable
to give a comparative account
of the action of the #{235}hlorine-derivatives
which our
search
has led us to examine,
many of them being substances
of
extraordinary
potency,
related
very closely in their physiological
properties,
and, in al probability,
not distantly
in their chemical
structure
to muscarine
itself.
Of. the substances
examined,
only a few, and those the more
active,
were made the subject
of at all a complete
physiological
.
.
ACTIONS
OF
ESTERS
AND
ETHERS
OF
CHOLINE
149
investigation.
These were three esters,
those of acetic,
nitrous,
and nitric
acids, and one ether,
the ethyl-ether.
This paper
is
mainly
concerned
with the details
of the action
of these four
substances.
Concerning
numerous
less active
substances,
all
bearing
some chemical
relation
to choline,
which were tested
in
the course of the investigation,
I can in most cases record
only a
rough estimate
of relative
activity,
usually
based on their effect
of the cat’s blood pressure.
A few of the experiments
have been made on intact
animals,
with hypodermic
injections
of the drug.
In all other experiments,
in which a living animal
has been used, it has been fully anaesthetised
throughou,t
the experiment,
usually
with
chloroform
followed
by ether,
except
in cases where
the anaesthetic
was
stopped
after the brain had been completely
destroyed.
All the substances
tested,
except
for a few which
could
be
obtained
pure commercially,
have
been prepared
synthetically
for me by Mr. A. J. Ewins who will elsewhere
describe
the preparation
of such as are new.
THE
ACTION
OF
NITRIC
THE
CHOLINE
ACIDS,
AND
ESTERS
OF
OF
CHOLINE
ACETIC,
NITROUS
AND
ETHYL-ETHER
As stated
above all these substances
Eave an action conforming
to the general
muscarine
type, one of them, the nitrous
acid ester,
having
been hitherto
commonly
known as “synthetic
muscarine,”
though
its difference
in some features
of its action
from the natural muscarine
has been recognized
since B#{246}hm’s5paper in 1885.
It will be convenient
to take the different
organs
and systems
separately
and compare
the actions
of the four substances
on
each in turn.
It will be clear that three of the group-the
nitrous
and nitric acid esters and the ethyl-ether-have
an action in most
respects
closely
similar,
while acetyl-choline
occupies
a somewhat unique
position,
due, as will be suggested,
to the facts that
it is an extraordinarily
active
but extremely
unstable
substance.
B#{246}hm:Arch.
f. exp.
Path.
U.
Pharm.,
xix,
187, 1885.
150
H.
ON
ACTION
THE
H.
DALE
CIRCULATORY
SYSTEM
The depressor
action
of acetyl-choline,
even in very minute
doses, was emphasised
by Hunt
and Taveau.6
They attributed
this to weakening
of the force of the heart-beat,
finding that, with
the very low range of dosage within which most of their observations were made, an effect on the rate was unusual.
With “very
large”
doses (e.g. 0.04 mgm. in a rabbit)
they observed
“great
slowing”
of the rate.
My own interpretation
of the effects
is
somewhat
different.
With an extremely
low range of dose (up
to 0.001 mgm.) I agree in finding
that the heart-rate
is little affected.
The fall of blood-pressure
which
such doses produce
I
regard as a vaso-dilator
effect, finding no evidence
of a weakening
/00rs4..t’.
-
C
AB
I-1_1
16
I
I.
I
IL
I
FIG.
Cat:
ether.
intravenously.
Carotid
blood-pressure.
At B, 2 cc. of normal
saline
1
1
1
1
1
1.
At A and
C, 2 cc.
with 0.000001
mgm.
of normal
saline
Acetyl-choline.
of the heart-beat.
The extent
of the fall produced
varies with
the size of the dose,
the anaesthetic
used, and the state
of
tone of the arteries
at the moment
of injection.
The arterial
system
seems to be more responsive,
and a fall therefrom
obtainable with lower doses, when the animal is anaesthetised
by ether,
or by destruction
of the brain,
than
when urethane
is used.
Even
under
identical
conditions
considerable
individual
variation is observable.
The lowest dose with which I have observed
a
definite
fall of pressure,
repeated
with subsequent
similar
injec‘Hunt
and Taveau:
bc.
cit.
ACTIONS
OF
ESTERS
AND
ETHERS
OF
151
CHOLINE
tions, was the almost incredibly
minute
amount
of 0.000001
mgm.
(the one-millionth
part of a milligram),
which in a cat under ether
produced
the effect illustrated
in figure 1. More commonly
the
minimal
effective
dose was of the order of ten times
this quantity.
My view as to the vaso-dilator
origin of this fall, obtained
with
minute
doses of acetyl-choline,
is based
on experiments
with the
myocardiograph
(Cushny),
with the plethysmograph
and with
the perfused
isolated
organ.
Figure
2 shows the effect on the
I
1
I
#{149}
1
=
o
1
#{182}
T
V
#{182}
T
1
-......
.-40
LJ
#{149}
#{149}
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
I
I
I
I
I
I
I
I
I
I
I
11L
2’
FIG.
Cat:
brain
destroyed.
Ventricular
Intravenous
injection
of 0.001 mgm.
2.
contractions
Acetyl-chobine.
and
carotid
blood-pressure.
blood-pressure
and the contractions
of the left ventricle
in a cat,
with brain
destroyed.
It will be seen that
the fall of bloodpressure
produced
by injecting
0.001 mgm.
of acetyl-choline
is
not accompanied
by any measuxeable
change
in the amplitude
or
rate of the ventricular
contractions.
Figure
3 shows that an increase in the volume
of an intestinal
loop and of a limb accom-.
Pr
152
H.
H.
DALE
panics
the fall of blood-pressure
produced
by such a dose.
The
volume
records
are from different
experiments,
and have been
superposed
for convenience
of reproduction;
the size of the animals,
method
of anaesthesia,
and the effect on the blood-pressure,
were
practically
identical
in the two cases.
FIG.
Cat:
ether.
blood-pressure.
Plethysmograph
records
Injection
of 0.O0kmgm.
3.
from
intestine
and
limb.
Carotid
Acetyl-chobine.
Figure
4 demonstrates
directly
the vaso-dilator
action
of the
ester, being taken from the drop record from a rabbit’s
ear, perfued
with Ringer’s
solution
at the room-temperature,
according
ACTIONS
to
the
method
OF
of
Rischbieter.8
It will
be
doses
of
acetyl-choline
type
cannot
be
a little
intense,
noted
ESTERS
AND
Krawkow
that
and
the
are
obtained,
ETHERS
CHOLINE
153
as
by
Bissemski,7
effects
of
small.
these
since
begins
action
modified
purely
Larger
however,
higher
another
action
though
evanescent
OF
effects
if the
to complicate
on the heart
vaso-dilator
of
dose
the
same
is pushed
the record,
making
its
an
ap-
pearance,
usually
when
the dose
reaches
the order
0.01 mgm.
The
effect
bears
a remarkable
resemblance
to that
of a brief
faradisation
of the vagus
nerve,
but is usually
followed
by a secondary
fall of pressure
during
which
the heart-beat
is quickened
even beyond
its original
rate.
of effects-immediate,
intense
lowed
by a period
of quickened
keeps
low or even falls further,
Typical
examples
of this sequence
slowing
of the heart-rhythm,
folrhythm,
during
which
the pressure
and then
gradually
returns
to the
FIG.
Upper
signal.
cannuba.
line
Effect
normal-can
drop-record
of injecting
=
be studied
4.
from
perfused
rabbit’s
0.005 mgm.
Acetyl-choline
in figures
5 and
ear.
Lower
into the arterial
6.
When
once
line
= time
perfusion
the
nor-
mal has been
regained,
which,
even
with
doses
of the order
of 1
mgm.
always
occurs
after
a few minutes,
the whole
effect
can be
reproduced
in all its features
by giving
another,
similar
injection.
The
tion
evanescence
of the effect,
and
with
successive
doses,
which,
the regularity
as we shall
istic of all the actions
of acetyl-choline,
some probability,
with the readiness
with
lysed
into its relatively
inert
constituents,
Ewins
and I found
that
such
hydrolysis
ity in watery
solutions
made
distinctly
*
Bissemski:
Rischbieter:
Wratsch,
Zeitschr.
1912, No. 5.
f. d. gee. exp.
Med.,
see,
of its reproducare character-
may
be connected,
with
which
the ester
is hydrocholine
and acetic
acid.
occurs
with
great
rapidalkaline,
even
at the
i, 355,
1913.
154
H.
ordinary
the
room
ester
temperature.
in
high
in the cold.
improbable
H.
Even
dilutions
In
that
DALE
Ringer’s
loses
the blood
an esterase
solution
activity
at
at body
temperature
contributes
to the
active
ester
from
the
circulation,
original
condition
of sensitiveness.
after
a dose
of adrenine,
which
containing
a perceptible
rate
it seems
not
removal
of the
and
the
restoration
The similarly
rapid
is oxidised
in alkaline
of the
recovery
solution
‘SOpIw.t.
140
.-..../3
30
Cholu,e
Ck4l-
1. 1 1
11
1
1
1
1
1
1
1 1 I
IL
I
I
I
I
I
I
FIG.
sure
Cat:
brain
of injecting
destroyed.
0.1 mgm.
only less easily
as an obvious
the
The
action
heart
and
chiefly
in being
than
parallel.
Artificial
Acetyl-choline
I
I
intense,
I
I
I
S
S
S
respiration.
Effect
intravenously.
is hydrolysed,
acid ester
(synthetic
differs
from
that
but
1
5555555
1
1
1
1
1
1
I
I
5.
acetyl-choline
of the nitrous
blood-pressure
less
I
more
persistent.
on carotid
blood-pres-
suggests
itself
muscarine)
of acetyl-choline
I have
not,
on
in
ACTIONS
this
case,
OF
analysed
ESTERS
the
AND
effect
of small
blood-pressure
mgm.
of this
can
ester,
be obtained
which
are
produced
doses
of acetyl-choline
there
being
any
by
ETHERS
doses;
one
a far
less
potent
ether.
nitrous
interesting,
Carotid
ester,
in view
blood-pressure.
at B 0.1 mgm.
of the
acetyl-choline,
in onset,
and
but as an
at the same
since
of 0.001
similar
hundred
than
falls
to
to
times
of
0.01
those
smaller,
doses
is, in
a acetyl-choline
is
6.
Intravenous
Acetyl-choline.
marked
in general,
and of other
esters
the dose is raised
a cardioinhibitor
not as an intense
initial
phase
but,
of the effect
of such
The
nitroso-choline
vaso-dilator
FIG.
Cat:
Choline
155
CHOLINE
with
injections
superficially
very
is a strong
presumption
in favour
mainly
due to vaso-dilatation.
case,
OF
vaso-dilator
injections.
At A 0.1 mgm.
effect
of nitrites
of nitrous
acid in particular.
effect
makes
its appearance,
of the action,
as in the case
effect
more
time much
As
of
moderate
in degree,
slower
more
persistent.
The vaso-
156
H.
dilator
effect
gradually
of smaller
obscured
higher,
until,
of
heart-beat
the
system,
shows
constituting
a comparison
acetic
and
cat
under
doses,
by
with
the
doses
is
H.
if such
cardiac
the
main
nitrous
acid
It will
esters,
Cat:
ether.
nitric
ester.
causes
worthy
choline
Carotid
a considerable
inhibition
causes
the
blood-pressure.
characteristic
as the
that
dose
on
is pushed
dose
circulatory
action.
mgm.
doses
into
of the
fact,
slowing
the
in succession
this
in
a prolonged
effect
Figure
6
of the
the
nitrous
same
ester
7.
Intravenous
fall of blood-pressure,
of the heart,
while
the
action
of the heart,
followed
by
accompanied
by some acceleration
The nitric
acid ester
of choline
becomes,
“muscarine”
effects
of 0.1
injected
be seen
be,
or more,
visible
FIG.
line
it
inhibition
of 0.5 mgm.
the typical
between
the
ether.
DALE
complex
injection
without
same
dose
of
initial
of 1 mgm.
Cho-
any noteof acetylvagus-like
a rather
slower
depressor
effect,
of the beat.
has an action
on the circulatory
ACTIONS
system
which
ester
similar
(fig. 7).
effect,
what
more
the
is not
of the
greater
the
mammal,
in the
which
but
1 mgm.
the
to
other
acetyl-choline
tense
in degree,
the
These
their
effects
origin.
to
be
must
AFTER
on
AND
blood-pressure
are
the
nicotine
in large
doses,
diminishes
The
production
of vaso-dilatation
has
already
Atropine,
been described.
on the other
hand,
the depressor
action
and
to light an action
of another
the
spinal
cord
cut
in
the
the
vagi,
the
in the
readily
and
cardioinhibitor
type,
seen best
neck
and
the
in view
substances
on
the
into
a depressor
action
with
extremely
in doses
maximal
of
with
intravenously
inhibition.
lower
of
that
a vaso-dilator
is extremely
the other
section
than
inhibition
with
doses
be given
NICOTINE
the
Neither
four
mainly
intense
onset,
acid
persisteice,
injected
marked
appears
a very
nitrous
might
be expected,
to hydrolysis.
are
cardiac
effect
and evanescent;
ACTION
persistent
we have
in all cases
case
of acetyl-choline
produce
this
duce an effect
of slower
greater
persistence.
of the
greater
of these
they
three
produce
more
action
seems
157
CHOLINE
that
The
of intensity,
of the ether
when
larger
doses
all
with
acetyl-choline
mgm.,
from
esters.
circulation,
OF
again,
produces
a very
closely
its action
appears
to be some-
especially
acid
same
order
resistance
doses,
With
beat:
and
nitric
the anasthetised
with
very
small,
minute
ETHERS
distinguishable
summarising
and
AND
The
ethyl-ether,
(cf. fig. 17) though
and
Briefly
heart
ESTERS
powerful,
nitrous
action
of the
OF
effect.
of the heartas low as 0.01
of the
In
order
the
rapid
in onset,
three
substances
intensity,
of
case
but
of
inpro-
much
ATROPINE
purely
nor
peripheral
the
iii
injection
of
cardioinhibitor
effect.
perfused
rabbit’s
ear
completely
abolishes
action,
and brings
in a cat which
has had
brain
destroyed
under
preliminary
anaesthesia,
and which
is then
kept
under
artificial
respiration
with pure air.
If the arterial
pressure
of such an animal
is recorded,
and 1 mgm.
of atropine
sulphate
injected
intravenously,
it is found
that
all the four choline
derivatives
have
lost
their depressor
and cadioinhibitor
effect
completely,
but that
any
158
H.
H.
DALE
1
0
C)
I)
0
0
0
C)
C,
Co
0
C,
I..
C)
#{231}
Co
0
C,
o
0
ACTIONS
of the
proditce
OF
ESTERS
three
esters,
given
a very
large
rise
to that
ethyl-ether,
type,
case
which,
it may be noted,
of natural
muscarine.
This
pressor
case
action
a central
not
only
of the
the
other
hand
effect,
bulbar
was
for
it can
but
it is completely
be
in the
B#{246}hm9in
acid
after
ester).
destruction
spinal
by
a dose
cord.
On
of nicotine
JILL
I
I
LJ
JUL
111(1
(tilL!
FIG.
abolished
by
whole
abolished
(fig. 8).
of this
or absent
nitrous
obtained
of the
Li
to paralyse
all
the
IL
It
ilti
9.
From
same
experiment
as Fig. 8, after further
tartrate.
Intravenous
injections,
at A 5 mgm.
mgm.
Choline
nitric
ester,
at C 10 mgrn. Choline
system-e.
These
action
hibitor
the
will
simi-
____C__
-
sufficient
weak
described
(i.e.,
centers,
159
CHOLINE
less of nicotine
very
little
effect
very
atropine
muscarine”
A__
I
or
has
is also
after
OF
dose,
such
as 5 mgms.,
having
a superficial
by 1 mgm.
other
hand,
of “synthetic
It is not
ETHERS
in a large
of pressure,
larity
The
the
produced
on the
AND
ganglia
injection
of 30 mgm.
Choline
nitrous
ester,
acetic
ester.
of the
involuntary
Nicotine
at B 10
nervous
g. 30 mgm.
for a cat (fig. 9).
choline-esters
have,
then,
two
quite
distinct
types
of
on the
heart
and
circulation-the
depressor,
cardioin“muscarine”
type
of action,
unaltered
by nicotine,
but
by
unaffected
B#{246}hm: bc.
by
atropine,
atropine,
and
but
a pressor
action
abolished
by
of the
large
doses
nicotine
‘1::
type,
of nicotine.
cit.
if
160
H.
This
secondary
primary,
The
was
type
of action
muscarine-like
secondary
of interest
H.
is,
action,
action
to enquire
DALE
glands
played
the suprarenal
rise of arterial
this
rather
is,
apparently,
In
nicotine
this
The
the
less
respect,
action
OF
that
their
which
action
of this
CHOLINE
marked
the question,
controversy
the
atrof)ine.
they
appears
of pure
being,
in his
is such
a state
a stable
of perfect
choline
crepancy
opinion,
some hands,
in others.
due
it
in its
esters
but
normally
to
be
of the
types
The
synthetic
in doses
to
or pressor;
decomposition
the
the conditions
to bring
out
predominance
we must
of action.
This
specimen
of
hydrochloride,
of 1 to
seems
of choline
whether
Popielski
and
pure
choline
has
by other
observersht
products.
in
dis-
depended
doses
to the nicotine-like
esterification
to be the
a
Choline
observers
employed
and
the muscarine-like
regard
of choline-
obtained
by synthesis
more
likely
that
the
different
choline
10 mgm.
action
in the case
the question
that
perfectly
effects
obtained
between
of action,
such
as
BLOOD-PRESSURE
in the
and so easily
that
it seemed
and to give
In that
case
both
explanation.
very
pure
duality
is depressor
substance,
purity,
of observation
on a duality
istered
being
ON
of its existence
has arisen
over
his coworkers’#{176} maintaining
pressor
action,
the depressant
venously
when
by
any considerable
part
glands
are excised
the
pressure
after
atropine,
than
again,
ACTION
discovery
raised
Much
sifying
seen
abolished
type.
DUAL
esters
itself.
only
been
being
obviously
of the nicotine-type,
whether
increased
output
of adrenine
from
the suprarenal
production.
When
still produce
a large
cause.
of course,
has
most
adminaction
in
action
as intenprobable
which
I have
used
is a
which,
when
injected
intra-
into
a cat
under
ether,
with
‘#{176}Popielski: Zeitsch.
f. physiol.
Chem.,
lxx, 250, 1910.
Modrakowski:
Pfl#{252}ger’s Arch.,
cxxiv,
601, 1908.
11 Cf. for example,
Mott
and Halliburton,
Phil. Trans.
B., cxci, 211, 1899.
Abderhalden
and MUller,
Zeitschr.
f. physiol.
Chem.,
lxv, 420, 1910, and lxxiv,
253, 1911.
Mendel,
Underhill
and Renshaw:
Journ.
of Pharm.
and exp. Therap.,
iii, 649,
1912.
ACTIONS
high
OF
blood-pressure,
similar
to
(e.g.
rise
that
caused
several
of
much
produced
by
by
ETHERS
a pure
small
the
doses
the
previous
weaker,
the
same
sample
A similar
esters
obviously
under
the
161
CHOLINE
of blood-pressure,
of
the
or
in the
larger
nitric
pithed
do’es,
produce
a pure
has been
made
on
this
point.
of
the
same
same
very
nitrous
‘other
hand,
of atropine,
of choline
observation
workers
is
OF
fall
ethyl
ether.
On the
received
a small
dose
25 mgm.)
of
of blood-pressure.
though
AND
produces
ester,
or of the
cat, which
has
by
ESTERS
The
type
conditions,
action,
as
since,
that
as in
LiIilII)liill(
FI.
Cat:
chloride
the
dose
brain
destroyed.
intravenously.
latter
case,
of nicotine
the
10.
1 *ngni. Atropine
At B, after 30 mgm.
effect
(fig.
ACTION
previously.
Nicotine,
is completely
At A 25 mgm. Choline
50 mgm. Choline
chloride.
abolished
by
a paralytic
10).
ON
THE
ISOLATED
HEART
It was suggested
that
the evanescence
of the effect
of acetylcholine
was due to the ease with which
it is hydrolysed
into relatively
inert
constituents.
If this is so, it is clear that no accurate
162
H.
idea of its
derivatives
relative
under
of intravenous
be
that
activity,
examination,
injection.
afforded
through
by
some
chosen
for
perature
such
the
activity
The
only
in high
rapidity.
satisfactory
bases,.
in Ringer’s
In
Ringer’s
but
in known
for some
mostly
hours.
used was
dilutions,
solution,
solution
at
though
show
wifi
when
to be hydrolysed
was,
therefore,
slowly,
dilutions
of the other
the method
comparison
Even
disappears
standing
solution
those
by
dilutions
seemed
The
frog’s
heart
comparison.
weaker
with
obtained
of the
organ.
the
after
Ringer’s
as compared
can be
perfusion
acetyl-choline
conditions
DALE
The
isolated
warmed,
acetyl-choline
with
considerable
H.
room-temeven
under
a perceptible
made
up
loss
according
of
to a
formula
recently
given
by Clark.’2
The
perfusion
was carried
out with
the aid of the 5-way
cannula
described
by Mines,’3
which
enables
an immediate
change
of solution
to be carried
out
without
alteration
of the
The nozzle
was
venosus
itself.
tied
The
pressure
either
apex
or
interruption
into the vena
of the ventricle
of
the
cava,
or into the
was
attached
flow.
sinus
by a
thread
to a lever,
which
it pulled
downwards
with systole,
against
the tension
of a light
spring.
A series
of records
obtained
with
one heart
is shown in figure
11.
It will be seen that,
under
these
#{149}conditions, acetyl-choline
beyond
that
recorded
stoppage
of the ventricle
in 100 millions
of solution,
one
part
in 1000
viously
much
has an action
even
for natural
being
obtainable
and a perceptible
millions.
weaker,
The
1 part
effect
in
on
the frog’s
heart
far
musarine,
complete
with
one part
of ester
inhibition
even with
of the
100,000
similar
manner
to 1 part
of the acetic
the effects
of one part
of the nitrous
nitrous
stopping
ester
ester
ester
the
is ob-
heart
in 100 millions;
in one mfflion
in a
while
and of
one part
of the acetic
ester
in 500 millions
show a close similarity.
Acetyl-choline
would
appear,
therefore,
to be about
500 times
as
strong
as the other
in action
on the frog’s
heart,
when
tested
under
the simple
conditions
of perfusion.
It may
be noted
in
passing
that
of the
nitrous
12
13
Clark:
Mines:
the
Journ.
Journ.
comparatively
ester
on
of Pharm.
of Physiol.,
the
low
frog’s
value
heart
and exp. Therap.,
xlvi, 190, 1913.
obtained
is the
iv, 403,
for the
one
1913.
apparent
activity
dis-
/
ACTIONS
OF
ESTERS
AND
ETHERS
OF
CHOLINE
163
,
T1ff1
Tff1j*
\t\\
ii
‘I
T1\
nnnrrnnftftt’
I
1U
‘VI
FIG.
11.
Perfused
heart
of frog, recorded
by suspension-lever.
to left, the vertical
linein
each case indicating
change
to similar
solution
containing
a choline-ester.
a Acetyl
choline
1 in 100 millions.
b Acetyl
choline
1 in 200 millions.
c Acetyl
choline
1 in 500 millions.
d Acetyl
choline
1 in 1000 millions.
e Nit’roso-choline
1 in 100,000.
f Nitroso-choline
1 in 1 million.
Tracings
from pure
read from right
Ringer’s
solution
--
-
-
164
-
II.
H.
DALE
crepancy
between
my observations
of previous
workers
on “synthetic
recent
paper
giving
of the latter,
temporaria)
quantitative
stoppage
fusion-fluid.
times
as
of the
This
would
great
as that
on this substance
muscarmne.”
1eterminations
Honda,’4
w’rking
and at the same
permanent
-
of the
with
the same
species
time
of year
(February),
heart
seem
which
with
1 part
to indicate
I observed.
and
the
In
activity
of frogs
(R.
obtained
in 1 million
an
those
most
activity
Honda
of per-
about
10
was
using
Williams’
apparatus,
in which
the heart
works
against
a pressure,
which
may
have
affected
the result.
But
the more
probable
source
of the apparent
discrepancy
is a difference
in the perfusionfluid.
In a few experiments
me at Cambridge,
in which
borate
in place
of sodium
nitrous
heart;
ester
in
but,
since
choline
in 250,000
which
a Ringer’s
bicarbonate
Mr. .Mines
kindly
made
for
solution
containing
sodium
was used,
1. part
of the
50,000
of Ringer’s
solution
in the same
experiments
produced
only
failed
to stop
the
one part
of acetyl-
a temporary
stoppage
for
a few
beats,
it was clear that
small
difference
of conditions
could
very
seriously
change
the scale
of the effective
dosage,
and that
no
significance
could
be attached
to the apparent
quantitative
discrepancy
between
Honda’s
results
and my own.
I was
nitric
unable
and
manner.
somewhat
to detect
nitrous
The
more
being
ment.
about
The
acetic
‘Like
ester when
muscarine
ether,
than
the
In
to produce
beats
increase
another
case
qualitative
one instance
an
of the
the
Arch.
effect
f. exp.
is almost
Path.
u. Pharm.,
this
of the same experiless active
than
the
exhibit
not
only
of activity
on different
of any of them
strong
will affect
the
being
attained
to infinite
entirely
xlv,
of the
in
itself
definitely
the activity-ratio
derivatives
pause
action
perfused
showed
esters,
differences
a dilution
diastolic
the
heart
stages
much
ultimate
arrest,
little,
stoppage
but
between
frog’s
however,
these
two
thus applied.
these
choline
but
gressive
“Honda:
ethyl
active
difference
on
2: 1 and 5: 1 at different
ethyl
ether
was, therefore,
quantitative
frog’s
hearts.
enough
individual
any
esters
on
454,
1911.
the
strength
of
by a pro-
‘duration.
strength
In
of the
-.
ACTIONS
beats,
ing
which
of the
small.
tremes
OF
have
-
ESTERS
become
intervals
AND
rapidly
between
four
when
heart
acetyl-choline
ETHERS
even
marked
intermediate
is by far
inadequate
to
esters
may
plied
to
a 2 per
slowing
cause
cause
its
the
in
fail.
Under
these
active
of the four
tion rarely
failing
judged
by the
by this
perfusion
most
test,
it is reasonable
t,he blood,
which
of
the
four
to
be
the
under
least
The
is quite
method.
and
gives
ON
relative
nitrous
and
frog’s
heart
but
OTHER
of the activity
canal-oesophagus,
they are injected
the
this
then
The
in
relatively
large
the effect
which
it produces
other
three
produce
more
ap-
infrequently
from that obtained
factor
is involved,
the
complication,
activity
of
action
active
appear
the
stable
value.
four
MUSCLE
choline-derivatives
are
of the muscular
walls
of the
stomach,
small
and large
intravenously
into the animal
under
anaesthetic,
or hypodermically
into
acetyl-choline
appears
to be very much
weaker
structures
than
the other
three
derivatives.
marked
stimulation
of intestinal
movements
intravenously
acid
when
is the hydrolytic
by far the most
INVOLUNTARY
All
not
nitric
is by far the most
of a 0.1 per cent soluorder
of the activities
therefore,
some other
to
of the
though
is usually
The
excluding
high
Canal.
powerful
stimulants
whole
alimentary
intestines.
When
different,
‘Clearly
ex-
weakest
of them
of the exposed
Under
such
of the
solution,
two
active
of acetyl-choline,
of the beat,
the ethyl-ether
application
heart.
The
conditions
active,
Alimentary
cent
widen-
vanishingly
powerfully
to suppose
that
this
makes
acetyl-choline,
a fictitiously
ACTION
1 per
little
these
it is the
the surface
circulation.
arrest.
stoppage
conditions
derivatives,
to stop the
of
ethyl-ether
complete
very
become
between
cent
solution
or weakening
complete
surface
they
165
CHOLINE
with
till
derivatives
when
thus
perfused,
the solution
is dropped
on to
of a pithed
frog,
with
natural
conditions
producing
OF
smaller,
them,
All types
of action
can be observed.
While
and
-
doses-e.g.
is markedly
powerful,
the
intact
animal,
in action
on these
To produce
any
it must
be given
0.5
mgm.
evanescent
much
more
Even
(Fg. 12).
prolonged
166
H.
intestinal
The
ready
contractions
effect
of such
shown,
small
H.
in smaller
doses
than
this,
on
heart
and
circulation
to those
produced
doses
the
in comparison
FIG.
Cat:
Carotid
equal
first
ether.
Contractions
of
blood-pressure.
Intravenous
dose
sight,
of
acetyl-choline
therefore,
DALE
that
small
such
as 0.1 mgm.
are,
by
an
12.
intestine
(T.rendelenburg’s
injection
of 0.5 mgm. Acetyl-choline.
(Cf.
as aleven
fig.
acetyl-choline
7).
It
differs
would
from
method).
appear,
the
at
other
ACTIONS
choline
circulatory
untary
OF
derivatives
in
system,
muscle,
pearance
isolated
is,
from
exhibits
choline,
a very
as to
ESTERS
being
and
such
less
as that
AND
ETHERS
more
powerful
powerful
degree
of the
in
alimentary
of sensitiveness
other
esters
its
action
to the
the
on
on other
canal.
a loop
of
in Ringer’s
and
167
CHOLINE
in its action
of the
however,
illusory.
When
the body
and
suspended
high
that
OF
This
the
involap-
intestines
solution
is
it
action
of acetylethyl-ether.
In
R
4
I
‘I
10
A
FIG.
Loop
synthetic
the bath.
13.
of Rabbit’s
small intestine
in 50 cc. Tyrode’s
Acetyl-choline,
at B 0.01 mgm.
Acetyl-choline
At R, R, fresh Tyrode’s
solution.
solution.
from
At A 0.01 mgm.
ergot,
added
to
the course
of the investigation
which
led to the isolation
of acetylcholine
from
ergot,
I used
as a test-object,
for the active
principle
which
we were
seeking,
a loop of rabbit’s
small
intestine,
suspended
in warm
oxygenated
Tyiode’s
solution.
In common
I
168
H.
with
other
observers,
for the maintenance
muscle
than
I find this
of regular
a Ringer’s
solution
and
more
generally
Figure
13 is a record
acetyl-choline
stance
of
solution,
the
made
case
of each
maximal
much
reaction
.higher
definite
tent
of
therefore,
heart.
dose,
At
A 0.05
being
can
order
augmentation
1 part
in
sometimes
up
of acetyl-choline
FIG.
13.
a much
activity
more
suitable
of isolated
according
medium
intestinal
to the
and shows
the sensitiveness
intestinal
muscle
suspended
concentration
Similar
to Fig.
nitrous
ester.
DALE
useful
formulae,
such
as that
of
in the final stage
of the identification
in ergot,
rabbit’s
the
H.
rngm.
sometimes
500
this,
Locke.
of
to this subin Tyrode’s
in the
bath,
in the
14.
Acetyl-choline,
1 in 5 millions.
than
older
be obtained
a sensitive
at
B 0.05
A distinct
with
preparation
ingin.
Choline
though
dilutions
not
of a
showing
of activity
when
acetyl-eholine
to the exmillions
is added.
The
sensitiveness
is,
of the same
high order
as that
of the frog’s
ACTIONS
The
nitrous
three,
and
when
stated,
OF
ESTERS
nitric
injected
a much
AND
esters
into
more
and
the
powerful
mentary
the latter
canal
than
acetyl-choline,
on the isolated
intestine,
a precise
moderate
numerical
value
to
doses,
so as to make
something
produces
the
between
but little
higher
action
on
the
the
it may
produce
and
and
nitric
able,
same
when
the three
are
isolated
preparation.
compared
The
from
those
three
nitrous
the
other
esters
a preparation,
medium
already
all
muscle
of
the
au-
When
given
in
of base in the bath
has
are
each
effects
gives
10 times
compounds
moderate
doses,
response
this
suggested
to
one
concentra-
to produce
acetyl-choline
been
on the
differs
it its ultimate
intenbecomes
decidedly
a definite
needing
ef-
indistinguish-
one another
acetyl-choline
in
the
added
in the
of the ethyl
practically
against
effect
of
derivatives,
which
already
14 shows
esters,
The
of onset
than
acetyl-choline
in 500 millions,
tion of any of the other
three
distinct
effect.
The
readiness
with
which
alkaline
though
as
Figure
nitrous
acid
one million.
in its greater
rapidity
With
very
low dosage
ester
difference.
dilution
less.
ether
of this
the
ether,
have,
are somewhat
less active
than
though
it is difficult
to assign
the
in
part
ethyl
animal,
and
part
superior,
the
169
CHOLINE
1 in 5 millions
to 1 in 500,000,
acetyl-choline
more
effect
than
the other
three:
indeed
with
doses
of
OF
whole
fects of the acetic
proportion
of one
rather
sity.
ETHERS
a similarly
is hydrolysed
in
in explanation
of the
an
evanescence
of its effect
on the blood-pressure.
Its comparatively
weak
effect
on the plain
muscle
of the alimentary
canal,
when
it is given
intravenously,
when
viewed
in conjunction
with
its
very
the
body,
intense
action
confirms
is extremely
the circulation
rapid.
brings
the
on the
suggestion
It may
it with
same
type
that
of muscle
its destruction
be pointed
great
rapidity
out
isolated
in the
that
injection
into contact
with
from
body
into
the
involuntary
muscle
of the heart
and
arteries,
so that
the mlnutest
doses
are capable
of producirg
circulatory
effects,
though
its re1y
destruction
makes
all its effects
evanescent.
‘The extra
delay
involved
before
it reaches
the muscular
coats
of the alimentary
canal
or other
viscera
apparently
allows
a considerable
further
destruction,
to take
place,
so that
a wholly
false impres-
r
170
sion
H.
is given
pared
An
of
its
different
derivatives,
on
organs.
‘
-.
DALE
activity
on
these
structures
on the one hand,
and
other,
on the isolated
the
Acetyl-choline,
on the intestinal
-Iminazolylethylamine
Laidlaw).’5
To
intestine
-
as com-
of the other
more
stable
choline
derivatives.
contrast
may
be drawn
between
the action
with that
interesting
these
choline
nazolylethylamine
relative
H.
-‘-
as we have
seen,
that
plain
of
of $-Imimuscle
of
has
an activity
muscle
of the rabbit
of the same order
as that
of
on the
uterine
muscle
(cf.
Dale
and
latter
base,
on the other
hand,
the rabbit’s
the
responds
but
feebly,
doses
of
the
order
even
of
I in
At
‘It,,’
#{149}
Isp
1-I -
is
$
-
5-1-5-.
FIG.
Lower
end
of
cat’s
oesophagus
$-Iminazolylethylamine,
50,000
failing
at B 0.01
to
intestine-e.g.
produce
the
-Iminazolylethy1amine.
on the
organ.
lower
The uterus.
reverse
being
“Dale
On
relation
very much
and
Laidlaw:
part
the
holds,
more
Journ.
50
mgm.
15.
cc. Tyrode’s
Acetyl-choline.
maximal
rabbit’s
portionS
of the oesophagus
the action
of the choline-esters
effects
isolated
in
solution.
tonus.
Other
rectum-and
show
the
At
A 0.1 mgm.
parts
a similar
relatively
high
sensitiveness
low sensitiveness
Figure
15
a comparison
of the
cat’s
and
shows
oesopbagus
of
the
plain-muscular
treated
to
to
of
as
the
an
uterine
muscle,
on the
other
hand,
the
the
action
of $-Iminazolylethyfamine
powerful
than
that
of the choline
derivaof Physiol..
xli,
318,
1910.
-
ACTIONS
tives.
pig’s
by
rat
The
uterus,
OF
contrast
and still
Guggenheim’6
was
exceptional
amine.
being
that
ESTERS
ETHERS
is,well-marked
better
in that
OF
confirmed
in which
augmentor
It was
-
CHOLINE
in the case
of the cat’s.
the uterine
muscle
in being
inhibited
I have
repeatedly
the only known
case
an action
other
than
malian
plain
muscle.
AND
of
171
of the guineaIt was shown
the non-pregnant
9-Iminazolylethyl-
by
this curious
anomaly;
-Iminazolylethylamine
this
has
on the activity
of isolated
mamof interest,
therefore,
to observe
4R.
it
/0”
Fio.
Uterine
horn
of virgin
at B 0.5 mgm.
Acetyl-choline.
that
the
action
The
choline
on the
urinary
derivatives
esters
uterine
bladder.
have
rat
16
in 50 cc.
had
muscle
On
a stimulant
Tyrode’s
their
solution.
usual,
At A 0.5
rather
weak
of this,
as of other
the urinary
bladder
action,
that
mgm.
stimulant
species
(fig. 16).
all four
choline
of acetyl-choline
again
much
less powerful
and persistent
than
that
of the
three
when
equal
doses
are given
intravenously.
Probably
inferiority
may
again
be attributed
to its smaller
stability.
The eye.
The action
of these
choline-derivatives
on the
muscle
special
ural
of the eye, and
interest.
One
muscarine
“Guggenheim:
is
the
Therapeut.
of the
of the
pupil
most
intense
Monatsh.,
in particular,
characteristic
myosis
xxvi,
which
Nov.
being
other
its
plain
has a somewhat
actions
of natit
1912.
p1.,
produces
in
the
-
172
-
-i
“w
#{149}
-
H.
H.
DALE
mammal.
The pupil
of the cat is reduced,
under
its action,
to a
narrow
line, the edges
coming
apparently
into complete
apposition.
The
failure
of “synthetic
muscarine”
to produce
this
intense
myosis
was
one
showing
its difference
the acetic
nor
the
duces
nously
We
more
into
than
the
of
from
nitrous
shall
see
of
these
that
esters
are
hand
the
nitric
ester
and
the
emphasized
the natural
base.
ester
(“synthetic
effect
muscarine-myosis,
intensity
and
intravenously
points
by B#{246}hm’mas
I find that
muscarine”)
neither
pro-
a trace
of brief
myosis
when
injected
anaesthetized
cat in a dose
of 1 mgm.
doses
acteristic
maximal
the
to
the
the
one,
being
I have
not
ganglionic
fibres.
The
deficient
when
hypodermically.
ethyl
ester
the effect
persistence
long
cat
peripheral
ganglion.
is similarly
given
under
On
both
in
with
ether.
produce
is
larger
the
other
the
char-
either
case
being
of
1 mgm.
doses,
giveim
The
effect
undiminished
by removal
yet tried
it after
degeneration
action
intraveor more.
is
of
abolished
by
relation
between
a purely
the
cifiary
of the post-
a small
dose
of
atropine.
pointed
Meyerl8
out
that
the
the
efficiencies
of the natural
and synthetic
muscarines,
the mammal,
was reversed
in the case of the bird.
synthetic
muscarine
caused
maximal
myosis
when
the bird’s
eye
no such effect.
iridis
in 1 per cent solution,
In the light
of the
is composed
of striated
while
natural
facts
that
the
muscle,
and
that
as seen in
He found
that
instilled
into
muscarine
had
bird’s
sphincter
the
action
third
nerve
thereon
is paralyzed
by curare
and not by
this observation
would
seem
to fall into line with
those
in other
sections
line nitrous
ester
which
ever,
is wanting
would
lead
and certainly
in the bird,
the
than
filled
results
by
the
of this paper,
pointing
(snythetic
muscarine)
in the
to the
natural
ethyl
ether
the nitrous
B#{246}hm:bc. cit.
“Meyer:
See Nothnagel,
would
ester.
This
that
have
This
a weaker
anticipation
the
.-
ccxxxii,
p. 286,
hownitric
ester,
myotic
effect,
is not ful-
‘
d. Pharm.,
by choaction,
interpretation,
probably
of experiment.
Arch.
of the
atropine,
recorded
to the possession
of a nicotine-like
base.
anticipation
myotic
1894.
ACTIONS
OF
ESTERS
In the fowl I could
not
1 or 2 per cent
solutions
In
the
pigeon,
however,
though
there
tion
of a 1 per
pigeons
for
was
cent
a strong
synthetic
effect,
and
a strongly
AND
considerable
In
necessary
myosis.
with
others
of the nitric
ester
and ethyl
in the pigeon,
and,
in cases
made
either
on the two eyes
of these
derivatives
The
ester
a solution
ether
where
the
had
little
to obtain
cent solu-
were
always
powerfully
direct
comparison
was
a 1 per cent
equivalent
of one individual,
was approximately
On
in some
description
cent solution
hand,
1 per
musculature
solution
of
in action
In no case
solution
of the nitrous
ester.
by instillation
of atropine.
bronchioles.
Instilla-
produced
Meyer’s
such
to use a 2 per
On the other
tions
myotic
to a 2 per cent
result
affected
variation.
nitrous
in accordance
173
CHOLINE
effect
by application
of
substances
to the eye.
effects
were
observed,
individual
of the
muscarine.
it was
marked
OF
obtain
a myotic
of any of these
well-marked
solution
myosis,
ETHERS
of
the
.
was
the
bronchioles
all
four derivatives
have
the constrictor
action
familiar
in the case
of muscarine.
In the case of acetyl-choline
the effect
is again
a
rapidly
evanescent
one, being
far more
persistent
and powerful
in the case of the other
three,
the ethyl-ether
the greatest
intensity
and persistence
of effect
The
retractor
penis
(dog).
Hitherto
the
muscle
supply,
we have
considered
from
the cranial
nervous
itor
system,
effect
of the
is that
these
certain
the
arterioles,
which
sacral
of the
vagus
choline
derivatives.
itor supply
from
or
receives
division
heart.
In
is reproduced,
The
plain
divisions
urethral
giving
with
only
an
of
this
as
and
inhibitor
nervethe involuntary
instance
we
have
muscle
receiving
of the system
sphincter
apparently
equal
doses.
involuntary
the
the
seen,
inhibby
the
a purely
includes
inhibthat
of
retractor
penis.
We shall deal in another
section
with the arterial
dilatation
the choline
derivatives
produce
in the genital
area.
As
rate tract
of plain
muscle
the retractor
penis
offers unique
which
a sepaadvan-
tages
for recording
a motor
or inhibitor
action,
when
such exists.
I experimented
on two dogs, under
morphia
and A. C. E. mixture.
The
retractor
penis
was dissected
clear
for about
2 cm. at its
distal
pulleys
end
and
to a lever,
attached
which
by
was
a thread
drawn
passing
down
against
over
the
a system
tension
of
of a
#{149}
-, #{149} --
-
-
174
H.
spring
by
of the
muscle.
killed,
the
and
its
contraction,
When
retractor
again
the
not
raised
the
experiment
by
and
tested
action
having,
DALE
and
removed
response
experiment
derivatives
H.
was
as an
that.
suggested
in
its
blood-pressure
to
which
that
produced
experiment
the
the muscle,
in situ, and
The
action
same
esters
ethylamine
therefore,
these
ester
and
by
nitric
when
added
was
a very
produced.
produced
one
bases,
which
as such,
seem
apart
to
from
derivatives
cause
first
as
In
a later
to
a weak
the
same
of tone
with
in
muscle
muscle.
that
of the
of -Iminazolylmuscle
seems,
in its
motor
of
of the
not un-
with
the
the isolated
uterus
fall
experiment
increase
that
latter
with
the
In
compared
with
The
isothis
response
to
action
on
plain
and
pancreatic
its innervation.
Action
All four
due
that
stimulation
of the retractor
of the
have
the
the other
the inves-
recorded
be
a small
on intestinal
muscle,
or
on the
retractor
penis.
to that
was
solution
In
of acetyl-choline.
weak
dog
tested,
into
relaxation
injected
intravenously
to the bath containing
to be analogous
muscle
the
found,
indeed,
by a relaxation
ester
both
when
organ.
might
injection
the
injection
of acetyl-choline
muscle
in situ.
On the
no definite
result
with
relations
the
I tested
this point,
vagus
was accompanied
like
me
natural
relaxation
in Ringer’s
only was
been brought
ester.
This
with
finished
isolated
of acetyl-choline
at that
time,
each
of the
obtain
muscle
spring
suspended
tigation.
In this
experiment
produced
a distinct
relaxation
lated
muscle,
however,
I could
the
the
on gland
a flow
cells
of saliva,
tears
juice.
The effect
on the pancreatic
flow is a comparatively
small
one, and like all the other
peripheral
effects
of these
substances,
readily
abolished
by atropine.
The
effect
on the salivary
flow
gives
ferent
duced
the best
opportunity
of comparing
the action
bases
on gland
cells.
As in the case of other
by injecting
these
substances
intravenously,
acetyl-choline
the
other
a dose
is weak
three.
of 0.5
and
The
mgrn.
evanescent
salivary
or so of this
\
flow,
ester,
as compared
in response
starts
of the difeffects
prothe effect
of
with
those
to an injection
after
a brief
interval,
of
of
#{149}
--
ACTIONS
attains
for a short
to complete
until
OF
period
arrest
it is found
AND
ESTERS
OF
a considerable
so suddenly
that
ETHERS
and
rapidity,
as to suggest
a second,
similar
blocking
injection
actly similar
effect.
The profuse
and long continued
flow
nitrous
ester is well known
from the
observers,
who have
regarded
it as
comparison
between
its effect and that
forded by the following
extract
from an
175
CHOLINE
then
of the
produces
slows
duct,
an
ex-
of saliva produced
by the
observations
of previous
synthetic
muscarine.
A
of acetyl-choline
is afexperimental
record:
Experiment.
Cat,
ether.
Salivary
flow
recorded
from
Wharton’s
duct.
The figures
indicate
the movement
of the meniscus
in millimeters,
along a horizontal
tube attached
to a scale, in 10 second periods.
Injections
by femoral
vein.
Chorda
tympani
and cervical
sympathetic
cut.
1. Effect
of 0.1 mgm. of acetyl-choline.
0, 0, 0, Injection
6, 27, 6, 0,
0. Total 39
2. Effect
of 0.1 mgin.
of choline
nitrous
ester 0, 0, 0, injectionS,
54,
34, 25, 21, 21, 22, 26, 31, 31, 36, 36, 35, 35, 30, 30, 30, 24, 22, 22, 19, 16,
14, 11, 13, 9, 10, 8, 7, 7, 7, 6, 6, 6,4, 7, 5, 5, 3,4, 3, 5, 2, 2, 2, etc. Total
825.
0,
It is difficult
to make
sialagogue
effects
of the
ether, the effect produced
beir
g so prolonged
that
a quantitative
comparison
between
the
nitrous
and nitric esters and the ethyl
by even a small dose of any one of them
the
effect
of fatigue
with
successive
doses
can hardly
be excluded,
while
it is difficult
to assure
constancy
of other
conditions
over
the long period
required.
So far as a
comparison
of results
obtained
in different
experiments
is any
guide,
it would
seem
that
actions
of the nitrous
and
the effect
of the ethyl-ether
experiment
methyl-ether,
taken,
0.5
ishing
when
comparing
there
is little
difference
its action
with
that
of the
from
the record
of which
the
mgm.
of the ethyl
ether
produced
persistence,
the experiment
which
was
between
the
nitric
esters
in this direction,
and that
is the most
persistent
of all.
In an
showed
abandoned.
no
sign
much
following
a secretion
of
becoming
less
active
extract
is
of astonslower
r
‘
V.
176
H.
H.
DALE
Experiment.
Cat
24 kilos.
Chloroform,
Then ether
throughout;
tracheotomy.
Cannula
in right Wharton’s
duct, connected
to narrow
tube on millimeter
scale.
Cannulae
in left carotid
artery,
to record
blood-pressure,
and right
femoral
vein, for injections.
Figures
represent movement
of salivary
column
along
the tube in millimeters
per
interval
of 10 seconds.
1. Effect of 1 mgm. of methyl-ether.
0,0,0,
injection
14, 28, 22, 22,
20, 23, 20, 23, 21, 19, 21, 18, 18, 19, 15, 16, 15, 12, 13, 10, 11, 11, 10, 10,
8, 8, 5, 2, 3, 2, 2, 2, 1, 2, 1, 1, 1, 1, 0, 1, 0, 0, stops.
2. Effect of 0.5 mgm. of ethyl-ether. 0, 0, 0, injection 19, 21, 16, 11,
13, 12, 13, 13, 11, 12, 14, 13, 13, 12, 12, 11, 16, 14, 15, 14, 15, 13, 14, 14,
15, 12, 14, 13, 13, 13, 12, 13, 13, 13, 12, 14, 14, 15, 11, 14, 14, 14, 13, 14,
14, 14, 13, 12, 13, 14, 12, 13, 13, 14, 12, 14, 10, 7, 7, 9, 11, 10, 13, 11, 12,
11, 12, 11, 12, 11, 11, 12, 12, 10, 10, 10, 10, 11, 12, 12, 11, 12, 12, 13, 12,
11, 14.
,
#{149}
Since
the
salivary
minutes
after
the
the cat killed.
#{149}
flow
showed
injection,
the
The action of any
doses up to 1 mgm.,
no
sign
of becoming
experiment
was
action
of the choline
derivatives
hardly,
All four substances
produce
a secretion
less pads
of the cat’s
foot,
that
caused
effect
may
The
dose
action
of the
or,
#{149}
#{149}
#{149}
the
is injected
still
tion directly
#{149} immediately
passed
off,
most
profuse
intravenously
be so small
and
by
injecting
and
into
evanescent
is readily
demonstrated,
ester hypodermically
better,
15
and
of these derivatives on the salivary flow, in
is immediately
annulled by a small dose of
atropine.
Ergotoxine,
on the other hand, in doses
abolish
entirely
the secretomotor
effect
of adrenine,
apparently
choline
slower
abandoned,
into
a minute
sufficient
leaves
if at all, affected.
of sweat
from
by the ethyl-ether
the
persistent.
When
the anaesthetized
as to be barely
hairbeing
acetylcat the
perceptible.
however,
by giving
the unanaesthetized
droplet
to
the
of 0.1 per
a large
animal,
cent
solu-
into the pad of the foot.
When
the local anaemia,
resulting
from
the
pressure
of the
injection,
has
the pad is seen to be flushed
by vaso-dilatation,
while
beads
of sweat
the whole
pad
exude
becomes
relatively
and
pale
dry.
from
the pores
pink and wet,
and soon
while
its
coalesce,
neighbors
so that
remain
ACTIONS
OF
The
In the
gland
cells,
tion
as seen
Action
on the cat.
are
effect.
20
mgm.,
certain
other
injected
when
weak
poured
tears,
and
borygmi
slime
were
from
the
pads
gave
the
mouth,
of the
evidence
feet
was passed
from
the
made,
without
actual
labored.
the action,
The
pupil
not seen
was
unaffected.
in the anaesthetized
of sweat.
of atropine,
It was
“synthetic
constriction
not come
weak
the
the
dissolved
in 1
produced
no persymp-
These
were mostly
in preceding
secto 158 per minute;
with
movement,
retching
respiration
additional
or pithed
secretion
sweat;
of
bor-
a little
movements
became
feature
animal,
of
was
urine
was passed.
No feature,
inthe picture
of a general
stimulant
sections
of the involuntary
nervof the pupil;
and the only effect
under
this heading
is the secretion
All these
effects
are prevented
by a prelimninary’dose
after
which
acetyl-choline
appears
inert.
necessary,
in order
to complete
its identification
with
muscarine,”
to examine
the effect
on the unanaes-
thetized
cat of the nitrous
nary
dose
of atropine.
exactly
of the
well-marked
moist
An
skin
seen
directly
into
when
injected
plentiful
intestinal
anus,
and
vomiting;
erection
of the penis.
A little
deed,
was wanting
to complete
action
on the extra-sympathetic
ous system,
except
present
vhich
does
was
became
of vigorous
as
acetyl-choline,
caused
there
the
it is injected
in its action
toms
in a smaller
cat, weighing
about
2 kilos.
attributable
to the effects
described
separately
tions.
The heart-beat
was slowed
from
300
saliva
or in
for descripeffects,
under
the hydrochloride,
into a large
cat,
however,
and
animal,
remains
be anticipated
10 mgm.
of
then
injected
and
muscle
or brainless
There
and
177
CHOLINE
on involuntary
described.
is so evanescent,
is relatively
very
circulation,
ceptible
effects
As might
OF
i,mjections
anaesthetized
been
derivatives
animal.
of which
hypodermically.
cc. of saline,
the
of these
choline
normal
ETHERS
of hypodermic
in the
have
combination
when
the
otherwise
AND
‘ections
organs,
the
effect
the
effect
preceding
isolated
ESTERS
with
the
“B#{246}hm: boc.cit.
description
In
acid ester
with
and without
a prelimiboth
cases
the, effect.
corresponded
given
by
B#{246}hm.1’ When
10 mgm.
of
#{149}
#{149}
1
178
H.
the
nitrous
ester
the
effects
described
appear
fusely
The
injected
heart
is strongly
and
obscured
the
by
muscular
DALE
hypodermically
from
into
injection
violent
form.
The
defaecates
repeatedly
inhibited,
penis
the
H.
as resulting
in much
more
and vomits
and
sweat,
eral
are
the
maximally
persistent
tremors
-
‘
pads
set
in,
salivates
prowith
violence.
feet
covered
Respiratory
vomiting.
After
beginning
with
changes
a few
in the
cat
of acetyl-choline
animal
and
of the
erected.
a normal
are
minutes
gen-
hind-quarters
and
spreading
rapidly,
and shortly
afterwards
the cat dies in, apparently,
asphyxia!
convulsions.
The
heart
beats
slowly
for some
time
after
respiration
has stopped.
The pupil
was very
slightly
narrowed
at first and then dilated
as asphyxia
came
on.
After
nitrous
a preliminary
ester
cause
dose
none
of atropine
(5 mgm.)
10 mgm.
of the symptoms
of involuntary
of the
nerve-
stimulation.
For
about
10 minutes
the
animal
is practically
normal;
then muscular
tremors
set in and the cat falls helpless
on
its side.
The
general
muscular
twitchirgs
continue,
and
the
respiration
becomes
very slow
ment
of this kind which
I made
again,
and the cat
ered
completely.
istic of the action
In the
gradually
corresponds
exactly
administered
to
doses
he observed
with
ester
that
given
by
B#{246}hmfor
was
I have
excessively
“synthetic
the atropinized
cat in
death
from a curare-like
given
to
the
rapid
this
dose.
paralysis
unanaesthetized
only after atropine.
The dose was again
10 mgm.
tremors
were
produced,
and the only effect,
apart
prostration,
only experiimproved
after
lying
narcotized
for several
hours,
recovThese
muscular
tremors
are very
characterof the nitrous
ester,
and the effect
observed
muscarine,”
With
larger
of respiration.
The
nitric
acid
and irregular.
the respiration
respiration,
cat
No muscular
from
a slight
which
passed
off
after
about
an hour.
This
same contrast
between
the two
is seen when
toth
are given
intravenously,
to the pithed
atropinized
cat,
in large
doses
(5 mgm.).
The
nitrous
causes
general
muscular
twitchings,
while
the
nitric
only a trace
of such an effect.
No such effect
is seen
of the ethyl
ether,
on the pithed
and atropinized
cat.
studied
its action
on the unanaesthetized
mammal.
ester
esters
and
ester
causes
in the
I have
case
not
_iii#{149}
r
TEiIT
ACTIONS
Other
OF
derivatives.
of choline
ESTERS
AND
Derivatives
ETHERS
also been examined.
Trimethyl-chiorethyl
which
in
by a halogen
They
are:
ammonium
is replaced
OF
atom,
181
CHOLINE
the
alcoholic
or an
hydroxyl
amino-group,
chloride
-Cl
.
have
N (CH,),.
CH2
N(CH,)
3CH,
CH,Cl.
Trimethyl-bromethyl
CH,Br.
Trimethyl
ammonium
aminoethyl
ammonium
CH,CH,NH,.
These
all show
a marked
the case of the chioro
-and
ether.
Carotid
blood-pressure.
methyl-ether,
at B 0.5 mgm.
produces
by
a
0.5
heart,
with
of the
activity
A derivative
alcoholic
OH
of
a different
diate
An
definite
Intravenous
ethyl-ether.
effect
of the
nitric
acid
HO
.
N(CH,),
in activity.
In
a dose of 5 mgrn.
injections.
comparable
It
myosis.
choline
-
17.
mgm.
of the nitrous
ester.
The
1 mgm.
produces
a well-marked
active;
the
muscarine-like
choline
Br.
-
hydroxide
advance
on
bromo-derivatives,
Fic.
Cat:
(‘holine
bromide
to
animo-base
muscarine-like
has,
apparently,
At
that
A 1 mgm.
produced
is even more
slowing
of
about
ester.
constructed
by substituting
a CN
of choline
showed
activity
complicated
kind,
which
deprived
it of interest
radicle
for the
by toxicity
for our imme-
purpose.
attempt
to
make
a
substance,
to
corresponding
in
empirical
_________________
#{149} -#{149}
182
H.
formula
nack,
with
and
the
analysis
having
the
H.
for
#{149} -
#{149}
-
DALE
natural
muscarine
given
by
Har-
structure
OH
CII,0II
resulted
in ring
N (CH;)2
formation,
with
‘
OH,
the
CH,OH,
elimination
of water.
HO
)N
(CH,),\
CH,7
H,
-OH,
This
substance,
activity
of any
dimethyl
oxazoliium
DISCUSSION
The
with
experiments
the
hydroxide,
showed
no
kind.
AND
described
identification
as acetyl-choline,
in
of the
have
not
yet
the
SUMMARY
foregoing
muscarine-like
led,
as was
sections,
starting
substance
hoped,
in
to the
ergot
elucida-
tion
of the chemical
structure
of true
muscarine.
Some
of the
observations
made
in the course
of the attempted
synthetic
identification
are, however,
not without
theoretical
interest.
In the first place,
it has been shown
that the substance
obtained
by the action
of fuming
nitric
acid on choline,
and identifed
by
Ewins
as the choline
ester
of nitrous
acid,
is in every
respect
physiologically
identical
pared
been
with
in this
manner
shown
to possess
the characteristic
and
may
to possess,
for brevity
indicated
muscarine.”
tinct
types
derivatives
briefly
by
with
the
“synthetic
muscarine”
in addition, an action
of a different
be called
a “nicotine-action,”
and
BOhm
Further
of activity
and even
pre-
by Schmiedeberg
and Harnack.
It has
most
of the actions
of true muscarine,
exception
of the
intense
myotic
action,
as
complicating
the
action
type,
which
which
was
of
“synthetic
investigation
showed
that
these
two discould
be recognized
in various
choline
in choline
itself.
Their
main
features
are
as follows:
It
-
-
#{149}“-T
.#{149};#{149}:I’#{149}
7
:
T-’#{149}I
ACTIONS
(1)
OF
“Muscarine”
exhibits
in
AND
the
form,
uncomplicated
familiar
in the
have
tives.
described
its
As numerous
production
writers
OF
action
which
by
case
true
the
muscarine
nicotine
of muscarine
by a number
have
pointed
183
CHOLINE
action.
itself,
of the choline
out, it may
and
of organs
this part
receiving
a double
of the system
and
effect
is frequently
pathetic
nerves
and adrenine.
cranial
nerve
on the pupil;
the chorda
tympani
on the
heart,
constriction
of the
muscular
the motor
all
and
from
antagonistic
to
and its vasodilator
action
are reproduced
faithfully
is produced
this
group,
such
fects
The
of cranio-sacral
sweat-glands,
by
as
substances
with
with
that
of true
no
The
involuntary
their
by the
intestine
on the external
by muscarine,
which
which
having
pilocarpine.
with
nerve-supply,
sympathetic,
canal,
produced
nerve
on the large
several
of the choline
derivatives
with
an intensity
exceeding
that
action
of the
sacral
in the
the
syrn-
The constrictor
effect
of the third
the powerful
secretomotor
action
of
salivary
glands;
the inhibition
of the
bronchioles,
and
contraction
of the
walls
of the alimentary
action
of the pelvic
bladder,
these
antagonistic
the true
I
derivabe sum-
with
but
small
qualification,
as a reproduction
of stimulating
nerves
belor gin g to the cranial
and
of the involuntary
(autonomic)
system,
so that,
muscarine
urinary
talia;
ETHERS
pure
has
case
from
ESTERS
been
This
marized,
effects
divisions
- - #{149}‘:‘-‘-
-
action-i.e.,
its
long
- -
and
geniby
this paper
deals,
the same
type
of
chemical
parallelism
nerves
anatomically
vagus;
and
relation
with
is not, indeed,
sympathetic
to
the
ef-
perfect.
nerve-
supply,
but
tives,
break
deed,
in the
ready
response
to muscarmne
and the choline
derivathe perfection
of the correspondence,
as they
do, incase of any such comparison
between
drug action
and
involuntary
nerve-supply.
In
other
lelism
is not strict.
Thus
the choline
dilatation
not only
in areas
supplied
tors, such as the chorda
tympani
and
ently,
limbs,
over the
whither
nerves
plain
is anatomically
muscle
of other
nounced
in
whole
the
organs
arterial
extension
a
motor
also,
the
paral-
derivatives
produce
vasoby cranio-sacral
vasodilanervi
erigentes,
but, appar-
system,
and
of cranial
not credible.
viscera,
again,
where
directions,
even
or
in areas such as the
sacral
involuntary.
The
motor
effect
while
particularly
cranio-sacral
on
nerve-supply
the
pro-
#{149}t’w’
#{149}
‘
184
H.
exists,
as
in
the
also in weaker
sympathetic
On
and little,
of the true
if at all,
sympathetic
allies.
These
“muscarine”
effects
by
in
unaffected
small
doses
and
the
whole,
nicotine
of
the
alimentary
however,
of atropine.
nature
DALE
and
function.
the
the
less
are
large
structure
canal,
which
purely
extends
has a purely
inhibitor
in
correspondence
perfect
system
is
very
than
that
between
and of adrenine
and
purely peripheral
The
#{149} --#{149}
-,.-
#{149}
to an organ
like the uterus,
supply,
and
that
often
striking,
actions
‘#{149}t1
-
.
H.
bronchioles
form
nerve
-
doses,
but
evidence
as
primarily
in their origin,
readily
to
the
its
abolished
the
exact
affected
is
by
position
incomplete.
We have
seen that
removal
of the diary
ganglion
has no immediate
effect
on the myotic
action
which
some of these
derivatives
exhibit
in
piocarpine,22
such
in
post-ganglionic
On the
responds
the
#{149}
degeneration
other
hand,
to muscarine
plexus-free
seems
Magnus’3
when
preparation
to need
further
the “muscarine”
ing the effects
ily paralyzed
(2)
marked
degree.
most
respects
so
with
similar,
would
leave
states
Auerbach’s
that
responds
to piocarpine.
investigation.
action
of cranial
by atropine.
“Nicotine”
Analogy
closely
the
effect
The
unchanged.
intestinal
muscle
only
plexus
is present,
though
In
any
possession
The
case
as a peripheral
action,
and sacral
involuntary
action.
the
action
of
suggests
that
point
we may
broadly
nerves,
define
reproducand read-
by quarternary
ammo-
nium
bases
of an action
of the curare
or nicotine
type is one of the
most
familiar
of pharmacological
generalizations.
The
curarelike action
of ammonium
bases
was pointed
out by Crum-Brown
and Fraser’4
to the rule.
and numerous
The nicotine-like
producedby
completely
possessing
22
Cf.
an
Anderson:
“Magnus:
‘4Crum,
2
action
Barger
Arch.,
Fraser:
and
Journ.
cviii,
Journ.
xxxiii,
1, 1905.
of Anat.
of Physiol.,
xli,
have
added
the quarternary
adrenine
and
examples
bases
other
“sym-
by Barger
and myself.’
choline
and
its derivatives
resembles
of Physiol.,
PflUgers’
Brown
and
Dale:
described
to find
which
Journ.
authors
action
of
methylating
bases
was
therefore,
pathomimetic”
is not surprising,
later
that
414,
of nicotine,
1905.
and,
and Physiol.,
19, 1910.
i, 224, 1868.
It
to
#{149}
ACTIONS
OF
ESTERS
AND
ETHERS
OF
some extent, that of curare.
As described
this action
is seen in uncomplicated
form
action
large
is excluded
doses
by
atropine,
of nicotine.
The
in preceding
sections,
when
the “muscarine”
can itself
and
absence
185
CHOLINE
of the
muscarin#{233} may raise some doubt
as to whether
indeed,
a choline
derivative and a quarternary
There
seems
little
doubt,
however,
as to its
be
suppressed
action
by
in the case of
this substance
ammonium
close chemical
be,
base.
rela-
tionship
with
choline.
In the
case
of the
choline
esters
and
ethers,
we have
seen
evidence
that,
though
the
“muscarine”
action
and “nicotine”
action
are both
increased
by substituting
the alcoholic
OH group
of choline
in various
ways,
the intensities
of the two types
of action
do not bear a constant
relation
to one
another.
Thus
the ethyl
action
but
a less
powerful
while
the
nitric
ester
ether has a more
nicotine
is
powerful
action than
intermediate
in
muscarine
the nitrous ester,
both
respects.
might, indeed, imagine
a series
of bases,
the extreme
which were muscarine,
on the one hand, and a completely
ated
phenolic amine,
the ends of the series
nicotine
both
action
types
such as hordenine
having,
therefore,
respectively.
of action,
would
We
terms
of
methyl-
methiodide,
on the other;
pure muscarine
and pure
The
choline
be intermediate
derivatives,
terms.
having
Thus:
Muscarine
V
HON
It would,
of course,
(OH3)3
OH,.
0112.
OC,H5
HON
(OH,),
OH,.
CII,
HON
(CH,),CH2. CII, ONO
HON
(OH,),
.
ONO,
E.
.
CII,
be impossible
OH<I>OH
to include
in such
a series
all
the choline deriyatives examined,
stillless all that might
be made.
We have evidence, in the case of the three ethers-methyl,
ethyl,
#{149}
#{149}
:
4?9#{149}’
-
186
H.
and
little,
propyl-that
or both
relative
intended,
derivatives
some
extent
already
in the
independently
with
of the
presence
has led
pure
type
of action
can
tion of the animal.
In the consideration
base
idea
of
such
by
series
since
suitable
as that
action,
either
prepara-
outlined
above,
but less active
formylIts
“muscarine”
action
one when
the observait is injected
intraveshort
and weakened;
the
suggested,
being
its extreme
This makes
it impossible
of its “nicotine”
outside
the
after
atropine
by acetylation,
molecule,
adxninistraAs I have
or pressor,
predominant
of any
the
of these
two independent
effects
to the controversy
as to whether
is depressor
be rendered
this, as I have
decomposition.
satisfactorily
it produces
intensified
-
form
in the action
both
types
of action,
by the previous
in adequate
dose.
acetyl-choline,
probably
with
the similar
choline,
occupies
a peculiar
position.
can be shown
to be an extremely
powerful
tion is made
on isolated
organs.
When
nously
the action
on most
organs
is cut
accurate
-
may
be increased
very
obvious
change
in their
modificatiotis
is suppressed
or nicotine
suggested,
the
action
of choline
reason
for
hydrolytic
---T
DALE
be seen in uncomplicated
normally
presenting
other
type
atropine
action
-#{149}_7_
The
suggestion
of such
a series
is merely
to emphasize
the fact
that
choline
and
its
two distinct
types
of activity,
which
vary
to
can each
derivative,
if one or the
tion of either
H.
-
both
types
of action
much,
without
any
very
intensities.
therefore,
have
and which
of a choline
the
-
since
this
liability
to form
cannot
to
any
he studied
body.
The rise of blood-pressure
shows
that
this action
of choline
but no more
definite
statement
which
is also
can be
made.
The
#{149}
and
action
birds,
of the
also
choline
nitrous
pupil, this being
needs
choline
special
derivations
mention.
ester
has
very
little
a point
emphasized
on the
We
pupil,
have
in mammals
seen
that
the
effect
on the mammalian
by B#{246}hmas distinguishing
“synthetic”
from natural
muscarine.
Meyer,
on the other
hand,
showed
that
“synthetic”
muscarine
(i.e.
choline
nitrous
ester)
caused
constriction
of the bird’s
pupil,
while
the natural
muscanine
had not this action.
Having
regard
to the fact that
the
bird’s
sphincter
iridis
is composed
of striated
muscle,
this could
.
#{149},#{149}
,
---
,_w
.
#{149}
ACTIONS
well
be interpreted
this view
that
would
expect
intense
the
OF
ESTERS
of
it is unmodified
that
the nitric
the
by
ester
on
ether,
comparatively
less efficient
comparison
gree
of biochemical
involuntary
nerve-fibers
muscle,
with
nerves
substances
which
does
affect
not
affinities
nected
of ganglion
with the true
pletely
the
seem
on the
two
and,
which
types
to
be
bird’s
both,
On
simple
the
other
aliphatic
hand,
and
the
same
quarternary
ammonium
of
mechan-
the
forms
affinity.
relation
of
bird’s
a con-
between
mechanism
methylating
amine
would
In no
one
the
concommight
have
a nicocase has this
by Banger
and myself,
results
(e.g. hondenine
from
such
as
bases
the
case
which
action.
as shown
action
of the
voluntary
of cranio-sacral
a whole
group
the terminal
system.
By
hand
series,
cells
of
of a sympathomimetic
been observed.
In some
cases,
a substance
of purely
nicotine-like
the
ganglion
in some respects
of biochemical
a base would
be produced
and a sympathomimetic
and another
is some
de-
terminations
one
and
sharpness,
comparison.
group
of the
of action,
that
there
the
in
pupil.
in fact,
than
the nitrous
ester.
between
“muscarine”
in
the
of
and,
nicotine-like
of the
they
are
termination
We have
both,
cells and
sympathetic
animo-group
expect
that
tine action
the
the peripheral
on the other.
iridis,
a structure
link between
the
hexylamine,
pupil,
weak
between
and
with
In that
case
one
ether,
with
their
mammalian
one type
conclude
similarity
system,
in striated
ism connected
involuntary
methiodide).
bases
of
it is in accord
activity
cannot
be made
with
absolute
on different
species
are included
in the
any evidence
enabling
us to regard
one
whole
There
and
constrictors
shows
that
as responsible
for the
other.
One can merely
sphincter
necting
the
187
CHOLINE
atropine.
and
ethyl
myotics,
in this case also,
then,
that
the distinction
“nicotine”
when
effects
Nor is there
molecule
for the
be
OF
action,
action
ethyl
action,
would
The experimental
more
potent
It is clear,
ETHERS
as a “nicotine”
muscarine-like
case
AND
are
sympathomimetic
isoamylamine
produced
and
which,
as was shown
long ago by Schmiedeberg
and Harnack,26
and by
Jordan,’7 combine
a muscarine
and nicotine action, like the choline
“Schrniedeberg
Jordan:
*7
Arch.
and Harnack:
f. exp.
Path.
Arch.
f. exp.
Path.
u. Pharm.,
viii, 15,
u. Pharm.,
1878.
vi,
101,
1877.
T#{149}-
188
H.
derivatives
here
and
‘
“curare
studied.
‘-action
H.
A
was
DALE
similar
observed
combination
by
Jacobi
tetramethyland tetraethyl-ammonium-tniiodides.
A curious
result
of the investigation
is the
tution
of the alcoholic
OH group
of choline
leads
to a greater
activity,
and
or less,
and
discoverable
that
both
the
in most
cases
the substituting
little
change
groups
such
of type,
in most
and ethers,
for example,
logically;
yet among
the
frequently
between
of certain
divisions
great
interest,
but
is available.
the one whose
fact
sity
that
and
to a very
types
of activity
of such
intensified
fact that
voluntary
so that
mentary
On the
the
Acetyl-choline
action’
is most
corresponding
indeed,
any
two
two
are
actions
to the
evidence
exists
in the body
ence of a substance
line
tion.
surpasses
when
are
and antagonistic,
other
hand,
there
and
Hunt:
great
increase
above
Nor
of activity,
Most
even that
considered
bases
absent
having
with
esters
the
the
of adrenine,
both
in conjunction
those
action
directions
at
gives
plenty
of scope
for
is no known
depot
of choline
adrenine
depOt
that
a substance
in
and
the
effects
is one of
evidence
substances
examined,
in this direction.
The
reproduces
from
the
in many
physiowe ‘find
significance,
esters
of
are
are
an imme-
nervous
system,
of which
little
is, of all
suggestive
in the adrenal
resembling
fopnd
evidence
gland,
which
in intenwith
the
effects
of the
once
of inother,
comple-
speculation.
derivatives,
medulla,
nor,
acetyl-choline
of the existwas not cho-
yielded
that
base in the process
of extrachowever,
or any substance
of comparable
activity,
existed
in the supra-renal
for chemical
detection,
its action
“Jacobi
“Reid
of choline
at all.
Reid
Hunt
in the supra-renal
itself,
but easily
If acetyl-choline,
substiany way
are relatively
inert
substances
esters
and ethers
of this series
the action
each
of these
nerves
which
the
in
described
action.
as produce
increase
classes
of compounds.
of the involuntary
one for the discussion
its action
evanescence,
Hagenberg
fact that
in almost
some of the.most
potent
of all known
substances
diately
toxic action.
The
question
of a possible
physiological
resemblance
of muscanineand
Hagenberg:
Arch. f. exp.
Amer.
Journ.
of Physiol.,
gland
in quantities
sufficient
would
inevitably
overpower
that
Path.
iii,
u. Pharm.,
xlviii,,
48, 1902.
p. xviii,
1899, and v, p. vi, 1901.
T:-r-
.
;
‘r
-j----
-
---
ACTIONS
of the adrenine
be admitted,
stable
#{149}
#{149}‘-
‘
ester,
‘#{149}‘-#{149}
OF
#{149}
AND
ESTERS
1:y’w
-
ETHERS
OF
in a gland
extract.
The
of acetyl-choline,
or some
arising
in the
body
and
r
possibility
similarly
being
may,
active
so rapidly
by the tissues that its detection
is impossible
Such
a suggestion
interest if methods
mental
verification
would
acquire
could
189
CHOLINE
by
indeed,
and un-
hydrolysed
known
methods.
for its experi-
be devised.
There
remains
for discu
sion the occurrence
of acetyl-choline
in ergot, and the possibilityof its presence contributing to or inter#{149}
fering with the therapeutic
is much
more irregular than
ciples.
during
Out of a large
number
of specimens
of ergot,
the past
ten years,
I have
only
found some
which
contained
it in such proportion,
in that
recognisable
quantity
present
of the extract.
was
so small
in
Even
as to exclude
if the extract
in such doses
the range
acetyl-choline
of therapeutic
practice.
which
I have yet found
The
largest
in an ergot
to a physiological
those
any
any perceptible
effect,
or even hypodermically,
per cc., according
examined
five or six,
that its action was
its producing
the mouth,
mgm.
#{149}
action
of the drug.
Its occurrence
that of the other
known
active prin-
clearly
cases
the
possibility
of
were given by
as come within
proportion
extract
was
estimation.
of
0.2
Such
a
quantity
could
not produce
any noticeable
effect,
unless
the extract
were
injected
intravenously.
In the latter
case it might
cause
a brief,
but alarming
inhibition
of the heart’s
action.
In
preparations
from
ergot
intended
for intravenous
injection,
the
presence
of acetyl-choline,
in
action, is clearly
undesirable.
that
its action
on uterine
that
fect
of iminazolylethylamine
on- intestinal
muscle.
regarded
as a valuable
quantity
We
muscle
In
on this organ,
no respect,
constituent
No information
is available
of forrr ation
of acetyl-choline
animal
The
be found
tissues.
following
in extracts
to produce
or with
therefore,
this
sections
,with
its own efis it to be
of ergot.
which
throws
any light on the
in ergot,
or on its significance
the metabolic
processes
of the
now that its natural occurrence
may
sufficient
have
seen in previous
is weak,
when
compared
from
fungus.
has been
other
It
seems
not
demonstrated,
fungi, and
are the chief conclusions
reached
mode
in
unlikely,
that
possibly
it
from
in this paper:
- ,-
-
.
190
H.
1. In the
#{149}
action
fication,
in the
distinct
types
paralysed
action
of action
by
atropine,
ethers
can
detected-a
and
esters
showing
Harnack),
Other
these
derivatives
by
types
of
ex-
action
nitrous
ester
muscarine”
ester,
show
two
action,
paralysed
choline
choline
analogous
of choline,
action,
nitric
and
of intensi-
“muscarine”
a “nicotine”
derivatives
degrees
Schmiedeberg
and
of
choline
these actions with
intensity.
3. When
ined,
these
independently;
and
base,
choline
a number
of quarternary
two
of action
are
such
bases
types
certain
peutic
ammonium
found
have
true
muscarine,
if (as is still doubtful)
represents
a type in which
the nicotine
esters
and
ethers
so far
position.
4. Acetyl-choline
occurs
bility
renders
it improbable
examined
to vary
a pure
bases
is exam-
to some
nicotine
extent
action,
it is an ammonium
action
is absent.
The
occupy
occasionally
in ergot,
that
its occurrence
an intermediate
but
its
has any
instathera-
significance.
It is a pleasure
#{149}
be
varying
“synthetic
less
F
with
with
marked
intensity
are acetyl-choline,
(which
is identical
with
the so-called
ethyl ether.
V
and,
of certain
and
cess of nicotine.
2. Among
choline
DALE
H.
of choline,
-
Wiechowski
our disposal
therefrom.
to acknowledge
debts
and Dr. 0. Rosenheim,
supplies
of dried
Amanita
of gratitude
who
generously
muscaria
and
to Prof.
W.
placed
at
of extract