THE

JOURNAL

OF

Copyright

PHARMACOLOGY

1975

THE

by

EXPERIMENTAL

AND

The

Williams

&

THERAPEUTICS

Wilkins

ACTIONS

EFFECTS

OF

OF

CENTRAL

CATECHOLAMINERGIC

E.

SETLER,

and

Division

of

U.S.A.

PERIPHERAL

G.

DRUGS

PENDLETON

AND

FINLAY

Development,

Smith

SmithKline

Kline

Corporation,

Accepted

No.

in

AND

BLOCKING

ROBERT

ELIZABETH
Research

DOPAMINE

AND

RECEPTOR

PAULETTE

192,

Printed

CARDIOVASCULAR
THE

\c1.

Co.

and

French

Laboratories,

Phikidelphia,

for publication

Pennsylvania

September

28, 1974

ABSTRACT
SETLER,

PAULETTE

vascular

actions

minergic

receptor

The cardiovascular
special
attention
receptor

cardiac

of

low

the

dogs.
studies,

Cardiac

pimozide,
blood
mediated
effect.

In
by

DA

Therefore,

cologically

Dopamine

the

total

renal

effects

studied
in
to inhibition
iv.

from
force.

9 to 81
Propranolol

injection

of DA

in the

central

and

increased.

pressure,

Send

a number
and

and

present

of dose-dependent
system

hemodynamic
vascular

re-

but

resistance

renal

(an

effect

bulbocapnine
may

not

and

emesis
receptors

and

effects

dilation

and

requests

Ph.D.,
Smith
Kline
sion of SmithKline
den St., Philadelphia,

June

had

no

be pharma-

to:

& French
Corporation,
Pa. 19101.

are

not

of.,

documented
establish
receptor

The

1965

detailed
one

effect
to be

dopamine,

and

of

on a
vaso-

IcNay

of various
antagonists

of

a
only

a direct
appears

effects

receptor
actions

well

require(l
to
cateeholamine
702

et
The

as

1964).

mediated
by
receptor

1966).

cardiovascular

Paulette
E. Settler,
Laboratories,
Divi1500 Spring
Gar-

undertaken

Eble,

(McNay,

catecholaminergic

12, 1974.

was

1966;

these
effects
dopamine-specific

on

vasodilation

1963 ; McNay

study

Goldberg,

including

chronotropic

Goldberg,

for publication
reprint

In
renal

Bulbocapnine,

whereas

dopamine

effect

Bulbocapnine

propranolol-treated

vascular

system)

pressor
increases

depressor

apomorphine-induced

central

3 tg/kg

doses.

resistance

Goldberg,
Received

the
high
and

blood

and

pro-

1 and

to DA.

nervous

vascular

at

response

abolished

1975.

j.tg/kg
produced
inhibited
the

depressor
were

702-712.

with

phenoxybenzamine

flow

on

of

cardio-

cateehola-

anesthetized
dogs
by catecholarninergic

potentiated
effect

peripheral

blood

pimozide

peripheral

vasoconstriction

heart,

and
dogs,

cardiovascular

inotropic

(McDonald

on the

192:

Ther.

rapid

pressor

in both

pressure,

receptors
the

DA

peripheral

distinct.

exerts

upon

the

conscious

by

the

no effect

blood
output

were
effects

The

FINLAY:

and

Exp.

phenoxybenzamine

of

had

ELIZABETH

of central

Pharmacol.

(DA)
of these

reversed

effect

abolished
flow.

J.

given

whereas

reduced

AND

effects

whereas
doses
cardiac
contractile

and

however,

the

durgs.

Dopamine

DA

depressor

DA

sistance.

the

of

PENDLETON

effects
of dopamine
the susceptibility

drugs.

Pimozide,

G.
and

blocking

contractility
doses

blocked

effects

ROBERT

depressor
responses
and increases
in

in

positive

to

blocking

duced
resposes

E.,

of dopamine

and

types
on

of
the

however,

such

evidence

the
existence
type
(Ariens,

of a
1964).

is
new
The

DOPAMINE

1975

prese1t
evaluation

tudv

was
undertaken
of the cardiovascular

pamine,

particularly

tibility

of

these

with

as a
actions

regard

effects

to

to

RECEPTORS

detailed
of do-

the

receptor

blocking

Methods
Mongrel
dogs of either
sex weighing
between
10
and 19 kg were anesthetized
either
with 25 mg/kg
(iv.)
of thiopental
sodium
(Abbott
Laboratories,
North
Chicago,
Ill.) followed
by 125 mg/kg
(i.v.)
of a-chloralose
(Fisher
Scientific
Company,
Pittsburgh,
Pa.) or with 25 to 30 mg/kg
of pentobarbital sodium
(Lentz)
.
Supplemental
doses
of a..
chloralose
or pentobarbital
sodium
were given
as
required
to maintain
surgical
anesthesia.
Statistical
analysis
of the data indicated
that there
were no
significant
differences
in the
responses
to dopamine
between
animals
anesthetized
with thiopentat plus chloralose
and the animals
anesthetized
ith
pentobarbital.
Therefore,
the animals
are discussd
as a single
population
throughout
this
paper.
Each
dog was artificially
ventilated
with room
air at a rate of 14 strokes/mm
and a tidal volume
of 10 to 12 ml/kg.
Blood
pressure
was recorded
from
a cannulated
femoral
artery
via
a Sanborn
transducer
(model
267 BC)
and a Sanborn
preamplifier
(model
350-1100B)
; the
blood
pressure
signal
was also fed into a cardiotachometer
(Sanborn modcl
350-3400A)
to monitor
heart
rate. The
chest
was opened
at the 3rd or 4th intercostal
space.
In the experiments
in which contractile
force
was measured,
a Walton-Brodie
strain
gauge
arch
was sutured
to the outer
wall of the right ventricle.
The response
of the gauge
was linear
and
care was
taken
to demonstrate
diastolic
tension
prior
to
the
experimental
recording.
For
hemodynamic
studies,
a blood
flow
transducer
(Statham
SP
7515 ; 12-15
mm
inside
diameter)
was
placed
on
the ascending
aorta
before
the first arterial
branch
exclusive
of the coronary
arteries.
The left renal
artery
was exposed
by a flank
incision
and
a
blood
flow transducer
(Statham
model
SP 7515;
2-3
mm inside
diameter)
placed
on the artery
at
a point
between
the aorta
and the bifurcation
of
the renal
vessel.
The blood
flow transducers
were
precalibrated
and
provided
with
an automatic
nonocelusive
zero ; this
zero-flow
reading
was
checked

at

regular

intervals

throughout

The

aortic

equivalent

ances

of

were

blood

flow

the

cardiac

calculated

the

experi-

blood
flow transducer
on a flowmeter
(Sta-

was

considered

output.

according

to

Vascular

to the

mean

Resistance
units)

(resistance

blood

formula:

be

the

resist-

Mean
arterial
blood
pressure
diastolic
pressure
plus one-third
sure. All blood
pressure
values
to mean
levels.
After
surgical
animal,
a 30-minute
equilibration
lowed
before
the experiment
was
Two

general

blood
(mm

suscep-

agents.

meat.
The signal from each
was monitored
individually
tham model
SP 2202).

703

series

of

pressure
Hg)

flow

(ml/min)

was calculated
as
of the pulse presin this report
refer
preparation
of the
period
was albegun.

experiments

were

per-

first, the effects

of dopamine
given
by rapid
iv. injection
on blood
pressure,
heart
rate and cardiac
contractile
force
were measured.
Doses
of dopamine
were given
in ascending
order
at 5- to 15-minute
intervals.
After
the sequence
of dopamine
doses,
either
phenoxybenzamine
(5
mg/kg)
or propranolol
(2 mg/kg)
was infused
intravenously
over
a period
of 10 minutes.
Ten
formed.

In

minutes

the

after

the

end

of

the

infusion,

the

se-

was given
as before.
Bulbocapnine
(1-3 mg/kg)
or pimozide
(1 mg/kg)
was infused
intravenously
for 10 minutes
at the
end of this sequence
and 10 minutes
later a third
series
of dopamine
injections
was given.
In some
experiments
with phenoxybenzamine-treated
dogs,
the initial
series of dopamine
injections
was omitted. The total elapsed
time for the experiments
in
this study was approximately
3% to 5 hours.
The
effects
of bulbocapnine
on blood
pressure
responses
to epinephrine
and isoproterenol
were
also
measured
in four
additional
dogs.
The
two
adrenergic
agonists
were
given
alternately
at 10minute
intervals,
each
at least
twice,
before
and
after
a dose
of 3 mg/kg
of bulbocapnine
administered
as described
above.
In the second
series
of (xlwriments,
the effects
of dopamine,
given
by rapid
injection
or slow infusion,
on blood
pressure,
blood
flow and vascular
resistance
were studied.
Doses
of dopamine
were
given
in
ascending
order
by rapid
injection
at
10-minute
intervals
or by
10-minute
infusion
(1
mt/mm)
at 40-minute
intervals.
In some
experiments,
only
one
dose
of dopamine
was given,
before or after
infusion
of bulbocapnine
or pimozide. Each
of these
experiments
required
6 to 8
hours for completion.
It should
be noted
that
although
the duration
of each
of the above
experimental
series
with dopamine
was long, no significant
changes
in the dopamine
responses
were noted
during
a similar
interval
in control
dogs
in which
vehicle
was
infused
in place of drug.
Bulbocapnine
and pimozide
were also tested
for
the ability
to prevent
apomorphine-induced
emesis. Apomorphine
was given
to conscious
mongrel
quence

d5

of

at

dopamine

a dose

of

doses

0.1

mg/kg

s.c.,

and

the

animals

SETLER

704
were
riod

ET

observed
for
of 40 minutes.

incidence
of emesis
for a peThe dogs responding
to apomorphine
(>90%
of the dogs screened)
were then
divided
into groups
of four each and on a subsequent
test day one group
was given bulbocapnine,
3 mg/kg
i.v., followed
10 minutes
later
by apomorphine.
Two other
groups
were given pimozide,
0.025 mg/kg
iv., followed
in either
10 or 60 mmutes by apomorphine.
Control
groups
of dogs were
given
the vehicle
for the iv. test drugs
followed
by apomorphine
at the
times
indicated
above.
All animals
were
observed
for 40 minutes
after
injection
of the emetic.
In the
studies
described
above,
all drugs
were
given
into
a cephalic
vein.
Infusions
were
given
at the rate of 1 ml/min
using a Harvard
infusion
pump
(model
940).
Pimozide
was dissolved
in
12%
tartaric
acid ; all other
drugs
were
given
as
solutions
in
0.9%
NaCl.
Ascorbic
acid
(0.2
mg/ml)
was added
as a preservative
to the solutions
of dopamine,
isoproterenol
and epinephrine.
The drugs used were : bulbocapnine
hydrochloride
(Smith
Kline
and French
Laboratories,
Philadelphia,

Pa.),

dopamine

hydrochloride

(Sigma

Effects

of

caused

a biphasic

shown

a slight

while

doses

immediate

doses
tractile
in

pressIlre.

in

only

that

blood

are

at
these

pressure

not

by

changes

slight

alterations

force.

The

effects

dogs

are

blood

1 1 mm

tions

were

to

illustrated
of

with

the

The

dose

plateau

34.1%

reduction

at

the

the

of

with

results
1 mg/kg

blood

mine

were

slightly

Bulbocapnine

pletelv

abolished

3 mg/kg

of hulbocapuine

given

responses

to

and

at

pres-

potentiation
high

of
the

of

dopaheart

dose
that

the

effects

(132

peak

were
effect

In
of

separate
single

at

of

the

pressor

of

did
6

reduced
in ani3 mg/kg,
depressor

and

a slight

effect

of the

experiments
of

1 mg/kg

of

and that
in the
4 the high doses
administered

after

of bulhocapnine

experiments,
.ses

blood
as
152

and,

effect

close

com-

to dopa-

1 mg/kg.
response

probably

of this

iv.

uhsequent

inhibitorv

Hg)

Hg)

of dopamine

residual

re-

4 mm

resting

9 mm

was short-lasting
illustrated
in figure

dopamine

passed.

doses

the

propranolol.
dogs.
I mg/kg

raised

at
depressor

of dopamine.

bulbocapnine
experiments

by

all

with
inc

after

inhibition

of the

showed

with

4.
in

pressure

mg/kg

phenoxybenzamine

caused

response

109

Hg) . Bulbocapnine,
dopamine-induced

mals

indicating

significantly

(88

the

126

-*

depressor

pressure

phenoxy-

pretreated

blood

in the dogs pretreated

phenoxybenzamine-treated

or

lrsin clogs

10 minutes

at

the

blend

the

:it

the
5

Phe-

studied

dogs
:

was

shown
in figure
iv..
caused
a rise

begun

(120

a marked

blood

in

infusion,

produced

changes

are

dopamineforce.

propranolol

pressure

injections

elevated.

effect

were

1 to

reached
pressure.

of l)rol)r:nolol

bulbocapnine
mained

from

blood

on

These
at
i.v.

doses

bulbocapnine

either

magnidirectly

depressor

to dopamine

was

the

response

mean

benzamine.
Bulbocapnine.
2 n/kcz

of

as

response
varied

the

pretreated

resting

of the
and,

also
reduced
the
in cardiac
contractile

responses

injec-

component

range

in

7 to

eliminated

conditions,

maximum

effects

140

response

9 .tg/kg

2.
the

dopamine

depressor

these

noxvbenzamine
induced
increase
sure

3, the

in

and

in pro-

reduced

from
time

pressor

depressor

pg/kg,

the

in figure

iv.,

was

Under
the

of dopamine

the

dopamine

potentiated.
tude

at

in figure

pres-

or on

diagrammed

pressure

Hg

begun.

response

Hg)

5 mg/kg

mean

1 10

i.v.,

blood

to dopamine
but greatly
all doses
of dopamine
on

Phenoxybenzamine,
resting

resting

5 mm

192

2 mg/kg

on

120

responses
effects
of

in

rate

produced

to

a fall

cardiac
con1. Included

of peak
are

contractile

the
an

propranolol,
effect

pranolol-treated

mm

pressure

pressure,

heart

time

pro-

produced

increased
in figure

changes

secondary

blood

at 81 pg/kg,
blood

as

3 tg/kg

j.g/kg

those

the

(122

of bulbocapnine

pressure

followed

Dopamine,

occurred
change;

rate.

27

response

1 are

blood

in mean

and

pressure.
injection,

of 1 and

from
9 to 81 jig/kg,
force,
also shown

sure
mine

elevation

figure

which

in

reduction
of

blood

intravenous

1 . Doses

pressor

marked

on
rapid

change

in figure

duced

blood

by

sure

with

significant

blood
pressure
reduced
the

mine
In

dopamine

given

no

The

Results
Dopamine,

Pretreatment
had

Chemi-

cal Company,
St. Louis,
Mo.),
epinephrine
hydorchloride
(Sigma),
isoproterenol
hydrochloride
(Alles
Collection)
, phenoxybenzamine
hydrochloride (Smith
Kline
and
French),
propranolol
bydrochioride
(Aldrich
Chemical
Company,
Inc.,
Cedar
Knotts,
N.J.)
and pimozide
(McNeil
Laboratories,
Inc.,
Fort
Washington,
Pa.) . Statistical
analysis
was by methods
described
by Snedecor
(1956)
.
Each
variability
term refers
to the standard error
of the mean.
Significance
of difference
between
groups
was calculated
using a paired
Students t test.

Vol.

AL.

dopamine

the

had
depressor

were

corn-

1975

DOPAMINE

#{149}80

RECEPTORS

705

#{149}60
.40

-r

.20

#{149}20

2:

-20

CONTROL

144

CONTROL

7 mmHg

132

: 10

heatsmin.

____________________

-40
1 0

3.0

DOSE

9.0

OF

27.0

81

1.0
DOSE

#{149}

DOPAMINE

3.0

90

OF

270

DOPAMINE

810
pg/kg

I V.

a
0

z
4
I

CONTROL
10

30

DOSE

90

OF

DOPAMINE

270

810
g/kq

I V

Fia. 1. Effects
of
represents
the mean

dopamine
on blood
pressure,
heart
rate and cardiac
contractile
force.
Each
point
of 12 observations
; standard
error
of
the
mean
is indicated.
The
control
value
shown
for
each
parameter
is its absolute
level
immediately
before
the
first
dopamine
injection.
a. Maximum
changes
in mean
blood
preure.
Where
biphasic
responses
occurred,
values
are shown
for both
pressor
(#{149}---#{149}) and depressor
(
#{149})
effects.
b. Change
in heart
rate
occurnng
at
the time of maximum
change
in blood
pressure.
c. Maximum
change
in cardiac
contractile
force. Contractilc
force expressed
in arbitrary
units equal
to the
amplitude
millimeters
of the recorded
signal.

pared

immediately

1 mg/kg
treated

dogs.

nine
the

under
nine

81 .cg/kg
illustrated

circumstances,
progressively

of low
petitive

closes which
antagonist

mg/kg
the

the

time
At

(1

the

tg/kg

whichever
test

the

conditions,

experiments

effect

of high

of

in

were
did

not

experiments.

of

experiment,

each

or isoproterenol
was

adequacy

appropriate,
of

4.

the

by

blockade

was

than

due
specific

than

of a comThe
effects
long-lasting

diminish

to

was
adrenergic

complete

adrenergic

are

was

and

shown

in figure
study

pressor

nificantly

altered

beg/kg)

of the

in each
case it was submaximal,
and short-lasting.
Bulbocapnine
significantly
reduced,
but

&g/kg

to

dose

response

was

to
3 mg/kg

to

epiand

agonists

selected

be-

reprodugiven
at 3
did not
re-

epinephrine.

to isoproterenol
after

non-

of bul-

measured

in this

response

receptor

5. The
(1

or

responses
were

cause
cible

depressor

given

pressure

depreswas

effects

used

the

propranolol;

effects
The

isoproterenol

epinephrine
i.v.),

blocking
explored.

blood

on

nephrine

or

in all cases.

that
inhibition
of the
dopamine
by bulbocapnine

actions

verse
(1

beta

bocapnine

mg/kg

during

phenoxybenzamine

The possibility
response
to

Even

of dol)amine

of these

iv.)

figure

however,
bulbocapless inhibition
of the
doses

blockade

sor

depressor

of dopamine

would
be expected
(Ariens,
1964)
effect

course

after

bulbocap-

of the

bulbocapnine

inhibitory
end

10 minutes

inhibition

of 9, 27 and
these
produced

and

these

greater

depressor

of

and

in phenoxybenzamine-

Under

produced

effects
in

before

of bulbocapnine

was
of

The
not

sig-

bulbocap-

nine.
Because

antagonism

by

bulbocapnine

of

do-

706

SETLER

ET

Vot

AL.

192

+100
81

81

I::

I-

+20

--I-

zo

CONTROL

-20

CONTROL-120Sm.n

#{163}

117 10

bssts/min.

1.0

1.0
3.0
9.0
27.0
81.0
DOSE OF DOPAMINE:
agk IV.

3.0

9.0

27.0

DOSE OF DOPAMINE:

81.0
gig/kg

IV.

<81

20

CONTROL

12 0.5mm

Hg

1.0
3.0
9.0
27
DOSE OF DOPAMINE: pg/kg IV.

Fia. 2. Effects
of dopamine
pretreated
with 2 mg/kg
(iv.)
the standard
error
of the mean
level immediately
prior
to the

pamine-induced
clopamine
receptor
dopamine
OU

blocker

(Janssen

had

a slight,

the

depressor

but

response

beuzamine-treated
This

slight

inhibition

effect
effect

but

not

significant

sor

resl)onse

also

seen

not

pg/kg

zamine-pretreated

of

effect

(2

dogs

mg/kg
of the

of dopainine

in five
(R.

G.

ing

on

in phenoxy4.

a non-

( -22%)

factor

was
these

iv.)
response

did
to

phenoxyben-

depressor
.tg/kg)

each

force in dogs
observations;
is its absolute

parameter

thereby
of pimozide

above
studies

doses
reduced
vascular

dose.

of
total

of

were

mine

values

table
were

I . When
given
by

dopamine
peripheral

minutes,

the

3 g/kg/min
tive

in figure
differences,

responses
transient.
for

elevated
The

were

9
and

cardiac

effects
effects

frequent

shown
of each
and

base-line,

parameter

6,

and

all

predopaare

listed

in

same
doses
of dopamine
intravenous
infusion
for 10

steady-state
were

In

in figure
(1,
3
resistance

and

The

each
the
slow

dopamine.

illustrated

resistance

Biphasic

ruling
out
as a contribut-

results.

effects

output
and renal
blood
flow.
in figure
6 are the predominant

shown
un-

to the

hemodynamic

changes

vasodepres-

Pendleton,

for

Hemodynamic

renal

figure
vasode-

probably
slight

shown

cardiac
contractile
the mean
of five

published
observation)
beta blocking
effect

ex-

1 mg/kg

in

of the

antagonism

value

the

of isoproterenol
of pimozide
in

Propranolol
any

be

dopamine

inhibition
0.5 jig/kg
1 mg/kg

after

produce

1 to Sl

the

nerv-

would

shown

by pimozide
was
because
a similar
to

experiments.

of

control

due
to
a potent

significant,
as

heart
rate and
point
represents

injection.

central
,

to dopamine
dogs

iressor
specific

is

effect.
at a dose
not

The

pimozide,
1968)

a].,

pressure,
Each

dopamine

in the

et

l)ected
to have a similar
Pimozide
when
given
i.v.

is indicated.

first

vasodepression
blockade,

receptor

system

on mean
blood
of propranolol.

responses

qualitatively

to
similar

6 although

there

especially

in

were
blood

1 and
to

to

those

quantitapressure.

1975

DOPAMINE

RECEPTORS

707

a
12
81
a

+20

:I__

a
a
4
I
I

+20

1
81

-40.

CONTROL-110llmmHg

__10

IONTROL

3.0
9.0
27.0
81.0
OF DOPAMINE: p9/kg IV.

DOSE

13 beats/mm

188

___________

1.0

3.0

9.0

27.0

31.0
IV.

DOSE OF DOPAMINE: pg/kg

b
81
U

a
0

a
U
U

+40
0

a
4

+20

C,

10

CONTROL

4
I
U

1.0

3.0

9.0

27.0

0.8 mm

18

Hg

81.0

DOSE OF DOPAMINE pg/kg IV.

Fir.. 3. Effects
of dopamine
on mean
blood
pressure,
heart
rate
pretreated
with 5 mg/kg
(i.v.)
of phenoxybenzamine.
Each
point
vations;
the standard
error of the mean
is indicated.
The control
its absolute
level immediately
prior to the first dopamine
injection.

When

given

for

dopamine
panied

and

an

resistance

dilation

was
in

renal

dynamic

are

the

presented

of

by

the

in figure

ended.

These

infusion

of dopamine

renal

vasodilation.

The

itive

response

dogs

are

was

not

least
included

a fall

renal
The

among

of

failed

criterion
in

10%.

termined

to profor

a pos-

vascular
nonresponding

those

the

dogs

of
with

(MoGiff

discussed

re-

in

of these
the

group

dopamine,

jg/kg/min),

et al.,

1969),

a beta

pamine

was

proterenol
in

two

an

caused
of

three

the

effective

dopanonre-

administered
vaso-

isoproterenol
agonist.

renal

Nei-

vasodilation

failed

to respond

to

animals

in which

do-

renal

significant

dogs

of
unde-

some

a renal

receptor

which
in

variability

and

and

produced

refailure

situation,

intravenously

of dogs
whereas

test

was

2.5%,
the

to

responding

(0.2

drugs

se or to

the
in

A1

due

per

compared

resistance
15.7

whether

was

variable

prostaglandin

ther

and

determine

response

was

dilator

2.5%

of dopamine

sponding
to

responses

(35%)

tested,

at

renal

peripheral

nonresponding

produced
periphto that
seen in re-

equivalent
(total

To

effect

mine

lasted
began

the

of

7. In

dopamine

16.0

the

contractile
force in dogs
the mean
of seven obsershown
for each parameter
is

in figure

shown

dogs

an
the

value

(0.05 tg/kg/min),

7.
proportion

dogs

of

and

sponding
spectively).

hemo-

dopamine

infusion

duce

sistance

to

The

and

at
vaso-

by

overriden

above

cardiac

represents

animals,
however,
eral vasodilation
decreased

vaso-

transiently,

response

infusion

significant

renal

pressure.

produced

changes

of
accom-

dopaminergic

was

perfusion

duration
when

In

the

vasoconstrictor

increased

abate

but

except

kidney

autoregulatory

the

reduced

observed,

the

jg/kg/min

response

increase
in cardiac
output
renal
blood
flow ; total
pewas

not

pressor

Conceivably,

dose.

dilation

for

minutes,
a

by a marked
increase
in

ripheral
this

10

produced

and

vasodilator,
renal

and

iso-

vasodilation

prostaglandin

AL

708

SETLER

ET

AL.

Vol.

19

8
+20

-I

--l-

CONTROL

-l264m.ni4

-I-----1

-20

CONTROL
l20+Smm

a
H,

0
5

1.0

3.0

9.0

DOSE OF DOPAMINE:

ps/k,

IV.

CONTROL

CONTROL125+4mmHg

13O

mm Hg

a
4

a
4

a
0
5

3.0

FIG.

Changes

of

in

(lOSelV

mean

blood

niimieked

three

dogs.

Thus,

SO(lilatiofl

front

caused

l)\

perhaps

effect

the

unreliability

animal

The

of

81.0

sg/kg

IV.

the

surgical

niust

be

system,

trauma

effects

of

bulbocapnine

responses

of 3 j.ig/kg/miii

of

8.
affect

rate

and

on

the

(lopamine-illduce(l
cardiac

mg/kg

iv.,

spouse

to

had
clopamine

output.
no

are

shown
reduced
but

increases
Pimozide,

on

10 or

70

10

did

in conscious
1

mm-

22

only

in

any

other

blood
pressure,
Hg).
Pimozide

mm

resting

22

administration,

change

mean

re-

137

heart

rate

(119
signifi-

(140

15

9 heats/ruin).

for

re-

significanfly

no significant

reduced

Bulbocapnine

and

antagonism
of

(151

of dopamine

including
116 11

106

close

itself

flow

time

was

there

in
the

at
the

blood

at the

cantlv
.-*

in heart
given

effect
either

on

infusions

vasculature

significant
giveti

pimozide

10-minute

dopamine
markedly

Bulbocapnine

of ciopamine

not

and
to

pretreated

Bulbocapnine

renal

mi/mm)
l)lIt.

changes

dogs
(---).

later.

parameter

the

to

pressure

in

duced

va-

test

blood

utes

in all

of renal
animal

the

dopamine

niic

effects

to

on

by

of dopamine

within

result

pimozide

produced

vessel.

hemoclvna

figure

and

pressure

the

variability

as

renal

bulbocapnine

27.0

produced
by dopamine.
with 2 mg/kg
of propaitolol
before
(S---)
and after
1 mg/kg
of bulbocapnine
Each
point
is the mean
of
five
observations
; standard
error
of the mean
is indicated.
b. Decrease
in mean
blood
pressure
produced
l)y (lopamine
in nine
(logs pretreated
with 5 mg/kg
of phenoxvhinzamine
1)efore
(-)
and
after
1 mg/kg
(S-#{149}; N
5) or 3 mg/kg
of bulbocapnine
(Q...._._Q : .V = 4) e. Decrease
in
nTseali blood
pressure
produced
by dopamine
in dogs
pretreated
with
5 mg/kg
of phenoxybenzamine
l)efore
(#{149}-#{149}) and after
1 mg/kg
of pimozide
(Q-#{149}-#{149}-O)
.
Each
point
is the mean
of four 01)servations.
The control
values
shown
refer to the absolute
mean
blood
pressure
immediately
before
the
first dopamine
injection.
a.

4. Effects

9.0
DOPAMINE:

OF

DOSE

of
dogs.

3 mg/kg

pimozide

were

also

tested

apomorphine-induced
Bulbocapnine
iv.

morphine

at

a dose

occurred

in all

four

minutes.

Pimozide,

10
of

was

minutes
0.1

animals
in contrast,

emesis
given

prior

mg/kg

s.c.

within

the

when

at

to

apo-

Emesis
next

given

40
at

DOPAMINE

1975

RECEPTORS

709

BULBOCAPNINE

3 mg/kg mv.

fl,50.
I F1

12
a

ISO.

a
a
C,

I
U
5

5. The effect of bulbocapnine,

3 mg/kg
changes
in blood
pressure
produced
epinephrine,
1 pg/kg
iv.
or by isoproterenol,

iv.,
by
1

jsg/kg

four

FIG.

on

the

i.v.

Each

observations.

bar

represents

<

*})

the

mean

of

.05.
20

dose
of 25 pg/kg,
pletely
abolished

in
the

three
emetic

of

four
response

later

and

dogs
cornto apo-

2s

30

morphine

given

dogs

abolished

phine

given

10 minutes
the

emetic

60 minutes

response

in all
to

four

apomor-

later.

,0

30

90

.q

DOSE OF OOPANINI

hq I V

Discussion

Fia.
The

results

of the

experiments

show

that

(1-3

&g/kg)

of dopamine

the

anesthetized

dog.

caused

small,

by

rapidly

fall

was

due

resistance;

creased.

Not

eral

of the

vasodilation

total
these
increases
When

in

renal

without

an

sponse

to

was

flow

in

pe-

was

of

fall

dopamine

the

fall

increased

heart

pressure,

by

BP

(O-O),

(0-0),

total

(L-),

renal

vascular
represents

change
produced
i.v. injection)
on

rapid

cardiac

peripheral
blood

flow,

resistance,
the mean

output,

resistance,
RBF

RVR
(U-U).
of six observations.

by
mean

CO
TPR
and
Each

in

measured.
renal
produced

blood

pressure.

a pressor

rate

blood

renal
point

maximum

in
and

infusion,

in

The
(given

in-

were
caused

6.

dopamine

of periph-

were
by

given

appreciable

and

fall

sites

vasodilation

doses

pressure

output

regional

blood

peripheral

High

to

in

resistance
were
identified
but
renal
vasodilation

dopamine

and

in blood

contributing

peripheral
experiments,

doses

hypotension

cardiac

all

here

administered
cause

The

dopamine

ripheral

described

and

TABLE

Predopainine
basal valuesfor
heinodynarnic
paranm eters
The value for each parameter
was obtained
immediately
before
the first
injection
or infusion
of
dopamine.

re-

contractile

Basal
\TaIlIe
.V = 20

Parameter

force.

The

effects

of

dopamine

attenuated
by propranolol
mine
causes
stimulation
nergic

receptors.

amine

of

suggests
rect

action

uptake
berg,
of

the
that

nephrine
thetic

The

of

is, at

dopamine,

displaced
nerve

reduction

inotropic
this

on

from

terminals

into

heart

were

that.
beta

dopaadre-

by phenoxybenzeffect

least

of
in

dopamine

part,

mediated

an
by

postganglionic
within

of dopamine
into these
1972) . Phenoxybenzamine

catecholamines

the

indicating
of cardiac

synaptic

the

mdi-

norepisympa-

heart

terminals
reduces
vesicles

after

Mean

blood

(mm

pressure

136

48

3.77

121.35

0.01

16.40

0. 18

Hg)

Cardiacoutput

1637.08

(mt/mm)

Total

peripheral

resistance

0. 09

(units)
Renal

blood

flow

167.96

(ml/min)
Renal

vascular

(Golduptake

(units)

(Iver-

a Value

for

resistance

left

renal

1 . 15

artery

only.

710

SETLER

ET

AL.

that

Vol.

bulbocapnine

attenuation

does

of

nergic

blocking

activity.

pamine-induced
therefore,
is

Goldberg

bulboca

re-

of

specific

observations

those

and

pnine

vasodepressor

These

(1963)

of do-

activation

with

adre-

attenuation

this

by

receptors.

beta

by

that

agreement

nonspecific

nor
The

mediated

dopamine
general

produce

vasodepression

indicates,
sponse

not

vasodepression

.192

are

in

McDonald

of

Tseng

and

and

Walaszek

(1970).
In

the

hemodynamic

abolished
had

no

significant

increases

in

contrast

to

on

rate

ide,
In . 12)

In . 33)

In . 10)

DOSE OF DOPAMINE

,/k/m.n.

mm .

In, 10

1965)

and

sure

may

inotropic
sor

also

by

of

doparnine

the

to

the

1967).
The
the dog are

was

to

by

reversed

in
of

The

shown

an

induced

treatment

phenoxybenzamine.

The
fected
benzamine

and

bocapnine
receptor

of dopamine
potentiated

inhibited

by

has been
shown
antagonist
because

central

nervous

capnine

also

activity

(van

effectively
sion

1971)

depressor
effect
by propranolol,

system

of the

by

mg/kg

an

intact

alpha

1965)

pressor
of

response

study
response

bulbocapnine.
to

isoproterenol

Bulbo-

doses

by

a partial

vasodepresto

in-

indicated

and

of

of

discrepancy

served

in

dopamine
ture

are

the

floor

and

Kai-

of phenothiazines

Yeh

made

markedly

reported
receptors
pharmacologically

here
in

order
of activas inhibitors
of
from
in

blocking
marked

specificity
suggest

peripheral
distinct

in
1965).

bulbocapnine

strongly
the

the
most

activity

(Janssen,
of

to

of the dopamine
nervous
system

system

comparison

Yeh,

attempt

observed

receptor
the

and

no

different

effectiveness

and

dopamine-

(Goldberg

nervous
the

at.,

receptors

attenuate

but the rank

antagonists

dopamine

This

in

(Zirkle

potencies
for central

was

of

pimozide

epinephrine

Preservation

Goldberg

central

acti-

et

dopamine

to

vasodilation

the

postrema

a number

renal

order

in

dopa-

direct

(Anden

system

shown

effects
in the dog,
ity of the dopamine

tests

which

and

vasodilation

central
a

block

the relative
antagonists

rank

adrenolytic

at

dopamine-induced
in our

Bul-

1965)

used

blocked
is gen-

1974).

been

evaluate
receptor

to be a dopamine
of its effects
on the

some

Rossum,

evidenced

hibition

bulbocapnine.

(Ernst,

possesses

inhibit

as

was unafby phenoxy-

which

Koe,

also

of the

area

nervous

Haloperidol
have

dose

ventricle
and
by antipsychotic
and
Wang,
1953 ; Peng,
1963;

central

1974;

the

pimoz-

effects
of apomorphine
in
by l-dopa
and are abolished

of the

1965)

the

ser,

prebe

destruction

of the
fourth
drugs
(Borison

at

while

completely
dog. Emesis

receptors

emetic
shared

for

nervous

Bulbocapnine,

of

one

by-

tested

central

apomorphine,

dopamine

Janssen,

such
pres-

reduction

phenoxybenzamine.
effect,

mo-

indirect

Other
factors
artery
perfusion

contribute

adrenergic

with

reduces

effects

effect

alpha

thus

of dopamine.
of coronary

be

of

In

on dopaof pimozand

effect

1/40

to

effects
of

true.

studies,
in the

but

output.

when

in the

significant

mg/kg,

accepted

vator

Yet

was

no

0.025

minergic

by

tropic
action
as reduction

at

erally

Fio. 7. The effects

of dopamine
(infused
for 10
minutes)
on mean
blood
pressure,
BP (fl-El),
cardiac
output,
CO (O-O),
total peripheral
resistance,
TPR
(L-L),
renal blood
flow, RBF
(#{149}-#{149}) and renal
vascular
resistance,
RVR

sen,

opposite
had

the
cardiovascular
apomorphine
emesis

I V.

cardiac

vasodilation

negligible.
activity

the

3 mg/kg,
9.0

or

of bulbocapnine
vasodilation,
the effect

was

system,

tion

dopamine-induced

effect

antidopaminergic

3.0

on

dopamine-induced

potension

10

bulbocapnine
vasadila

effect

heart
the

mine-induced

ide

study,

dopamine-induced

oband
that

vasculafrom

dopa-

DOPAMINE

1975

RECEPTORS

+40

+20
C,

a
4

+10

I
U
5

-10
CONTROL

-20

10 POST-BULBOCAPNINE
N=7

C,

4
I
U

CONTROL
10

POST-PIMOZIDE

70

POST-PIMOZIDE

N=4

RRF

RVR

CO

TPR

BP

HR

Fii;. 8. The effects

of bulbocapnine,
3 mg/kg
iv., and pimozide,
1 mg/kg
iv., on the hemodynamic
cliaiiges
J)r(Iuc((1
during
t
10-minute
infusion
of dopanine,
3 /zg/kg
iv.
RI3F,
renal
blood
flow. HVR,
renal
vascular
resistance
: CO, cardiac
output
; TPR,
total
peripheral
reit:tncc
; BP,
blood
possure
HR, heart
rate. P < .05 (paired
Students
t test).

mine

receptors

in

the

central

nervous

Ijart icula rlv t hoe in I he inedullarv

tor trigger
zone.
Alternatively,
because
of differential
tribution,
may

intravenously
have

in the

easier

central

access

reason

and

to suspect

expert

and

than

the
There

Sheldon

dis-

pimozide
receptors
to receptors

is the

authors

assistance

Mr.

193-230,
EBLE.
J.

reverse
could
be
is, however,
no a
this

The

technical

Woodward

drug

dopamine

that

Acknowledgment.
the

to
system

in the
vasculature
true
of bulbocapnine.
priori

(henoreeel)-

administered

nervous

BonisoN.
H.
pharmacology

system,

case.

acknowledge
of

Mr.

Paul

W.

S. Sherman.

References
ANDEN,

N.

H#{212}KFELT,

E.,

RUBENSON,

T. : Evidence

for

A., FUXE,
dopamine
J. Pharm.

stimulation
by apomorphine.
cot. 19: 627-629,
1967.
ARIENS,
E. J. : Molecular
Pharmacology,
Press, New York, 1964.

K. AND
receptor
PharmaAcademic

L.

AND

WANG,

of vomiting.

S. C. Physiology
and
Pharmacol.
Rev.
5:

1953.

N. : A proposed
mechanism
for the depressor
effect
of dopamine
in the anesthetized
dog. J. Pharmacol.
Exp. Ther.
145:
64-70,
1964.
ERNST,
A. M. : Relation
between
the action
of
dopamine
and apomorphine
and their O-methylated
derivatives
upon
the central
nervous
systern. Psychopharmacologia
7 : 391-399,
1965.
GOLDBERG,
L. I. : Cardiovascular
and renal
actions
of dopamine.
Pharmacol.
Rev. 24: 1-29, 1972.
GOLDBERG,
L. I. AND YEH,
B. K. : Attenuation
of
dopamine-induced
renal
vasodilation
in
the dog
by
phenothiazines.
Eur.
J.
Pharmacol.
15:
36-40, 1971.
IVERSEN,
L. L. : The uptake
of catecholamines
at
high perfusion
concentrations
in the rat isolated
heart.
A novel
catecholamine
uptake
process.
Brit. J. Pharmacol.
25: 18-33, 1965.
JANSSEN,
P. A. T. : The
pharmacology
of neuroleptic
drugs.
In The
Action
of Neuroleptic
Drugs,
ed. by H. J. Haase
and P. Janssen,
Year
Book
Medical
Publishers,
Chicago,
1965.
JANSSEN,
P.
A. T., NIEMF.GEES,
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