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Br. J. Pharmac. (1969), 37, 618-626.
The pulmonary and systemic circulatory
response to dopamine infusion
D. C. HARRISON, SUELLEN PIRAGES, SHERILYN C. ROBISON AND
B. U. WINTROUB
Cardiology Division, Stanford Uniiversity School of Medicine, Palo Alto, (^) California 94305
- The pulmonary and systemic circulatory responses to dopamine infused at 8, 15, 25 and 30 ,g/kg per (^) min were (^) studied in (^) eight mongrel dogs.
- Mean pulmonary artery pressure, mean left atrial (^) pressure, mean (^) aortic pressure, mean aortic flow and the electrocardiogram were monitored in open- chest preparations. Pulmonary vascular resistance, systemic vascular resistance and stroke volume were calculated.
- (^) Significant increases in mean pulmonary and aortic pressures were noted at
dopamine infusions of 25 and 30 ,ug/kg per min. The left atrial pressure fell
significantly at 15 pg/kg per min and rose significantly at 30 ,g/kg per min.
Mean aortic flow increased at all four doses, while (^) heart rate showed no change.
Pulmonary vascular resistance did not change significantly at any dose level,
but systemic vascular resistance fell slightly at 8 and 15 jug/kg per min and
rose significantly at 30 pg/kg per min. Stroke volume was significantly elevated
at infusions of 25 and (^30) jig/kg per min.
- The systemic circulatory response to dopamine is similar to that described by previous investigators.
- The increased (^) pulmonary pressures without change in resistance suggest a dopamine-induced (^) increase in smooth muscle tension in the pulmonary vasculature.
Dopamine (3,4 dihydroxyphenylethylamine) is a naturally occurring catecholamine and is the direct biochemical precursor to norepinephrine (^) (Blaschko, 1957). Investi- gators have recently described the cardiovascular response to this agent in animals and in man (^) (McDonald & Goldberg, 1963; Black & Rolett, 1966, 1968). Vasocon- striction has been (^) noted in the femoral vascular bed (McDonald & Goldiberg, 1963). At low doses, however, a slight but significant drop in systemic vascular (^) resistance has been reported without significant change in heart rate or arterial pressure
(McDonald & Goldberg, 1963; Black & Rolett, 1966, 1968). In addition, animal
studies demonstrate direct cardiac stimulation through (^) a beta-adrenoceptor mechanism (Black & Rolett, 1966). Studies in (^) both dogs and man offer evidence that dopamine is a selective renal and mesenteric vasodilator (McNay, McDonald &
Goldberg, 1965; McDonald, Goldberg, McNay & Tuttle, 1964 ; Goldberg, McDonald
& (^) Zimmerman, 1963). These properties make dopamine an attractive agent for the
Dopamine on pulmonary circulation
treatment of patients with acute cardiovascular failure and shock. Two (^) reports
describing the response to dopamine treatment of patients in congestive heart failure
(Goldberg et al., 1963) and shock (MacConnell, McNay, Meyer & Goldberg, 1966)
have been published. Although dopamine has been considered for clinical use in
patients with^ circulatory failure, no^ studies^ have^ reported the effect^ of^ dopamine on
the altered pulmonary vascular responsiveness and hypoxia which often accompany
this failure. It is the purpose of this report to describe the haemodynamic response
of the pulmonary circulation to dopamine infusion at four different doses and, at the
same time, to compare the pulmonary vascular response to changes induced in the
systemic circulation.
Methods
Eight mongrel dogs (15-22 kg) were anaesthetized with a mixture of alpha-
chloralose and urethane, 65 mg/kg, and 400 mg/kg, respectively. Supplemental
anaesthetic was administered when corneal reflexes were noted. The chest was
opened in the mid-line and the animals (^) were prepared to record changes in the
circulatory system. Pulmonary artery pressure was monitored through a No. 7
Birdseye catheter positioned in the main pulmonary artery via the right external
jugular vein. Left atrial pressures were measured by a flange-tipped PE 260
catheter positioned through a stab wound in the left atrial appendage and secured
with a purse-string suture. Central aortic pressure was monitored through a PE 260 fluid-filled catheter placed in the ascending aorta via the right femoral artery. The
right femoral vein was cannulated with a PE 260 catheter for drug infusion. All
fluid-filled catheters were flushed frequently, and/or kept patent by means of a
heparinized (4 U.S.P. units/ml.) saline (^) drip. All pressures were measured with Statham P23Db pressure transducers. Mean (^) pressures were electrically determined by integration of the phasic pressure tracings.
Mean aortic blood flow was measured with a gated sine wave electromagnetic
flow (^) meter (Biotronex, Silver Spring, Md.) placed around the ascending aorta distal to the (^) coronary arteries. Each aortic flow probe was calibrated ,by comparison
with multiple cardiac outputs determined by standard indicator dilution techniques.
Aortic flow was used as (^) cardiac output for all of these studies, and aortic flow was assumed to equal pulmonary (^) blood flow. (^) The electrocardiogram was followed by means of subcutaneous electrodes placed in the (^) appropriate extremity. All record- ings were made on a multi-channel Beckman Model R (^) direct-writing oscillograph. The animals were intubated with a cuffed endotracheal tube and ventilated with a (^) Harvard respirator. Arterial blood samples were analysed frequently utilizing a
Model AME-1 Astrup micro-apparatus. The pH and PO2 were measured S min
before any intervention and before killing each (^) animal. In order to determine pulmonary and systemic responses to dopamine, the drug was infused (^) for 10 min periods at doses of 8, 15, 25 and 30 pLg/kg per min. These doses were (^) administered in randomized fashion from animal to animal, and all infusions were delivered with a variable-speed (^) Harvard apparatus infusion pump. After control measurements, each infusion was begun and data recorded (^) throughout the 10 min infusion period. Because the animals reached steady state within (^5) min,
5 min data were chosen as peak response data. At least 15 min were allowed
between infusions for each animal (^) to return to control.
Dopamine on pulmonary circulation
Left atrial pressure
Mean left atrial (^) pressure fell (^) slightly but (^) significantly in (^) response to (^) dopamine infused at 15 jig/kg per min and rose (^) significantly when infused at (^30) ,g/kg per
min, but no significant change occurred at 8 or 25 ptg/kg per min (Talble 1). The
15 pg/kg per min response differed significantly from the 30 ,g/kg per min response
(P<O-05).
TABLE 1. Haemodynamic response to dopamine Dose: (^8) jiglkg per min
PA mean pressure mmHg LA mean pressure mmHg Ao mean pressure mmHg PVR (^) mmHg/l. per min SVR mmHgf1. per min Flow ./mmin SV ml./beat Heart rate
PA (^) mean pressure mmHg LA mean pressure mmHg Ao mean pressure mmHg PVR mmHg/l. per min SVR mmHg/l. per min Flow b.!min SV (^) m]./beat Heart rate
PA mean pressure mmHg LA mean pressure mmHg Ao mean pressure mmHg PVR mmHg/l. per min SVR mmHg/1. per min Flow (^) l,bmin SV ml./beat Heart rate
PA mean pressure mmHg LA mean pressure mmHg Ao (^) mean pressure mmHg PVR mmHg1l. per min SVR (^) mmHg!l. per min
Flow b, min
SV (^) ml.bbeat Heart rate
Control 17-2± 1- 7-54± 109-6±7- 6-7±0- 70-7±6- 1-6±0- 9-3±1- 172-4±6- Dose: 17-64±0- 7-1 1 0 108-5±4- 6-5±0- 66-9±7- 1-8±0- 9.6±1^1 180.9±5- Dose: 17.3±0- 7-4±1- 105-4±5- 6-5±0- 70-0±8- 1.7+0. 9-5± 1- 174-3±7. Dose: 16-9±0- 8-2±0- 98-6±6- 5-8±0- 63-4±5- 1-6±0- 9-5±0- 165-8±9-
Absolute change Significance 0-740-4 NS -0-4±0-4 NS -5-5±3-1 NS -0-4±0-2 NS -9-1±3-1 <0- 0-23±0-07 < 0- 0-4±0-5 NS 13-8±7-2 NS
15 pggkg per min
0-5±04 NS -1-0±0-3 <^ 0- 2-7±7-3 NS -0-3±0-3 NS -6-9±3-1 NS 0-28±0-07 < 0- 0-8±0-5 NS 12-8±6-0 NS (^25) ,gg'kg per min 2-6±1-0 <0- -0-0±0-7 NS 22-6±8-1 < 0- -0-5±0-3 (^) NS -3-3±10-0 NS 0-51±0-12 < 0- 2-4±0-7 <0- 9-5±8-9 NS (^30) jig/kg per min 3-1±0-7 <0- 1-8±0-8 <0- 47-0±9-8 < 0- -0-2±0-2 NS 27-3±11-2 <0- 0-23±0-10 < 0- 3-7±1-4 <0- -5-8±6-5 (^) NS
O% change^ Significance
5-0±2-7 NS -3.4±6-6 NS 4-2±2-9 NS -5-6±3-0 NS -12-6±4-0 <^ 0- 15-8±6-1 < 0- 6-6±6-2 NS 9-2±5-6 NS
2-3±2-1 NS -14.714-2 < (^0 ) 3-1±6.7 NS 4-0±4-6 NS -12-0±4-8 < 0- 17.8±4-4 < 0- 11-2±6-1 NS 7-4±3-5 NS
14-3±5-1 < 0- 2-0±10-4 NS 21.8±8-3 <0- 9-4±5-0 NS 2-0±11-5 NS 36-7+11-7 (^) <0- 28-1±9-5 <0- 6-3±5-0 NS
17-8±3- 21-5±9- 48-7± 12- -4-5±4- 41-4±16- 12-0±5- 42-4±18- -2-9±3-
<0- NS <0- NS <0- <0- NS NS Responses to dopamine at 5 min for all infusions. PA mean, Mean pulmonary artery pressure: LA (^) mean, mean left atrial (^) pressure; Ao (^) mean, mean aortic pressure; PVR, pulmonary vascular (^) resistance; SVR, systemic vascular (^) resistance; AoF, mean aortic flow; SV, stroke volume; HR, heart rate.
621
D. C. Harrison (^) and others
Aortic pressure
Aortic pressure did not change significantly with infusion of the two low (^) doses;
however, a significant pressor response was induced with infusion of 25 and 30 gg/
kg per min (Fig. 2, Table 1). It was impossilble to separate the responses to 8 and 15 ,g/kg per min. Pressor responses induced by (^) the high doses (25 and (^30) jag/kg
per min) were significantly greater than the low dose response. In addition, the
increase in pressure at 30 ,ug/kg per min was significantly greater than the increase
at 25 ug/kg per min (P<001).
Mean aortic flow
Significant increases in cardiac output were demonstrated at all doses (Talble 1).
No significant difference was demonstrated between the four doses of dopamine
administered.
P<0-0I 60
50 -
40 -
..I 1-^ 0- , 30.
c^
° 20 c 660 X
10
-*
P<0.
NS
NS
I I I 8 15 25
Dopamine (1&g/kg per min)
30
FIG. 2. Mean (^) change (%A) and standard errors of the (^) change in aortic (^) pressure produced by various concentrations of (^) dopamine are shown. No (^) significant changes were noted at 8 and (^15) ,ug/kg per min, whereas (^) significant increases were noted at 25 and 30 (^) jg/kg per min dopamine infusion. The increase^ at^30 pg/kg per min was (^) significantly greater than that at 25 p,g/kg per min.
D. C. Harrison and others
Systemic vascular resistance
A significant fall in systemic vascular resistance at the two low doses^ was^ noted
(Fig. 3). There was no significant change at 25 ug/kg per min, but peripheral
resistance rose significantly by 4144+16.2% at 30 ,ug/kg per min (Talble 1). The
responses at 8, 15 and 25 ug/kg per min could not be separated statistically; how-
ever, the increase in resistance demonstrated at 30 (^) ,ug/kg per min was significantly
greater than the response observed during the first three doses (P<0-01).
Stroke volume
Low dose infusion of dopamine (8 and 15^ jug/kg^ per^ min) failed^ to^ increase^ the
stroke volume significantly; however,^ infusions^ at 25 and 30^ ,ug/kg^ per^ min pro- duced statistically^ significant^ increases (Table^ 1).^ The response at higher^ doses^ was significantly greater than the response at low doses (P<005), but again it was
impossible to separate the changes at 8 ,g/kg per min from 15 jg/kg per min or
(^25) Ag/kg per min from 30 (^) ,ug/kg per min.
Blood gases
Average blood gases before dopamine infusion were pH=7.42 and p02=98.
At the end of the experiments, average blood gases were pH =^ 7.39^ and^ P02^ =^ 95.
These values did not differ significantly.
Discussion
The pulmonary and systemic circulatory responses to dopamine infusion were
studied in this investigation. The pulmonary artery pressure rose with all four of
the dopamine doses administered. Only at the higher doses (25 and 30 (^) ,gg/kg per
min), however, was evidence of a statistically significant pressor response noted;
the pressor responses at 25 and 30 ,g/kg per min were of comparable magnitudes.
At no time were the increased pulmonary pressures accompanied by significant
changes in pulmonary vascular resistance (Table 1).^ Therefore,^ since^ vessel caliibre
remained unchanged while^ pressure^ rose,^ dopamine^ must act^ by^ increasing^ the^ level
of smooth muscle^ tension^ in^ the^ blood^ vessels of^ the^ lung.^ The^ very^ slight^ tendency
toward decreased pulmonary vascular resistance which occurred suggests that the
action of dopamine on vessel calibre in the pulmonary vascular^ beds during increased
cardiac output is that of slight dilatation only. This would^ be^ comparable with^ its
effect on the peripheral circulation, where a^ small^ reduction^ in^ systemic resistance
generally occurs.
Increase in aortic pressure in response to larger doses^ of^ dopamine-25 and^30 jig/kg per min^ (Table^1 and^ Fig.^ 2)-are^ in^ accord with^ findings^ of^ other^ investi-
gators (McDonald &^ Goldberg, 1963).
Heart rate^ did^ not^ change significantly^ at^ any^ level of^ dopamine^ infusion.^ How-
ever, the^ tendency toward^ an^ increase^ at^ the three low doses and^ a^ decrease^ at
(^30) pg/kg per min was noted. This decrease in heart rate^ at^ the^ highest administered dose was (^) probably due to the activation of baroreceptors and other pressor receptor mechanisms by the increase in^ peripheral pressure. The systemic vascular^ response to^ dopamine was^ dose-dependent; a^ slight^ but significant decrease in^ resistance^ occurred^ at^ the^ two^ low doses^ (8^ and 15^ jig/kg
Dopamine on pulmonary circulation
per min) and^ a^ very large, significant vasoconstriction^ at^ the^ high,^ ,ug/kg^30 per^ min.
Similar dose-related responses of the systemic circulation have been reported
(McDonald &^ Goldberg,^ 1963;^ Black &^ Rolett,^ 1968).^ The^25 ,g/kg^ per^ min
response, an^ intermediate^ response, may represent a^ balanced stimulation^ of^ peri.
pheral alpha and^ beta-adrenoceptors. Thus,^ low^ doses of^ dopamine^ would appear
to stimulate the beta-adrenoceptor, thereby causing a^ fall in^ resistance.^ It^ is also
possible, however,^ that^ dopamine has^ a^ slight direct^ vasodilatory^ effect,^ independent
of beta-adrenoceptor stimulation.
Although mean^ aortic flow^ rose^ significantly with^ all levels of^ infusion,^ statistically
significant incremental increases^ in^ output with^ increasing^ doses^ of^ dopamine could
not be demonstrated. It appears that the output increases as the^ dose is raised
from 8 to 25 ,ug/kg per min and then increases to a lesser degree at^ the^30 ,pg/kg per
min level.^ The smaller increase in^ output^ at^30 ,g/kg^ per^ min^ is^ correlated^ with a
large increase in^ peripheral pressure and^ resistance;^ it^ may^ represent^ inadequate
response to^ increasing afterload^ secondary to^ direct^ peripheral^ vasoconstriction
caused by high doses of dopamine. However, it may also be due to the reflex
slowing of^ the^ heart^ rate, since^ the stroke volume did^ change^ significantly.^ The
latter explanation seems more likely.
The significant decrease in left atrial pressure when dopamine was infused at
15 g/kgg1 per min and slight increasein response to the 30 ,ug/kg per^ min^ dose did
not produce atrial pressures outside the normal physiological range.^ The fall at
15 j&g/kg per min is explained by an increase in cardiac output without a significant
change in^ afterload.^ These^ findings would^ imply an increase in^ cardiac^ contractility,
which has been observed tby others (Black & Rolett, 1966). A similar increase in
cardiac output, accompanied by increases in peripheral pressure and systemic
resistance, accounted for the rise at 30,ug/kg per min.
The increase in stroke volume was significant at only 25 and 30 jig/kg^ per^ min,
but at all doses the trend was toward increased stroke volume, the increases^ appear-
ing to^ be^ dose-related^ (Table 1). Since^ the cardiac^ output^ produced^ by 30jug/kg
per min was less than that^ produced by 25 ,ug/kg per min,^ the maintenance^ of stroke
volume may be explained by the decreased heart rate which occurred as^ a result^ of
the large pressor response.
The results of this study confirm previous reports on systemic response to dopa-
mine (McDonald &Goldberg, 1963 ; Black & Rolett, 1966, 1968), as well as demon-
strate that dopamine causes a pressor response in the pulmonary artery at high doses
but creates no significant change in pulmonary resistance. However, these results
do suggest that dopamine increases smooth muscle^ tension in^ the^ pulmonary^ vascu-
lature. Dopamine-induced increases^ in^ pulmonary pressures would^ then^ be
secondary to increased cardiac output and increased wall tension.
Despite the^ difficulties inherent in^ applying an^ open-chested,^ anaesthetized^ animal
model to the clinical situation, it seems that these findings may have^ clinical rele-
vance. The dopamine-induced elevation of^ pulmonary pressures in^ the^ clinical
setting of^ pulmonary hypertension may be^ detrimental^ to the^ patient^ with a com-
promised right heart.^ It^ is^ even^ possible that an^ increase^ in smooth^ muscle^ tension
without accompanying increase in cardiac output might result in undesirable^ vaso-
constriction in the patient with pulmonary hypertension or congestive^ heart^ failure.
These studies were (^) supported in (^) part by N.I.H. Grants Nos. HE-09058, HE-5709 and HE-05866, and a grant from the American Heart Association, No. 67-708.
