A
POSSIBLE
MODE OF
Tatsuo
OF
CARDIOVASCULAR
DOPAMINE
FURUKAWA,*
IN
ACTIONS
DOGS
NobufUrni ONO, Yukihide
Tamio NAKAHARA
MAEDA,
and Kanji YOSHIHARA
Department of Pharmacology, School of Medicine* and Pharmaceutical Sciences, Fukuoka University, Fukuoka 814, Japan Accepted May 14, 1976
Abstract-A possible mode of cardiovascular actions of dopamine was studied using ephedrine. In the dog pretreated with repeated administrations of ephedrine (total dose, 40 or 80 mg/kg, i.v.) or with combined administrations of ephedrine (total dose, 90 mg/ kg, s.c. and i.v.) and reserpine (2 mg/kg, s.c., 24 hr previously), pressor responses to dopamine were eliminated and reversed to depressor responses whereas depressor responses to dopamine were potentiated. Positive chronotropic effects of dopamine were almost eliminated. Pressor and positive chronotropic effects of tyramine were almost abolished. Sympathomimetic effect of noradrenaline and adrenaline were potentiated while those of isoprenaline were inhibited. In the heart-lung preparation of ephedrine-treated dogs (total dose, 40 mg/kg, i.v.), cardiac stimulating effects of dopamine and tyrarnine were strongly depressed, and those of noradrenaline, adrenaline and isoprenaline were reduced to some extent. In the open-chest dogs, after pretreatment with cocaine (4 mg/kg, i.v.), pressor, positive inotropic and chronotropic effects of noradrenaline were potentiated whilst those of tyramine were inhibited. Those of dopamine were not visibly altered, but depressor, negative chronotropic and inotropic effects of dopamine appeared at small doses. In the ephedrine-pretreated dogs, these sympathomimetic effects of dopamine and tyramine after cocaine were strongly de pressed and those of noradrenaline were inhibited to a certain degree. The results obtained with ephedrine suggest that dopamine differs from other catecholamines and tyramine in the mode of cardiovascular actions.
Studies have shown that sympathomimetic as acting
directly on the receptors,
those with mixed action,
these classifications
in the effects after pretreatment
by chronic
dopamine,
other workers
or cocaine
led to classification
the reserpine-pretreated the concept actions,
reported
of dopamine
was slightly potentiated
was potentiated
in the cat.
and
based on the modifications
in responses
to dopamine
although
(5, 6). Farmer
while the positive
by denervation
amine (2-4).
to be of importance
in order
As results
in
to confirm
it has direct sympathomimetic
(7) reported chronotropic
We have already observed
24 hr after pretreatment
nerve terminals
cocaine or reserpine (1). Concerning
as a directly-acting
of direct and indirect effect, dopamine,
slightly 24 hr after reserpine to dopamine
being principally
are considered
does to some extent act indirectly
on the adrenergic
denervation,
modifications
of dopamine
animals
agents can be classified in their mode of action
acting indirectly
that the pressor effect effect was reduced
that the pressor response
with reserpine
(8), whereas
the re
This work was funded by grants from the Ministry of Education, Japan, and from the Kanae Foundation for Medical Research
sponse was eliminated and reversed to a depressor response (dopamine reversal) after ephedrine tachyphylaxis although responses to noradrenaline and adrenaline were poten tiated, thus suggesting the possibility that dopamine acts for the greater part indirectly (9). The influence of pretreatment with reserpine on responses to sympathomimetic amines has been well documented, however, the influence of pretreatment with ephedrine has been given little attention despite the fact that the influence is not the same. The possible mode of cardiovascular actions of dopamine using ephedrine in the dog was investigated herein. MATERIALS AND METHODS Animals:
Adult mongrel dogs of either sex, weighing between 6 and 18 kg, were
anesthetized with pentobarbital
sodium 35 mg/ kg given i.p. and, in the reserpine and
ephedrine treated animals, 20 mg/kg was given.
Supplemental doses of 3-5 mg/kg were
given i.v. as required to maintain a constant state of anesthesia. Experiments on intact animals: Systemic arterial blood pressure was measured with a pressure transducer (LPU-05-360-0-L11) from the cannulated left femoral artery.
The
ECG was obtained from standard limb leads and heart rate was integrated with a cardio tachometer (Nihon Kohden, RT-2) to give a continuous record. In the experiment on open chest dogs, the cardiac contractile force was obtained from a strain gauge arch (Nihon Kohden) attached to the left ventricle. These parameters were recorded on a multipurpose polygraph (Nihon Kohden, RM-85). The vagus nerves were cut bilaterally at the cervical region 15 min before observation of dose-responses to amines. Intravenous drug injections were given through a polyethylene tube which had been previously inserted into the left femoral vein. Experiments on heart-lung preparations:
The preparation was made principally accord
ing to the method described by Paasonen and Krayer (10). Mean arterial pressure was kept at approx. 100 mmHg using a Starling resistance and the pressure was measured using a pressure transducer.
Cardiac output was measured with an extracorporeal flowmeter probe
(Nihon Kohden, MF-2T) connected to an electromagnetic flowmeter (Nihon Kohden, MF-2), and the values were 100 to 230 ml/min in the normal preparation and 140 to 300 ml/min in the ephedrine-pretreated
preparation, respectively.
was measured with a force-displacement
Myocardial contractile force
transducer (Nihon Kohden, SB-1T) which was
connected with thread to the apex cordis and the resting tension was adjusted to approx. 50 g. Electrocardiogram
was obtained from the opened chest wall and heart rate was in
tegrated with a cardiotachometer to give a continuous record. All parameters were recorded synchronously on a multipurpose
polygraph (Nihon Kohden, RM-85).
The reservoir,
which contained the blood obtained from a donor dog, was positioned 154 2 cm above the right atrium.
Total blood volume was approx. 800 ml and the blood was rendered in
coagulable by administration of heparin in a dose of 250 unit/kg.
The temperature of the
preparation was kept at 36-37 °C by passing the blood through a glass coil in a thermos tatically controlled water bath. Drugs were injected into the tube leading to the superior
vena
cava.
Drugs:
Drugs used were dopamine hydrochloride (Nutritional Biochemicals), tyramine
hydrochloride (Nakarai Chemicals), (-)-adrenaline
hydrochloride (Daiichi Pharmaceutical),
(-)-noradrenaline hydrochloride (Sankyo), (i_)-isoprenaline hydrochloride (Sterling Win throp), (-)-ephedrine hydrochloride (Dainippon Pharmaceutical), reserpine (Inverni and Della Beffa), cocaine hydrochloride (Takeda Pharmaceutical), pentobarbital sodium (Abbott) and heparin sodium (Novo Industries).
The sympathomimetic amines except ephedrine
were dissolved as 1 °o solution in 1; 100 N hydrochloric acid and used within a week. All drugs were diluted with saline before injection.
Reserpine was dissolved according to the
method described by Orlans et al. (11), and ephedrine suspension was prepared as 50 mg/kg solution using salad oil. Dosages of all drugs are expressed in terms of their salt. Administration of drugs:
Pretreatments
with ephedrine included successive i.v. in
jections of the drug into the femoral vein at 30 min intervals in single doses of 1 mg,/kg, 2 x 2 mg/kg, 7 x 5 mg7kg for a total of 40 mg/kg, or I mg/kg, 3 mg/kg, 6 mg/kg and 10 x 7 mg/kg for a total of 80 nmg'kg, with the exception of the latter case of 80 mg;'kg in which ephedrine was administered at 15 min intervals for the last total dose of 35 mg/kg. Combined administrations of reserpine and ephedrine were given as follows; reserpine (2 mg/kg) and ephedrine (20 mg/kg) suspended in oil were simultaneously administered by a s.c. injection, and ephedrine suspended (20 mg' kg) was additionally injected 8 and 18 hr later. The animals were used for the experiment 24 hr later, and ephedrine dissolved in saline (5 mg/kg) was given i.v. 6 times at intervals of 15 min (finally reserpine, 2 mgjkg, s.c. and total ephedrine, 90 mg/kg, s.c. and i.v.). In experiments using the heart-lung preparation, ephedrine was injected repeatedly to both the experimental and donor dog in a total dose of 40 mg/kg. Cocaine (4 mg/kg) was given i.v. about 15 min before a dose-response run.
Dose-responses
to each sympathomimetic amine were obtained by i.v. dosing to separate animals 30 min after the last i.v. pretreatment with ephedrine and the amines were administered from smaller doses about 5 min after previous changes had been restored. Expression of data and statistical analyses:
Peak changes in blood pressure, heart rate,
cardiac output and contractile force were used for analysis, and the values refer to mean' standard error of the mean.
The results were statistically compared using Student's t test
(p
POSSIBLE
MODE OF
Tatsuo
OF
CARDIOVASCULAR
DOPAMINE
FURUKAWA,*
IN
ACTIONS
DOGS
NobufUrni ONO, Yukihide
Tamio NAKAHARA
MAEDA,
and Kanji YOSHIHARA
Department of Pharmacology, School of Medicine* and Pharmaceutical Sciences, Fukuoka University, Fukuoka 814, Japan Accepted May 14, 1976
Abstract-A possible mode of cardiovascular actions of dopamine was studied using ephedrine. In the dog pretreated with repeated administrations of ephedrine (total dose, 40 or 80 mg/kg, i.v.) or with combined administrations of ephedrine (total dose, 90 mg/ kg, s.c. and i.v.) and reserpine (2 mg/kg, s.c., 24 hr previously), pressor responses to dopamine were eliminated and reversed to depressor responses whereas depressor responses to dopamine were potentiated. Positive chronotropic effects of dopamine were almost eliminated. Pressor and positive chronotropic effects of tyramine were almost abolished. Sympathomimetic effect of noradrenaline and adrenaline were potentiated while those of isoprenaline were inhibited. In the heart-lung preparation of ephedrine-treated dogs (total dose, 40 mg/kg, i.v.), cardiac stimulating effects of dopamine and tyrarnine were strongly depressed, and those of noradrenaline, adrenaline and isoprenaline were reduced to some extent. In the open-chest dogs, after pretreatment with cocaine (4 mg/kg, i.v.), pressor, positive inotropic and chronotropic effects of noradrenaline were potentiated whilst those of tyramine were inhibited. Those of dopamine were not visibly altered, but depressor, negative chronotropic and inotropic effects of dopamine appeared at small doses. In the ephedrine-pretreated dogs, these sympathomimetic effects of dopamine and tyramine after cocaine were strongly de pressed and those of noradrenaline were inhibited to a certain degree. The results obtained with ephedrine suggest that dopamine differs from other catecholamines and tyramine in the mode of cardiovascular actions.
Studies have shown that sympathomimetic as acting
directly on the receptors,
those with mixed action,
these classifications
in the effects after pretreatment
by chronic
dopamine,
other workers
or cocaine
led to classification
the reserpine-pretreated the concept actions,
reported
of dopamine
was slightly potentiated
was potentiated
in the cat.
and
based on the modifications
in responses
to dopamine
although
(5, 6). Farmer
while the positive
by denervation
amine (2-4).
to be of importance
in order
As results
in
to confirm
it has direct sympathomimetic
(7) reported chronotropic
We have already observed
24 hr after pretreatment
nerve terminals
cocaine or reserpine (1). Concerning
as a directly-acting
of direct and indirect effect, dopamine,
slightly 24 hr after reserpine to dopamine
being principally
are considered
does to some extent act indirectly
on the adrenergic
denervation,
modifications
of dopamine
animals
agents can be classified in their mode of action
acting indirectly
that the pressor effect effect was reduced
that the pressor response
with reserpine
(8), whereas
the re
This work was funded by grants from the Ministry of Education, Japan, and from the Kanae Foundation for Medical Research
sponse was eliminated and reversed to a depressor response (dopamine reversal) after ephedrine tachyphylaxis although responses to noradrenaline and adrenaline were poten tiated, thus suggesting the possibility that dopamine acts for the greater part indirectly (9). The influence of pretreatment with reserpine on responses to sympathomimetic amines has been well documented, however, the influence of pretreatment with ephedrine has been given little attention despite the fact that the influence is not the same. The possible mode of cardiovascular actions of dopamine using ephedrine in the dog was investigated herein. MATERIALS AND METHODS Animals:
Adult mongrel dogs of either sex, weighing between 6 and 18 kg, were
anesthetized with pentobarbital
sodium 35 mg/ kg given i.p. and, in the reserpine and
ephedrine treated animals, 20 mg/kg was given.
Supplemental doses of 3-5 mg/kg were
given i.v. as required to maintain a constant state of anesthesia. Experiments on intact animals: Systemic arterial blood pressure was measured with a pressure transducer (LPU-05-360-0-L11) from the cannulated left femoral artery.
The
ECG was obtained from standard limb leads and heart rate was integrated with a cardio tachometer (Nihon Kohden, RT-2) to give a continuous record. In the experiment on open chest dogs, the cardiac contractile force was obtained from a strain gauge arch (Nihon Kohden) attached to the left ventricle. These parameters were recorded on a multipurpose polygraph (Nihon Kohden, RM-85). The vagus nerves were cut bilaterally at the cervical region 15 min before observation of dose-responses to amines. Intravenous drug injections were given through a polyethylene tube which had been previously inserted into the left femoral vein. Experiments on heart-lung preparations:
The preparation was made principally accord
ing to the method described by Paasonen and Krayer (10). Mean arterial pressure was kept at approx. 100 mmHg using a Starling resistance and the pressure was measured using a pressure transducer.
Cardiac output was measured with an extracorporeal flowmeter probe
(Nihon Kohden, MF-2T) connected to an electromagnetic flowmeter (Nihon Kohden, MF-2), and the values were 100 to 230 ml/min in the normal preparation and 140 to 300 ml/min in the ephedrine-pretreated
preparation, respectively.
was measured with a force-displacement
Myocardial contractile force
transducer (Nihon Kohden, SB-1T) which was
connected with thread to the apex cordis and the resting tension was adjusted to approx. 50 g. Electrocardiogram
was obtained from the opened chest wall and heart rate was in
tegrated with a cardiotachometer to give a continuous record. All parameters were recorded synchronously on a multipurpose
polygraph (Nihon Kohden, RM-85).
The reservoir,
which contained the blood obtained from a donor dog, was positioned 154 2 cm above the right atrium.
Total blood volume was approx. 800 ml and the blood was rendered in
coagulable by administration of heparin in a dose of 250 unit/kg.
The temperature of the
preparation was kept at 36-37 °C by passing the blood through a glass coil in a thermos tatically controlled water bath. Drugs were injected into the tube leading to the superior
vena
cava.
Drugs:
Drugs used were dopamine hydrochloride (Nutritional Biochemicals), tyramine
hydrochloride (Nakarai Chemicals), (-)-adrenaline
hydrochloride (Daiichi Pharmaceutical),
(-)-noradrenaline hydrochloride (Sankyo), (i_)-isoprenaline hydrochloride (Sterling Win throp), (-)-ephedrine hydrochloride (Dainippon Pharmaceutical), reserpine (Inverni and Della Beffa), cocaine hydrochloride (Takeda Pharmaceutical), pentobarbital sodium (Abbott) and heparin sodium (Novo Industries).
The sympathomimetic amines except ephedrine
were dissolved as 1 °o solution in 1; 100 N hydrochloric acid and used within a week. All drugs were diluted with saline before injection.
Reserpine was dissolved according to the
method described by Orlans et al. (11), and ephedrine suspension was prepared as 50 mg/kg solution using salad oil. Dosages of all drugs are expressed in terms of their salt. Administration of drugs:
Pretreatments
with ephedrine included successive i.v. in
jections of the drug into the femoral vein at 30 min intervals in single doses of 1 mg,/kg, 2 x 2 mg/kg, 7 x 5 mg7kg for a total of 40 mg/kg, or I mg/kg, 3 mg/kg, 6 mg/kg and 10 x 7 mg/kg for a total of 80 nmg'kg, with the exception of the latter case of 80 mg;'kg in which ephedrine was administered at 15 min intervals for the last total dose of 35 mg/kg. Combined administrations of reserpine and ephedrine were given as follows; reserpine (2 mg/kg) and ephedrine (20 mg/kg) suspended in oil were simultaneously administered by a s.c. injection, and ephedrine suspended (20 mg' kg) was additionally injected 8 and 18 hr later. The animals were used for the experiment 24 hr later, and ephedrine dissolved in saline (5 mg/kg) was given i.v. 6 times at intervals of 15 min (finally reserpine, 2 mgjkg, s.c. and total ephedrine, 90 mg/kg, s.c. and i.v.). In experiments using the heart-lung preparation, ephedrine was injected repeatedly to both the experimental and donor dog in a total dose of 40 mg/kg. Cocaine (4 mg/kg) was given i.v. about 15 min before a dose-response run.
Dose-responses
to each sympathomimetic amine were obtained by i.v. dosing to separate animals 30 min after the last i.v. pretreatment with ephedrine and the amines were administered from smaller doses about 5 min after previous changes had been restored. Expression of data and statistical analyses:
Peak changes in blood pressure, heart rate,
cardiac output and contractile force were used for analysis, and the values refer to mean' standard error of the mean.
The results were statistically compared using Student's t test
(p
![Cardiovascular actions of prostacyclin (PCI2) in chloralose anaesthetized dogs [proceedings].](/assets/img/hold.png)
