THE
PHYSIOLOGICAL
ACTIVE
ALKALOID
H.
From
the
Wellcome
H.
ACTION
OF
OF LABURNUM
LABURNUM)
DALE
Phl7siological
Research
Received
I.
was
Cytisine
first
Laburnum
has led
Most
fatal
toms
not
laburnum):
of accidental
in children,
collected
most
recent
twitchings,
cold sweats.
of
are
convulsions,
In Vallette’s
numbness
in
respiratory
‘Cf.
Rev.
by
presence
poisoning.’
who eat the
accounts
detailed
a stage
delirium,
the
E.
in
seeds
latter
in play.
by Vallette,’
who
in 1908
a dish in which
laburnum
agent,
in mistake
for those
symptom
appears
torpor,
which
may
of excitement.
salivation,
patients
the
of 131 cases,
including
account
of the symp.-
hallucinations,
hands.
S.
of plants,
which
of the common
its
The
most
constant
by prostration
and
be preceded
described
London,
1, 1911
in a number
and other
parts
toms
which
we have
seen was given
attended
three
women
who had eaten
flowers
had been
used
as a flavoring
or may
Hill,
INTRODTJCTORY
present
seeds
of Robinia
pseudacacia.
to be vomiting,
succeeded
Herne
October
in 1888
The
THE
LAIDLAW
Laboratories,
AND
alkaloid,
from
the
ones.
P.
publication,
tree
(Cytisus
to numerous
cases
of the cases occur
Radziwillowicz’
five
for
HISTORICAL
is an
isolated
P.
AND
CYTISINE,
(CYTISUS-
Other
mydriasis,
sympmuscular
diarrhoea,
vertigo,
pallor
and
the first symptom
was a feeling
Death,
when
it
occurs,
is
due
to
paralysis.
Radziwillowicz:
med.
de
Ia
Arh.
Suisse
Lancet,
1877,
ii, pp.
Journ.,
1870,
i. p,
341
79;
d. pharm.
Inst.
Romande,-1908,
and
1882,
414;
i, p.
1901,
199,
z.,
p.
ii, p.491;
1883,
Dorpat
366.
i, p.
II,
Also
1905,
p. 56,
various
ii, p.635;
1888.
Vallette:
authors
and
the
in
Brit.
The
Med.
1117.
205
This
One
lIIIIllIll11111
lullHhl
1lUlIIH
IIIU
WXWG-Y9Z-B922
206
H.
The
pure
alkaloid
by
H.
was
Husemann
including
DALE
P.
P.
prepared
and
named
by
and
Marm#{233}, and
further
studied
who
and more
on animals
assigned
to
shown
to be identical
with
salivation
muscular
peripheral
sis.
With
of
excitation
death
being
life can
respiration.
be
succeeded
injection
is said
due
to
to
be
Most
by
weakness,
lethargy
of a few milligrammes
by paralysis
of the
indefinitely
obtained
According
to
of peripheral
ford
sitive
some
2
Bradford
origin,
is abolished,
and
limb.
Increased
of the
accounts
br Cytisine.
These
centres
resulting
in
and a very large rise of bloodtremors,
partly
central,
partly
succeeded
paralysis
prolonged
Bradford
to motor
nerves
pletely
severed
others,
formula
Binet,8
and Radziwillowicz.’
of “ulexine,”
an alkaloid
of the common
gorse,
and
respiratory
by
the
and narcothe stage
of the
centres,
centre,
so
that
the application
of artificial
rise
of blood-pressire
in
the dog after
section
of the cervical
cord.
scribe
a curare-like
action,
which,
according
produced
with relative
ease in the cat and
the frog.
least
partly
isolated
by
accepted
of poisoning
of medullary
and vomiting,
twitchings
and
in origin,
intravenous
the
Cytisine.
agree as to the obvious
symptoms
are described
as a stimulation
dyspnoea,
pressure,
it
Gray,2
recently,
Freund
and his pupils.5
has been
described
by Gray,
Husemann
and Marm#{233},6 Cornevin,7
Prevost
and
#{149}
Bradford9
also described
the action
obtained
by Gerrard
from
the seeds
since
LAIDLAW
first
Partheil,4
C11H14N20,
Its action
AND
Most
observers
to Radziwfflowicz,
dog, as compared
the muscular
as they
continue
persist
diuresis
tremors
after
for some time
is mentioned
deis
with
are at
response
in a comby Brad-
and by Radziwillowicz.
Rodents
are relatively
very
insento the poison
(Prevost
and
Binet,
Radziwillowicz).
On
points
there
is lack of agreement
between
different
observEdinburgh
Zeitsch.
Med.
f. Chem.,
Journ.,
z, p.
viz,
161,
ii, pp.
908,
1025,
1862.
1865.
Berichte
d. deutsch.
Chem.
Gesell.,
‘Ibid.,
XXXIV,
p. 615, 1901; xxxvii,
#{149}
Loc. cit.
Also Marm#{233}: Nachr.
d.
1887 (Ref. Therap.
Monatsh.,
1887, p.
Comptes
Rendus,
1886,
p. 777.
$ Rev.
med. de Ia Suisse
Romande,
#{149}
Journ.
of Physiol.,
viii, p. 79, 1887.
xxiii,
p. 3201,
1890.
p. 16, 1904; xxxix,
p. 814,
k#{246}n.
Gesell.
z. Wissensch.,
156).
1887,
pp.
516
and
553,
and
1906.
z. Gottingen,
1888,
p. 670.
I
#{149}
ACTION
cr5.
tinal
Thus Prevost
and
peristalsis,
though
Radziwillowicz.
nerves
in the
the heart.
Radziwillowicz,
The
is not
obtained
produce
it.
of the
while
very
frog
fore-limbs
reverse
relation
who
emphasises
frog
in the
nitrate,
again,
before
small
doses,
observed
curare-action
though
of the
comparatively
which
show
are stifi
capable
same
observer
given
describe
the motor
the vagus
effect
on
was,
apparently,
the fact that
the
with
frog,
the
hind-limbs
suggestive.
The
Cytisine
the absence
of effect on inteseffect
on this is described
by
Prevost
and
Binet,
as being
paralysed
description
207
CYTISINE
Binet
noted
a stimulant
in the
His
OF
larger
early
by
doses
paralysis
a cataleptic’#{176} condition
of feeble
found
that
subcutaneously,
caused
movement,
10 mgms.
stiff
is
of
extension
of
the hind-limbs
in a fowl;
12 mgms.
killed
it.
He also observed
powerful,
peristaltic
contraction
of the
uterus
of a pregnant
cat
as the
result
of injecting
1 mgm.
intravenously.
Both
Marine
and Radziwillowicz
found
that
the alkaloid
was excreted
unchanged
in the urine.
It is evident
that
the
the action
of Cytisine
without
any essential
not made,
however,
direct
application
arrest
is produced
pharmacological
curare
and,
concluding
nine
Our
of the
closely
for
that
and
curare,
of
description
Cytisine
these
very
to
the
frog’s
heart,
to that
produced
were
regarded
as
clear
its action
but
by
observers
of
might
be transferred
to that of nicotine”
alteration.
The
general
comparison
was
though
Prevost
and Binet
remark
that,
on
“similar
affinities
no
given
nearer
reason,
strychnine;
between
that
former.
own experiments
confirm
the
accounts
of previous
workers
similar
to that
of nicotine.
impression
that
the
It may
Its
with
Radziwillowicz
is intermediate
of the
a momentary
by nicotine.”
being
rather
those
of strych-
made
by perusal
action
of Cytisine
is
be reealled
that
a
‘#{176}
The statement
is that the fore-limbs
“wie gelahmt
verharren
bei jeder Lageveranderung
in derselben
Stellung.”
The meaning
is not clear,
but we imagine
that
a description
is intended
of the cataleptic
condition,
which
is very easily
observed.
“We
have
not attempted
to give the individual
authority
for the different
details
of the action
of nicotine
to which
reference
is made.
Most
of the points
to which
we refer will be found in the paper
by Langley
and Dickinson,
Journ.
of
Physiol.,
xi, p. 265, 1890, in which full references
to earlier
literature
are given.
4
..
t
.
208
H.
H.
DALE
AND
similarly
close
or even
closer
was observed
by Edmunds’2
II.
For
our
supply
P.
P.
LAIDLAW
resemblance
in the case
to nicotine
of Lobeline.
in action
EXPERIMENTAL
of Cytisine
we
are
indebted
to
our
colleague’
Mr.
Ewins,
who
extracted
it from
Laburnum
seeds.
For
our
experiments
the alkaloid
was dissolved
in water,
in which
it is
readily
soluble,
the strongly
alkaline
solution
being
then
exactly
neutralised
base.
from
with
HC1
Further
this stock
effects
of Cytisine
observers.
Points
separate
correspond
of difference
muscles.
when
in
and
varying
stimulation
from
like
injected
contain
cent
of the
physiological
on the general
1 per
saline
toxic
nicotine,
causes
intravenously.
muscular
These
origin,
being
depressed
by pithing
the cord.
twitching
of the cat’s ears,
of an intravenous
injection
methiodide
in that
animal,
quite
sation.
about
to
made
with
observations
in the main with those
of previous
can be noted
in dealing
with
the
Cytisine,
in mammals
less partly
central
other
anaesthetic
doses
found
diluted
were
Our
systems.
Skeletal
mors
and
dilutions
solution.
by
The
tre-
are doubt-
chloroform
characteristic
or
which
is one of the first visible
effects
of nicotine,
lobeline
or hordenineis not produced
by Cytisine.
After
6 to 10 mgms.
in different
of the sciatic
nerve
in the
ineffective:
the muscles
In curare-like
action
as powerful
as nicotine.
still responded
on the cat,
The rabbit,
experiments
anaesthetised
we
cat
well to direct
faraditherefore,
Cytisine
is
as noted
by previous
observers,
is relatively
reistant.
Five
milligrammes
intravenously,
in a rabbit
of 24 kilos,
produced
a mere
trace
of muscular
twitching.
Ten milligranimes
subsequently
caused
violent
general
twitching,
passing
into fatal
convulsions.
The jaw muscles
continued
to twitch
long
We have
noted
th’t
produced
by nicotLie,
fowl
as
with
ether,
1American
the
effect
with
Journ.
after
the death
a stiff extension
was
observed
of injecting
the
of
Cytisine.
gastrocnemius
Physiol.,
of the animal.
of the legs, recalling
by Radziwillowicz
xi,
In
tendon
p.
79,
1904.
a fowl
of one
in
that
the
anaesthetised
leg isolated
and
I
ACTION
attached
to
a lever
as
OF
209
CYTISINE
described
by
Langley,’
marked
mgms.
and persistent
tonic
contraction
of
of Cytisine
were injected
intravenously.
is that
the
effect
was
less
tion of nicotine
would
to be certain
of this,
or abolished
cannot
be
than
have
since
that
which
produced.
the effect
we
the
observed
muscle
when
Our impression
a corresponding
It is impossible,
of either
alkaloid
by a previous
injection
of the
compared
on the same
animal.
a
2
injechowever,
is reduced
other,
so that
the two
The effect of Cytisine
on the frog is strongly
reminiscent
of that
of nicotine.
One-half
milligramme
injected
into the dorsal
lymph-sac
caused
slowness
of
movement
in four minutes.
In five minutes
the fore-limbs
were
paralysed,
attempted
being
trailed
alongside
to jump,
so that the nose
In six minutes
a pronounced
the
was
cataleptic
was present:
respiration
had also
tary
movement
of the hind-limbs
however,
and they
still exhibited
body
thrust
when
against
condition
ceased.
was
weak
of the
Slight
retained
twitches
the
the
animal
table.
fore-limbs
power
of volunlong
after
this,
thirty
minutes
after
the injection..
The
frog
was then
pithed
and
dissected,
when
it was found
that
the muscles
of the hind-limbs
responded
well to stimulation
of the sciatic
plexus.
In another
frog 2 mgms.
produced
a complete
curare-like
effect,
the muscles
being,
however,
still fully
isolated
muscles
responsive
of the
to
frog
direct
excitation.
was
compared
tine.
Pairs of sartorii
were isolated
in tap-water
saline
(0.6 per cent).
Keith-Lucas’4
muscle-trough
filled
of the contraction
produced
when
with
The
action
on
that
of nico-
from several
frogs and placed
They
were fixed in turn
in a
with
saline,
and records
taken
the saline
was replaced
by 0.1
per cent solution
of nicotine
or Cytisine
made up with saline.
In
each
case the action
of nicotine
on one sartorius
was compared
with
that of Cytisine
on the other
muscle
from
the same
frog.
One-tenth
contraction,
per
cent Cytisine
always
but this was in every
in maximum
the
and
corresponding
“Journ.
‘4
Journ.
more
evanescent
muscle.
of
Physiol.,
xxxiii,
of
Physiol.,
XL,
produced
instance
p.
p.
than
Nicotine,
lxiv
380,
(Proc.
a well-marked
slower
in onset,
the
effect
added
1905.
Phys.
Soc.),
of nicotine
subsequently
1910.
tonic
lower
on
to
210
H.
subsidence
H.
of the
produced
similar
the
results
to but
appear
two
Previous
a paralytic
observed
intravenous
P.
or Cytisine
were
observers
action
on
in the
anaesthetised
followed
by
respiration
be
after
the
cessation
the
the
respiration
cord.
Heart and circulation.
The
observers,’
stimulation
pointed
out
ulexine
after
muscle
is, on
has
by
of
the
animal
violent
the
respiratory
If
begins
artificial
again
in
with
the
smaller
doses
resumed;
after an additional
abolished,
the convulsions
to asphyxial
stimulation
been
cervical
a
hand,
in which
we made
anaesthesia,
we observed
centre.
Immediately
recorded
generally
of the
medullary
vaso-motor
that
a rise of blood-pressure
section
in which
of blood-pressure
them
in
a stimulant
centre.
This
respiration.
ceased:
rise
the
that
of nicotine:
identical.
respiration
In a rabbit,
on the other
by the ear-vein
without
stimulation
of the respiratory
injection
previous
skeletal
causes
of
normal
(up to 5 mgms.)
it was soon gradually
dose of 10 mgms.
it was permanently
ensuing
being
possibly
due in part
the
the gastroc-
cat,
movements
nicotine,
with
have
described
the respiratory
of 1 to 2 mgms.
applied
after
obtained
weaker
than
to be nearly
injection
few minutes.
the injection
no primary
LAIDLAW
contraction,
Similar
whole,
therefore,
curare-like
action
is easily
P.
flexor
longus
digitorum.
action
of Cytisine
on
and the
excitatory
Respiration.
followed
by
AND
Cytisine
no effect.
nemius
The
DALE
cord.
by all
attributed
centre.
was stifi
We
of
to
Bradford
produced
by
find
that
after
extirpation
of the whole
cord
of a cat by pithing,
the pressor
effect
is obtained
practically
unimpaired.
The
first
effect
on
the circulatory
mechanism
of injecting
0.25 to 1 mgm.
of Cytisine
intravenously,
even
with
the vagi cut, is inhibition
of the heart:
this may
especially
ascending
way to
ation
‘
but
pass off rapidly
as the blood-pressure
with
larger
doses,
may
persist
for
limb
of
pronounced
and
The
they
effect
the pressure-curve.
acceleration.
vaso-constriction
was
subsequently
denied
The
produced
by
observed
Prevost
it.
and
Binet
begins
a large
to rise, or,
part
of the
Sooner
combined
or
by
mgm.
in
0.25
their
first
later
it gives
cardio-acceler-
and
drive
main
the
paper,
.
.
b
.
z
.
#{149}0 i
:
C)
1..
.
o
..-;
..
C)
C)
.
C)
±
.-
-
.
.
co
d’
C)
.
.0
.
00.
6
212
H.
pressure
up
ditions
duced
30
to
H.
the
DALE
maximum
mgms.
in
all
have
nicotine
injection,
an animal
similarly
tine.
Each,
which
the
toxine
a fall
(about
in place
given
to produce
to render
the
After
rapid
to be more
of a given
rapidly
submaximal
blood-pressure
any further
produce
no
to further
paralyses
the
a sufficient
dose
Cytisine
strucOf ergo-
produces
activities
of the two alkaIn a cat with
completely
mgm.
of Cytisine
is found
greater
rise
of
nicotine,
in
of pressure
than
whichever
order
of this quantity
of Cytisine
effect,
the difference
becomes
the effect
of nicotine
thus
paralysed
dose
in
height
by that
as soon
as sufficient
the effect
of further
rise.
conrepro20 to
on the blood-pressure;
is unaffected
by nico-
and
dose
the
and
After
irresponsive
a cat)
of the pressor
be employed.
system
0.25
same
under
injections
is usuallyneededin
of blood-pressure.
a more
by
cat
quantity
stimulates.
ever,
still be surpassed
dose of nicotine,
and
has been given to annul
on the
produce
the
a cat
they
are given.
As a first injection
frequently
produces
a supra-maximal
more
marked
with
later
injections,
appearing
The
effect
to
further
in sufficient
other
4 mgms.
of a rise
produced
LAIDLAW
Cytisine
is without
effect
paralysed
by Cytisine
For the comparison
loids
small
doses
must
pithed
central
nervous
always
P.
The effect
is evanescent,
by successive
doses.
been
therefore,
tures
P.
possible
of the experiment.
in diminishing
degrees
effect
on the blood-pressure.
After
sufficient
nicotine
that
AND
altogether,
In primary
no
of
(see
figs.
Cytisine
1 and
2).
can,
how-
of a sufficiently
large
nicotine,
or Cytisine,
injections
of nicotine
amount
stimulant
of Cytisine
action,
then,
will
on
peripheral
sympathetic
neurones
concerned
with
cardio-acceleration
and vaso-constriction,
Cytisine
is considerably
more
active
than
nicotine:
in secondary
paralytic
action
on the same
structures
the two are apparently
about
equal.
We hope to study
the
relation
between
the two actions
in greater
detail:
there
are certain
points
arising
in the comparison
of which
the meaning
is
not
yet
clear.
The
initial
stimulation
of the vagus
inhibitor
mechanism
are
trunk.
is
given,
by
In
this
succeeded,
pa4ralysis
respect
when
of the
again,
larger
effect
the
doses
(e.g.,
of excitation
action
is like
10
of
that
the
mgms.)
vagus
of nicotine;
ACTION
OF
213
CYTISINE
the likeness
is rendered
more
striking
by the production
after
2 mgms.
of Cytisine,
and especially
in a cat under
paraldehyde,
of the
phenomenon
of reversed
which
we described
produced
by about
Application
heart
causes
mal
only
3.
FIG.
vagus
on
Cat:
the
Alimentary
accelerated
rate.
acceleration
or
of the
Carotid
heart-beat
canal.
and
drops
of 1 per cent
inhibition
followed
Paraldehyde.
rate
action
in a recent
paper,’6
2 mgms.
of nicotine.
of a few
transitory
or slightly
produces
vagus
Stimulation
augmentation
Vomiting
2 mgms.
is one
heart
(fig.
which
was
likewise
Cytisine
by return
blood-pressure.
after
on the
to the frog’s
to the nor-
of the
vagus
of
heart-beat.
the
Reversed
3)
effect
then
of
the
Cytisine.
of
the
earliest
and
most
characteristic
symptoms
of the action
of Cytisine
on the dog or
cat.
It is incompletely
suppressed
by anaesthesia,
vomiting
efforts
of some vigour
being
produced
in a cat under
ether
by the
injection
of 2 mgms.
intravenously.
Sometimes
they
are effective to the extent
of producing
regurgitation
of part of the more
fluid contents
of the stomach.
The
small
intestine
of the cat exhibits
inhibition
during
the
rise of pressure
produced
by Cytisine,
followed
by some exagger6
Journ.
of
Physiol.,
XLI,
I#{149}
1, 1910.
214
H.
ation
of the
to the normal
becomes
whole
normal
(fig.
H.
4))
DALE
pendulum
The
progressively
effect
by nicotine
the
P.
P.
LAIDLAW
movement
as the pressure
returns
effect,
like that on the blood-pressure,
weaker
is qualitatively
under
AND
with
repeated
indistinguishable
same
conditions:
from
from
was
rabbit,
not
of a small
made
in this
the bowel,
Intravenous
rabbit,
instance.
again
like
injection
with
pithed
In
the
caused
The
produced
comparison
jejunum:
(Note
the
that
of nicotine,
of 2 mgm.
into
brain,
that
a quantitative
Fio. 4. Cat:
Brain
pithed.
Balloon
record
pressure.
Effect
of 2 mgms.
Cytisine
intravenously.
effect
on the rate of the heart-beat.)
sine on
motor.
injections.
the
carotid
bloodinitial
inhibitor
effect
of Cyti-
is predominantly
the jugular
a pronounced
rein
writhing
w
#{216};
AcTION
peristalsis
the
of the
whole
caecum.
By recording
jejunum
of rabbit’s
difference
the
in the
of the
OF
CYTISINE
small
and
longitudinal
added
inhibition
of pendulum
of tonus
and rhythm,
which
by weak
inhibition
of both
a slight
transient
the tonus
of nicotine
inhibition,
ent tonic-contraction,
After
recovery
from
of an
however,
Cytisine
Ringer’s
solution,
Two
milligramines
intestines,
a distinct
including
isolated
loop
quantitative
of the two alkaloids.
Two milligrammes
of
bath
of 250 cc. Ringer’s
solution,
caused
momentary
increase
succeeded
large
contractions
we observed,
action
to the
215
movement,
after
about
(fig. 5).
rhythm
and
then
were
added,
much
larger
were
a very
followed
30 seconds
On changing
by
was
the
slowly
recovered.
and caused,
after
and
also succeeded
by an inhibitor
this, in clean Ringer’s
solution,
more
persist-
phase
(fig. 6).
a further
dose
of 5 mgms. of Cytisine
caused
but weak motor
and inhibitor
effe’cts,
much
weaker
than
those
produced
by a subsequent
2 mgms.
of
nicotine.
motor
action
We
two
shall
alkaloids
Salivary
observers
the cat
and
Cystine,
therefore,
on the rabbit’s
is much
weaker
than
that
the same is true
of the motor
on the cat’s bladder.
glands.
Salivation
has been
mentioned
see
as a prominent
dog.
The
fact
nicotine
in
intestine.
symptom
of poisoning
that
vomiting
is also
effects
by
of the
several
by Cytisine
in
one of its most
constant
effects
suggests
the probability
that
the salivation
may
be largely
reflex,
or at any rate central
in origin.
It is not, however, wholly
so, since Cytisine
again
resembles
nicotine
in producing some
flow of saliva
in the anaesthetised
dog or cat after
section of the chorda
tympani.
Unless
the first dose is very small,
subsequent
injections
produce
little
or no
The effect of the first small dose of nicotine
“to such an extent
the effect
of subsequent
of either
alkaloid
on the
salivary
flow,
that
flow.
or Cytisine
depresses
similarly
small
doses
we found
it impossible
to establish
a comparison
between
their
activities
in this direction.
We found
the effects
of chorda
stimulation
in the dog only
slightly
reduced
after intravenous
injections
amounting
to 3mgms.
After 18 mgms. in all the immediate
effect of stimulation
was very
216
H.
H.
DALE
AND
P.
P.
LAIDLAW
.
b
1..
I-
4,
4,
I-
o
#{149}e
4?
-
c4
H
#{231}z,ai
.6.
4)
.0
-
Hidu’
4)04)
oi
?
.0
.601
0
.6
-
tI0
01
C
C)
ACTION
slight.
The
OP
ganglion-cells,
217
CYTISINE
however,
were
not
completely
para-
lysed;
for not only
was a slight
secretion
produced
during
the
stimulation,
but after
the stimulation
was stopped,
secretion
continued
for some time and at a considerably
greater
rate.
Renewal
of chorda
stimulation
during
this after-period
promptly
reduced
the
rate,
which
tion
was stopped.
apparently
sine would
been
again
The
the
but
there
accelerated
reversed
long
became
was
a further
stimulation
A similar
with
smaller
The details
If
gradually
of
more
chorda
once
doses
of Cytisine.
of some of these
obtained
could
stimulation
were
during
sudden
stimulaCytihad
a prolonged
its progress,
acceleration
was
action
as the
the effect of the
if the experiment
accelerated
and
ceased.
reversal
when
though
off in time
enough.
flow
as soon
action
be repeated
indefinitely,
doubtless
have passed
continued
given
became
observed
experiments
have
when
the
the
cat
in
been
published
elsewhere.’8
The fact that
the secreto-motor
effect of the chorda
may be mainly
an after
effect,
after
incompletely
paralytic
doses
of nicotine,
was shown
by Langley
in 1890.’
The inhibition
of
the delayed
phenomenon
secretion
by
to the reversed
we described
methiodide,’
as occurring
and now
effect
scribed
of the pelvic
by Langley.”
us is
action
the addition
of Cytisine
The eye.
of an injection
In
of stimulating
retraction
of
palpebral
Journ.
after nicotine,
after
Cytisine,
of
and
another
point
that
of nicotine.
the dog
of Cytisine,
the
the
and
The
xi,
18 Journ.
of
Phys.,
XLIII,
19 Journ.
of
Phys.,
XL,
cat
tropine,
and the
curare,
similarly
bladder
interest
after
of the
sympathetic-dilatation
membrane
retraction
succeeded
several
p. 123,
p.
proc.
of
similarity
the primary
that
of nicotine,
like
cervical
nictitating
is soon
after
of Phys.,
is clearly
an analogous
on the cat’s heart,
which
nerve
on the cat’s
The
immediate
fissure.
is brief,
and
the membrane,
restimulation
vagus
effect
of
the
and
hordeninereversed
curare
matter
defor
between
effect
on
is similar
of
widening
nictitating
the
the eye,
to that
the
pupil,
of the
membrane
by a movement
forward,
milligrammes
of the alkaloid,
so that
covers
1890.
196,
Phys.
1911.
Soc.,
p. lxii,
1910.
Also
XLIII.
p.
125,
1911.
- --
-
218
H.
one-half
With
to
H.
DALE
two-thirds
doses
up
to
of
10 mgms.
ANfl
the
in
P.
P.
-
LAIDLAW
visible
portion
the
the
cat
of
the
pupils
eyeball.
remain
large.
In the rabbit,
on which
we only made
one experiment,
and that
on the intact
unanesthetised
animal,
2 to 5 mgms.
by the
earvein
caused
constriction
of the pupil
and retraction
of the nictitating
membrane.
In a dog, which
received
30 mgms.
hypodermically,
the pupils
dilated
and
the
nictitating
membranes
gradually
rotated
became
upwards
respects
the
So also
ganglion.
greatly
prolapsed,
and
outwards
to
action
is again
is the paralytic
Application
closely
effect,
as
following
the
Stimulation
of
carotid
produced
the
result
record,
action
of the
that
parallel
the
eyes
In
vision.
to
that
must
be
all these
of
nicotine.
effect
on the cells of the superior
cervical
of 1 per cent Cytisine
to the superior
cervi-
cal ganglion
of a cat under
ether
pathetic
stimulation
on the eye
of the cervical
sympathetic
nerve
the ganglion.
to the internal
so
permit
of
which
caused
a brief
effect
followed
by complete
to electrical
stimulation
the
the
intravenous
illustrates
branches
normal
injections,
incidentally
from
effect.
the
of symparalysis
up to
ganglion
The
same
is shown
other
in
features
the
of
alkaloid.
Cat.
11.10
a.m.
11.30
a.m.
11.35
a.m.
11.37
a.m.
Chloroform.
Then
A. C. E. throughout.
Tracheotomy.
Cannula
in femoral
vein, by which
all injections
were
made.
Pupils
medium:
nicbitating
membrane
partly
forward.
1 mgm.
Cytisine.
Widening
of pupil and retraction
of
memb.
nict.
The
latter
then
moved
forward
with
continued
widening
of the pupil.
A few deep respirations: then normal
again.
Pupils nearly
maximal:
memb.
nict.
three-quarters
prolapsed.
Two
milligrams.
A very
few deep
respirations.
Then
vomiting
movements
during
which
respiration
ceases.
After a short period of artificial
respiration
it is resumed
normally.
Heart-beat
very slow.
Right
cervical
sympathetic
cut and isolated
for stimulation.
-
---
-
-
.
.
ACTION
11.52
a.m.
11.54
a.m.
11.55
a.m.
11.57
a.m.
11.58
a.m.
12.2
12.4
p.m.
p.m.
12.6
p.m.
Cytisine,
OF
219
CYTISINE
Cat
having
artificial
respiration
with
A. C. E.
Pupil
practically
maximal.
Stimulate
cervical
sympathetic
with coil at 20 cm.
Good retraction
of nictitating
membrane.
Five milligrams
Cytisine.
Memb.
nict. retracts
slightly
and
then
returns.
Pupils
maximal.
Slight
tremors
of paws.
Stimulate
cervical
sympathetic
with coil at 20 and 15 cm.
No effect.
With
coil at 10 cm. trace
of retraction
of
memb.
nict.
Stimulate
sciatic
(coil at 10 cm.)-feeble
twitches
of foot.
Stimulate
cervical
sympathetic
(coil
at 15 cm.)-memb.
nict.
retracts
very
slightly
and then
returns
during
stimulation,
retracting
again
on cessation
of stimulus.
Repeated
with identical
effect.
Five milligrams
Cytisine.
Stimulate
sciatic,
coil at 10 cm.
No effect.
Same stimulus directly
to thigh
muscles-normal
contraction.
Stimulate
cervical
sympathetic,
coil at 10 cm.-very
weak
and slow retraction
of memb.
nict.
Repeat-no
effect.
Isolate
branches
from ganglion
to internal
carotid
and
stimulate
with coil at 20 cm.-normal
retraction
of
nictitating
membrane.
therefore,
like
nicotine,
produces
its
stimulant
effects
when
directly
applied
to the ganglion-cells
which
it ultimately
paralyses.
On the other
hand
we find that
its dilator
action
on
the pupil,
at any rate,
is, again
like that
of nicotine,
not wholly
due to action
on the superior
cervical
ganglion,
since
the pupil
still dilates
when Cytisine
glion
has been
removed.
The uterus.
We have
of the cat
of Cytisine
is injected
intravenously
experimented
with
after
Cytisine
only.
In this animal,
as might
be expected,
changes
like that of the sympathetic
nerve
the
on the
ganuterus
the action
supply
and
of adrenine
or nicotine,
being
inhibitor
in the virgin
organ,
motor
in the pregnant,
when
the uterus
is in its natural
relations
and
the alkaloid
administered
intravenously.
Like nicotine,
Cytisine
in small
doses
has practically
no effect on the cat’s uterus
isolated
from
the body.
220
H.
The urinary
cat’s
bladder.
bladder.
We have
In all our experiments
nervous
system
This
excluded
cord;
initial
H.
DALE
of the
indirect
but
the bladder
tone, the effect
connected
with
nicotine,
the
be
initial
tonus.
under
obtained
pelvic
Our
contrast.
main
small
at regular
by Cytisine
figs.
1 and
The
results
statement
on the
central
having
but
little
on the motor
ganglia
under
more
object
was
as
the
favorable
to
alternating
case
of
the
the
contractions
be regularly
Cytisine,
greater
rise
of
ganglia
of
extent
with that
reveals
doses
the
to
the
conditions
compare
by Cytisine
The comparison
intervals,
are found
in
sympathetic
of
produced
a curious
two
alkaloids
of the bladder
much
less than
as mentioned
above,
of blood-pressure
2).
III.
in the
the
effect
organ
the
Probably,
from
those produced
by nicotine,
whereas
regularly
produces
a quicker
and
(see
LAIDLAW
examined
on this
nerves.
effect
produced
of nicotine.
When
are given
produced
P.
these
conditions
was only that
inhibition
demonstrated
the main
motor
by an equal
dose
P.
cat was destroyed
completely
by pithing.
effects
from
stimulation
of centres
in the
a secondary
could
AND
of this
that,
SUMMARY
AND
investigation
in nearly
DISCUSSION
may
every
be
respect,
roughly
the action
summarised
of Cytisine
is qualitatively
indistinguishable
from
that
of nicotine.
Such
small
points
of difference
as its failure
to produce
the characteristic twitching
of the ears in the cat have
possibly
a diagnostic,
but at present
no great
theoretical
importance.
We have
indicated
certain
alkaloids,
such
in the cat, and
quantitative
differences
in
the
action
of
the
two
as the more
powerful
pressor
action
of Cytisne
its less powerful
action
on the rabbit’s
intestine
and the cat’s
bladder.
In one case
two, nicotine
produced
a more
marked
effect
on the cat’s heart
than
Cytisine.
bids
paralyse
ganglia
in succession
it useless
to attempt
to give numerical
stimulant
activities
on any particular
ourselves,
therefore,
with
this
mere
in which
we compared
the
primary
inhibition
(vagus)
The fact that
both
alkato
their
stimulation
makes
expression
to their
relative
organ.
We have contented
indication
of the
order
of
ACTION
-
their
activities
in these
be a comparison
OF
few
of their
instances.
potency
of ganglia,
since, for obvious
in this respect
on the same
ences
permit
this direction
us to judge,
on the cat
affinity
shown
of the action
in the production
nerves
under
the
221
CYTISINE
Still
more
in producing
reasons,
animal.
we
and
the two
As far
should
say that
dog are of the
their
same
activities
order.
of nicotine
of certain
of incompletely
would
paralysis
cannot
be compared
as individual
differ-
of Cytisine
with that
of a reversed
action
influence
difficult
secondary
paralytic
in
The
is further
autonomic
doses,
such
as has previously
been
demonstrated
with
nicotine,
curare
and
other
alkaloids
of the same
group.
One of us has previously
shown
the resemblance
of the action
of hordenine_methiodide2o
to that of nicotine,
with
which
it has
no obvious
points
of chemical
similarity.
The
similarity
with
nicotine
in
Cytisine:
of such
action
is very
much
so close,
indeed,
that
exact parallelism
is known
which
are
not
close
chemical
closer,
however,
we doubt
to exist
relatives,
in
whether
in the case
except
in the
the
case
of
any instance
of substances
case
of the
apparently
still closer
resemblance
in action
to nicotine
exhibited
by Lobebine.
At present
but little
is known
of the constitution
of Cytisine,
though
there
are indications
that
its structure
in some
points
resembles
that
of nicotine.
An exact
knowledge
of its
structure
between
On
certain
sine.
may
give
interest
to the
the two
actions
as well as
small
points
of difference
to their
general
similarity.
the basis
of less complete
pharmacological
investigations
therapeutic
uses have
been
suggested
and tried for CytiThus
Radziwillowicz
tried
it in cases of migraine
with low
blood-pressure,
experiments
apeutically
and
lend no
valuable.
Bradford
support
For
be used
in place
of nicotine,
in its easy
preparation,
with
cheaply
can be
distilled
tried
ulexine
as
to the suggestion
of its
physiological
investigations
and would
have
certain
large
yield,
from
the
being
it
Our
thercould
advantages
readily
and
obtainable
Laburnum
seeds;
in the ease with
which
it
purified-the
alkaloid
itself
crystaffises
well and can be
under
reduced
pressure;
and in its comparatively
great
stability.
20 Barger
a diuretic.
and
Dale:
Journ
of Phys.,
XLI,
p.
35,
1910.
