614
High Urinary Dopa and Low Urinary
Dopamine-to-Dopa Ratio in
Salt-Sensitive Hypertension
John R. Gill Jr., Ehud Grossman, and David S. Goldstein
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Dopamine in urine is derived substantially from renal uptake and decarfooxylation of
3,4-dihydroxyphenylalanine (dopa), and increases in excretion of dopa normally parallel
increases in excretion of dopamine during salt loading. Since patients with salt-sensitive
hypertension may have decreased urinary excretion of dopamine during dietary salt loading,
the present study was designed to evaluate the response of dopa to salt loading. Sixteen
inpatients with normal-renin essential hypertension ate a constant metabolic diet containing 9
mmol/day sodium for 7 days, followed by the same diet but containing 249 mmol/day sodium for
7 days. Salt sensitivity was defined as an increase in mean arterial pressure of 8 mm Hg between
the diets; on this basis, nine patients were salt-sensitive and seven, salt-resistant The rate of
urinary dopa excretion was significantly higher in the salt-sensitive patients throughout the
study (mean rates 132±13 nmol/day in the salt-sensitive group and 78±9 nmol/day in the
salt-resistant group for the 14 days of observation, p<0.01). When dietary sodium intake was
increased to 249 mmol/day, urinary dopa excretion increased significantly more in salt-sensitive
patients than salt-resistant patients. At the end of the high salt diet, dopamine excretion was
significantly attenuated in the salt-sensitive patients, despite higher rates of dopa excretion.
Thus, the urinary ratio of dopamine to dopa was decreased in salt-sensitive patients, regardless
of salt intake. Among individual patients, cumulative sodium retention during the first 3 days
of salt loading was unrelated to the magnitude of the pressor response; however, the dopa
excretion rate was positively correlated with the magnitude of the pressor response (r=0.62,
p=0.015). The results suggest that salt-sensitive patients have decreased renal uptake or
decarboxylation of dopa and that this deficiency is associated with enhanced delivery of dopa
to renal uptake sites during dietary salt loading. A high rate of urinary excretion of dopa and
a low urinary dopamine/dopa ratio appear to be markers of salt-sensitive hypertension in
humans. (Hypertension 1991;18:614-621)
B
lood pressure responses to acute salt loading
or restriction vary markedly among hypertensive patients. The prevalence of salt-sensitive hypertension depends on the criterion used to
define it. When salt-sensitive patients were defined as
those whose mean arterial pressure increased by 8
mm Hg or more during a sodium intake of 249
mmol/day after 7 days on a 9 mmol/day sodium
intake, about half of the hypertensive study group
were classified as salt-sensitive.1
Many mechanisms have been proposed to explain
salt-sensitive hypertension. One suggests that it may,
in part, be caused by an attenuated response of
dopamine, with subnormal sodium excretion and
From the Hypertension-Endocrine Branch, National Heart,
Lung, and Blood Institute, Bcthesda, Md.
Address for correspondence: Dr. John R. Gill Jr., NHLBI, NIH,
Building 10, Room 8C103, Bethesda, MD 20892.
Received August 1,1990; accepted in revised form Jury 12,1991.
failure to suppress release of norepinephrine, during
dietary salt loading. Urinary excretion of dopamine
normally increases in people on a high salt diet. 2
Since administration of dopamine produces natriuresis,3 and blockade of dopamine receptors or of production of dopamine from its precursor, 3,4-dihydroxyphenylalanine (dopa), may blunt the natriuretic
response, 4 ' 5 dopamine may contribute to sodium homeostasis. Conversely, plasma levels and urinary
excretion of norepinephrine, the sympathetic neurotransmitter synthesized from dopamine, tend to decrease during dietary salt loading,6 and renal sympathetic stimulation has an antinatriuretic effect.7-8
Studies of salt-sensitive humans and laboratory animals have indicated decreased responses of urinary
excretion of dopamine, 19 - 13 no decrease in norepinephrine levels,14-17 or both 1 when dietary salt intake
is increased.
Urinary dopamine appears to be derived substantially from renal uptake and decarboxylation of
Gill et al Dopa and Salt Sensitivity
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dopa.1819 Changes in dietary salt intake normally
produce similar proportionate changes in urinary
dopa and dopamine,20 consistent with the view that
the rate of delivery of dopa to proximal tubular cells
of the kidney largely determines the rate of urinary
excretion of dopamine. If this were true, then during
dietary salt loading, salt-sensitive patients with attenuated dopamine excretory responses would be expected also to have attenuated dopa excretory responses. Alternatively, if there were an abnormality
in the uptake of dopa into the tubule cells or in the
intracellular conversion of dopa to dopamine, then
salt-sensitive patients would have normal (or even
increased) urinary excretion of dopa, and the urinary
dopamine/dopa ratio would be low.
The present study examined these possibilities in
inpatients. Measurements of daily, 24-hour urinary
excretion rates of catechols in each subject allowed
quantitative assessments of trends of catechol excretion over time both within subjects and between
salt-sensitive and salt-resistant groups.
Normal values for urinary excretion of dopa and
dopamine have not been established as a function of
normal aging. To examine possible effects of aging
mismatch between hypertensive and normotensive
groups, 24-hour urine collections were obtained from
a large number of outpatient volunteers ranging in
age from 18 to 65 years, and the urinary contents of
catechols and sodium were assayed.
Methods
Patients and Procedure
The clinical protocols were approved by the Intramural Research Board, National Heart, Lung, and
Blood Institute. All subjects gave written informed
consent.
Sixteen patients with mild or moderate, uncomplicated, normal-renin essential hypertension were admitted to the Clinical Center, National Institutes of
Health, at least 2 weeks after they had discontinued
antihypertensive medications. Clinical characteristics
of the subjects on the first day of the study diet are
summarized in Table 1.
Throughout the study, the subjects ate a constant,
isocaloric diet containing 9 mmol/day sodium. After 7
days of a low salt diet (9 mmol/day), the diet was
supplemented with 240 mmol/day sodium as sodium
chloride (high salt diet) for 7 days. Measurements of
TABLE 1. Clinical Charateristies of Hypertensive Patients
Groups
Characteristics
Number
Age (yr)
Sex ratio (male/femaJe)
Race (Caucasian/black)
Salt-resistant
Salt-sensitive
7
52±4
9
58±4
5/4
4/3
7/0
Weight (kg)
Mean arterial pressure (mm Hg)
85+6
109±3
Creatinine clearance (ml/min)
96±9
6/3
77+4
120±3
82+2
615
urinary sodium excretion confirmed that the subjects
had attained a stable sodium balance by the fourth
day of each diet. Fluid intake was constant throughout the study.
Blood pressure was measured every 4 hours using
a cuff and sphygmomanometer after at least 5 minutes of rest; mean arterial pressure was calculated by
adding one third of the pulse pressure to the diastolic
pressure. The values for mean arterial pressure were
averaged for each day in each subject.
Urine was collected daily throughout the study in
24-hour aliquots and equally divided between a container with 30 ml of 6N HC1 and one without
preservative.
On the last day of each diet, forearm venous blood
for assay of plasma catechols was obtained from each
subject in the fasting state. This was performed after
overnight bed rest and at least 20 minutes after
insertion of an indwelling needle, first with the
subject supine and then after the subject had been
standing for 5 minutes.
Ten normal volunteers (six women and four men,
aged 20-24 years) with no family history of hypertension underwent the same testing protocol as inpatients. Some results from this group have been
published previously.20
In 36 healthy normotensive outpatients (15 women
and 21 men, aged 18-65 years), 24-hour collections
of urine were obtained for measurement of sodium,
dopa, dopamine, and norepinephrine levels.
Assays
Urinary sodium excretion was determined by flame
photometry.
Aliquots of 100 fil urine and 1 ml plasma were
assayed for catechols, including dopa, dopamine,
norepinephrine, adrenaline, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), and the
norepinephrine metabolite dihydroxyphenylglycol
(DHPG), using liquid chromatography (Waters Associates, Milford, Mass.) with electrochemical detection (ESA, Bedford, Mass.), according to previously
published methods.21-22 The limits of detection were
about 60 pmol/1 (10 pg/ml) each for plasma norepinephrine and dopa, 150 pmol/l (25 pg/ml) for DHPG
and dopamine, and about 600 pmol/1 (100 pg/ml) for
urinary norepinephrine, dopa, and dopamine. Levels
of adrenaline were below limits of detection in
several samples, and those data are not reported.
Data Analysis
Subjects were categorized as salt-sensitive if their
mean arterial pressure increased by a mean of 8
mm Hg or more between the 9 and 249 mmol/day
diets. Subjects with increments in mean arterial
pressure of less than 8 mm Hg were categorized as
salt-resistant. As indicated in Table 1, when this
criterion was used, about half the patients were
salt-sensitive and half were salt-resistant.
The statistical significance of changes in rates of
excretion and in plasma levels of catechols as a
616
HO
Hypertension
LOW
SALT
man
SALT
Vol 18, No 5 November 1991
LOW
SALT
HIGH
SALT
3
o
5
C 100
u
E
o
x
X
m
SALT-RESISTANT
2
SALT-SENSmVE
o
o
2 "
NORMOTENStVE
SUBJECTS
SALT-RESISTANT
PATIENTS
SALT-SENSmVE
PATIENTS
1. Graphs show urinary dopa excretion during low
and high salt diets. Each point is the mean daily excretion
rate of the last 2 days of low salt (9 mmol sodium/day) and
the last 2 days of high salt (249 mmol sodium/day) intake in
each subject. Horizontal bars indicate group mean values.
All but one subject demonstrated increased urinary dopa
excretion during dietary salt loading (p<0.001). Regardless
of dietary salt intake, salt-sensitive patients had a significantly higher mean rate of urinary dopa excretion than
salt-resistant patients.
NORMOTENOVE8
0
1
2
1
4
S
6
7
S
9 1 0 1 1 1 2 1 3 1 4 1 8
T H E (days)
FIGURE
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function of day and diagnosis was assessed by analyses
of variance for repeated measures. Differences in
mean excretion rates and plasma levels also were
averaged for each dietary condition and compared by
t tests for dependent or independent means. Linear
regression analysis was applied to scatter plots relating
changes in the biochemical values to changes in mean
arterial pressure during the dietary manipulation.
Mean values were expressed ±1 SEM. A value of
/?<0.05 defined statistical significance.
Results
Blood Pressure and Sodium Excretion
Mean daily diastolic blood pressure for each of the
hypertensive patients was greater than 90 mm Hg at
the time of the study. Changes in mean arterial
pressure during dietary salt loading varied widely
among the subjects. In the salt-resistant group, the
change in mean arterial pressure averaged -0.3 ±1.6
mm Hg, whereas in the salt-sensitive group, the
change in mean arterial pressure averaged 11.6±0.8
mm Hg (p< 0.001), with virtually all of the increase
occurring during the first 3 days of the high salt diet.
In all subjects, urinary sodium excretion was about
the same as dietary sodium intake by day 3 after
initiation of each dietary manipulation (data not
shown). Cumulative sodium retention was unrelated
to the magnitude of the pressor response.
Dopa
In all but one subject, urinary excretion of dopa
increased during dietary salt loading (Figure 1).
Whereas dopa excretion was similar in salt-resistant
and control subjects during the low salt diet and
increased similarly in the two groups during salt
loading, urinary dopa excretion was significantly
FIGURE 2. Line graph shows mean urinary dopa excretion
as a function of day during low and high salt diets. Each point
represents the mean daily excretion rate of the salt-sensitive,
salt-resistant, and normotensive control groups. Salt-sensitive
patients had significantly increased urinary dopa excretion
especially during the first 3 days of dietary salt loading
(p<0.01 by analysis of variance).
higher in the salt-sensitive group than in the other
groups throughout the study (Figure 2), and increased markedly during the first few days of high salt
intake. For instance, on the last day of the low salt
diet, urinary dopa excretion averaged 89 ±10 nmol/
day in the salt-sensitive group and 53 ±6 nmol/day in
the salt-resistant group (/><0.01). On the second day
of the high salt diet, urinary dopa excretion averaged
174±20 nmol/day in the salt-sensitive group and
80±9 nmol/day in the salt-resistant group (/?<0.01).
On the last day of the low salt intake, the urinary
clearance of dopa (expressed per 100 ml creatinine
clearance to correct for any difference in excretion
that may have occurred as a result of a difference in
glomerular filtration rate) was 8.05 ±0.85 ml/min in
the salt-sensitive patients, significantly higher than in
the normal subjects (4.15 ±0.73 ml/min) and in the
salt-resistant patients (5.19±0.74 ml/min). In all
three groups, urinary clearance of dopa increased
significantly between the last day of the low salt diet
and the last day of the high salt diet. At the end of the
high salt diet, the dopa clearance was higher in the
salt-sensitive group (12.99±2.35 ml/min per 100 ml
creatinine clearance) than in the salt-resistant group
(9.11 + 1.22 ml/min) or in the normal subjects
(7.46 ±1.46 ml/min) but was significant only if the
salt-resistant hypertensive patients and the normal
subjects were considered as a single group.
During the first 3 days of the high salt diet, the rate
of increase in mean urinary dopa excretion was much
greater in the salt-sensitive group than in the saltresistant group or the normal subjects. This rate of
increase correlated with the change in mean arterial
pressure during this period of time (r=0.62,p=0.015)
(Figure 3). Urinary dopa excretion was unrelated to
cumulative sodium retention during either the first 3
days or all 7 days of the high salt diet (/-=-0.05, and
r=-0.08).
GUI et al
1
M0->
2S0
URINARY OOF>A EXCRET1I
s
O
SALT-RESBTAHT
•
SALT-SEN3mVE
rmOJtt; P . 0 4 1 5
150'
O
O °
100'
O
°
50-
-10
o°
-S
0
6
10
IS
20
AMAP (mm Hg)
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FIGURE 3. Scatter plot shows correlation between urinary
dopa excretion and change in mean arterial pressure (AMAP)
during dietary salt loading. Each point indicates the mean
value for the 3 days after initiation of the high salt diet. Urinary
dopa excretion was significantly positively correlated with the
magnitude of the pressor response (p=0.015).
Plasma dopa levels did not differ among the groups
on either diet. In hypertensive patients considered as
a single group, the mean plasma dopa level decreased
slightly but significantly during salt loading (Table 2).
For instance, on the last day of the low salt diet, the
plasma dopa concentration averaged 10.0 ±1.3 nmol/1
in the control subjects, 8.2±1.1 nmol/1 in the saltresistant patients, and 9.7 ±0.8 nmol/1 in the saltsensitive patients; on the last day of the high salt diet,
the mean values were 9.1±1.5, 7.3±0.8, and 9.2±0.8
nmol/1, respectively.
Dopamine
Urinary dopamine excretion did not differ significantly between the salt-resistant and salt-sensitive
groups (Figure 4). When the hypertensive patients
were considered as a single group, the mean urinary
dopamine excretion in the hypertensive patients was
significantly higher than that in the normotensive
control subjects. The higher urinary dopamine excre-
Dopa and Salt Sensitivity
tion in the hypertensive patients was most apparent
during the low salt diet.
Urinary excretion of dopamine increased in most
but not all subjects during dietary salt loading. The
increases in urinary dopamine excretion were similar
in the groups during the first few days of salt loading,
but by the end of the high salt diet, differences
emerged. By the last 2 days of the high salt diet,
urinary dopamine excretion in the control subjects
and the salt-resistant patients had increased significantly by 60 ±26% and 50 ±17%, respectively, compared with the last 2 days of the low salt diet. These
increases in dopamine were associated with increases
in dopa excretion, averaging 75 ±22% and 79 ±14%,
respectively. By contrast, in the salt-sensitive patients, the increases in urinary excretion of dopamine
averaged only 10±5% (/?=NS), whereas dopa excretion was increased by 60±16% (Figure 5).
Dopamine I Dopa Ratio
Since in the salt-sensitive patients the responses of
urinary excretion of dopamine were smaller and the
responses of urinary excretion of dopa larger during
dietary salt loading than in patients in the other groups,
the ratio of dopamine/dopa in urine was markedly
decreased in the salt-sensitive group. The ratio was
lower in this group than in the other groups during both
the low and high salt diets (Figure 6). When the mean
dopamine/dopa ratio for the 14 days of observation was
calculated for each subject, the values were significantly
lower in the salt-sensitive than in the salt-resistant
group (8.77 ±0.82 for salt-sensitive patients versus
1429±2.88 for salt-resistant patients, p<0.01).
In all three groups, the urinary dopamine/dopa ratio
decreased significantly during the high salt diet (Figure 6), reflecting an increase in dopa excretion that
was larger than the increase in dopamine excretion.
Norepinephrine
Plasma norepinephrine decreased significantly in
the supine and upright positions during the high salt
TABLE 2. Plasma Concentrations of Catechols (nmol/1) in Salt-Resistant and Salt-Sensitive Hypertensive Patients
After 7 Days of Low Salt Diet (LSD) and 7 Days of High Salt Diet (HSD)
Catechol
DHPG
Norepinephrine
Dopa
DOPAC
Dopamine
Posture*
Supine
Upright
Supine
Upright
Supine
Upright
Supine
Upright
Supine
Upright
617
Salt-resistant group
HSD
LSD
5.29±0.76
5.06±0.61
5.24±0.81
6.42 ±0.85
1.28±0.19
1.04±0.29t
4.01 ±038
2.76±0.31t
8.22±1.11
734±0.80t
8.03±1.03
7.29±0.75t
1630±3.61
16.56±4.36
17.07±3.19
16.52±4.07
0.29±0.23
0.28+0.16
0.24±0.17
0.40±0.36
Salt-sensitive group
HSD
LSD
6.95 ±0.85
6.08±0.46
7.52±0.88
6.82±0J8
2.04±0J7
1.36±0.19t
3.55 ±0.69
4.04 ±0.69
9.66±0.82
9.20±0.81t
9.81 ±0.81
9.12±0.80t
15.92±3.43
14.40±3.30
16.57±3J4
14.98±3.33
0.18±0.05
0.17±0.05
0.16±0.05
0.17±0.05
DHPG, dihydroxyphenviglycol; Dopa, 3,4-dihydroxvphenyialanine; DOPAC, dihydrcoyphenylacetic arid.
'Supine denned as after overnight bed rest; upright denned as after standing or walking 5 minutes.
tSignificant difference between low and high salt diet when hypertensive patients were considered as one group.
618
Hypertension
Vol 18, No 5
November 1991
SALT-DESSTAHT
SALT-SEHSmVE
HORMOTEKSVE8
1
8
o
SALT-RESET AMT
SALT-SEHSTTTVE
HORMOTENSnES
•
101111111419
TIME (dty>)
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FIGURE 4. Line graph shows mean urinary dopamine (DA)
excretion as a function of day during low and high salt diets.
Each point represents the mean daily excretion rate of the
salt-sensitive, salt-resistant, and normotensive control groups.
Hypertensive patients had higher dopamine excretion than
normotensive control subjects; this difference was most apparent during the low salt diet. Mean dopamine excretion did not
differ between the salt-sensitive and salt-resistant groups.
diet in the salt-resistant patients and control subjects,
and urinary excretion of norepinephrine was decreased similarly in all three groups (Figure 7). In the
salt-sensitive patients, plasma levels of norepinephrine in the upright position were not suppressed at
the end of the high salt diet compared with the levels
at the end of the low salt diet (Table 2).
Age and Excretion Rate of Dopa and Dopamine
Among normotensive outpatients, urinary dopa
excretion tended to decline as a function of subject
age (r=0.34, 0.05<p<0.01) (Figure 8). Urinary dopamine excretion was unrelated to subject age.
NORMOTENSIVES
SALT-RESISTANT
SALT-SENSITIVE
FIGURE 6. Line graph shows daily mean ratio of urinary
dopamine (DA) to dopa during low and high salt diets.
Dopamine Idopa ratio was significantly decreased in saltsensitive patients compared with salt-resistant patients and
normotensive control subjects, regardless of dietary salt intake
Discussion
Dopamine in urine appears to be derived substantially from renal uptake and decarboxylation of
dopa,18-20 and dietary salt loading normally elicits
proportionately similar increases in the rates of urinary excretion of dopa and dopamine.20 Since we1
and others9-13 have reported attenuated responses of
urinary dopamine excretion during dietary salt loading in salt-sensitive hypertension, we thought that
patients with deficient dopamine excretory responses
would also have either deficient dopa excretory responses or impaired renal uptake or decarboxylation
of dopa during dietary salt loading.
In the present study, dietary salt loading during an
otherwise constant diet elicited rapid increases in
urinary excretion of dopa in virtually all subjects.
Urinary dopa excretion was significantly increased in
the salt-sensitive patients on both the low and high
salt diets, and dopa excretory responses during salt
loading were exaggerated in salt-sensitive patients
|
SSD-
DOPA
DA
FIGURE 5. Bar graph shows changes in urinary excretion of
dopa and dopamine (DA) during low and high salt diets.
Each bar shows the mean ±SEM value for the percentage of
change between the last 2 days of each diet Proportional
increase in urinary dopamine excretion during salt loading was
significantly smaller in the salt-sensitive group than in the
salt-resistant or normotensive control groups, whereas the
proportional increases in urinary dopa excretion were similar
in the three groups. + Significant difference from low salt diet,
p<0.01; 'significant differences from salt-sensitive and normotensive groups, p<0.05.
no-
E
150
ec
o
241 mmoi Kxtturtd
O—
•—
O—
•
AA
B0<
o
• amat (OdluaM
|
SALT-RESISTANT
SALT-SENSnTVE
MORM0TEMSVE8
100a
0
I
11 11 11 14 IS
TIME (dry.)
FIGURE 7. Line graph shows mean urinary norepinephrine
(NE) excretion as a function of day during low and high salt
diets. Each point represents the mean daily excretion rate of
the salt-sensitive, salt-resistant, and normotensive control
groups. In all three groups, urinary norepinephrine excretion
was suppressed significantly during dietary salt loading.
Gilt et at Dopa and Salt Sensitivity
1000
«.
• •
2•*
• t • v*
100
o o
Ul
°
c
o
• •. •
o° o
10O DOPA
•
E
O
X
Ul
10
20
30
AGE
40
50
50
DA
70
(years)
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FIGURE 8. Scatter plot shows urinary dopa and dopamine
(DA) excretion (on a log scale) in relation to subject age in 36
healthy volunteers. Dopa excretion tended to decrease with
increasing subject age (r=0.34, 0.05<p<0.01). Dopamine
excretion was unrelated to subject age.
compared with salt-resistant patients and normotensive control subjects. In contrast, responses of urinary
dopamine excretion were blunted in salt-sensitive
patients, so that, regardless of dietary salt intake, the
urinary dopamine/dopa ratio was highly significantly
decreased in the salt-sensitive patients.
The rate of urinary excretion of dopa was significantly positively correlated with the magnitude of the
pressor response during the first 3 days of the high
salt diet. These relations did not appear to be due to
effects of high blood pressure itself on dopa excretion
because during the low salt diet, when their blood
pressure was lower, the salt-sensitive group still had a
significantly higher mean rate of dopa excretion than
did the salt-resistant group. Also, dopa excretion in
the hypertensive patients as a group did not differ
significantly from that in the control subjects. The
results suggest that a high rate of urinary dopa
excretion and a low urinary dopamine/dopa ratio in
urine may be markers of salt-sensitive hypertension.
This was not the case for dopamine excretion or
norepinephrine excretion alone, or for the magnitude
of the increase in dopamine excretion or of the
decrease in norepinephrine excretion during salt
loading.
Previous reports about urinary catecholamine responses during alterations of dietary salt intake generally have not reported results in each subject for
each day during the dietary manipulation. The present results show that the extent to which responses of
urinary dopamine were attenuated in salt-sensitive
hypertensive patients depended on the day on which
the urine collection was obtained, since in the first
few days of salt loading, salt-sensitive patients had
normal increases in urinary dopamine excretion, apparently due to supernormal increases in delivery of
dopa to the kidney.
The high rate of urinary excretion of dopa without
a correspondingly high rate of excretion of dopamine
is consistent either with deficient uptake of dopa into
619
proximal tubular cells of the kidney—a process that is
sodium-dependent22—or with deficient intracellular
conversion of dopa to dopamine in salt-sensitive
patients. Dopa is taken up by many cell types in the
body and converted to dopamine intracellularly.
Whether the present findings in salt-sensitive patients reflect a generalized abnormality or one confined to the kidney is unknown.
There are several potential explanations for high
urinary excretion rates of dopa in salt-sensitive patients. It is possible that the renal synthesis of dopamine is subject to feedback regulation and that release
of dopa into the bloodstream is enhanced in a compensatory fashion in salt-sensitive patients. In rats,
we23 recently observed that dietary salt loading resulted in significantly increased spillover of dopa into
arterial plasma, and this response was exaggerated in
rats with bilateral renal denervation. Conversion of
tyrosine to dopa by tyrosine hydroxylase occurs
mainly, if not only, in catecholamine-synthesizing
cells.24 Increases in urinary excretion of dopa, therefore, could reflect increased tyrosine hydroxylase activity, increased efficiency of uptake of tyrosine into
dopa-synthesizing cells, or increased release of dopa
from or decreased removal of dopa into nonneuronal
storage pools.25
During the low salt diet, the group of hypertensive
patients had a significantly higher mean rate of
urinary dopamine excretion than did the normotensive control group. Although the patients in the
hypertensive group were older than those in the
normotensive group, this age mismatch does not
explain the observation that dopamine excretion was
higher in the hypertensive subjects than in normotensive subjects, because dopamine excretion did not
change with age in a large group of healthy outpatients aged 20-65 years. It should be noted, however,
that a preliminary publication indicates that very old
subjects, aged 70-89 years, may have lower dopamine excretion than young subjects aged 18-26
years.26 Urinary dopa excretion tended to decrease
with age (Figure 8), consistent with age-related decrease in plasma dopa,27 and in contrast to plasma
and urinary norepinephrine levels, which tend to
increase. Hypertensive patients on a low salt diet
previously were found to have a higher mean rate of
dopamine excretion than normotensive control subjects of unspecified age.12 Normotensive subjects with
a family history of hypertension have been reported
to lack the usual positive relation between dopamine
and sodium excretion, because of relatively high
values for urinary dopamine excretion in some subjects with relatively low values for sodium excretion28;
and patients with borderline hypertension had higher
urinary dopamine excretion rates than did normotensive control subjects or patients with established
hypertension.29
Our findings that salt-sensitive patients tended to
have decreased plasma dopamine concentrations and
blunted dopamine excretory responses to dietary salt
loading are similar to results reported for "non-mod-
620
Hypertension
Vol 18, No 5 November 1991
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ulating" hypertensive patients who as a group tend to
be salt-sensitive.30 These changes in plasma and
urinary dopamine of the salt-sensitive group were
minor compared with the abnormalities in dopa
excretion.
The extents of suppression of plasma levels of
norepinephrine and of urinary excretion of norepinephrine during 1 week of dietary salt loading did not
differ in salt-sensitive and salt-resistant patients. In
other studies, Fujita et al15 noted suppression of
plasma norepinephrine levels in salt-sensitive patients at 3 days but not 4 days of salt loading.
Campese et al14 reported no suppression of plasma
norepinephrine levels in salt-sensitive patients after 1
week of salt loading. Koolen and van Brummelen16
found normal suppression of norepinephrine levels
at the end of 1 week but not at the end of 2 weeks of
salt loading. We previously1 reported that plasma
norepinephrine levels in salt-sensitive patients were
more suppressed on day 4 than on day 8 of high salt
intake. Dustan,31 Masuo et al,17 and Shikuma et al10
reported that the extent of suppression of plasma
norepinephrine levels or urinary norepinephrine excretion did not distinguish salt-sensitive and saltresistant groups. Thus, although most studies have
indicated that plasma norepinephrine levels do not
decrease normally in salt-sensitive patients during
dietary salt loading, the pattern of response has been
variable.
In conclusion, dietary salt loading increased the
rate of urinary excretion of dopa. Patients with
salt-sensitive hypertension, who as a group tend to
have blunted responses of urinary dopamine excretion to salt loading, had exaggerated responses of
urinary dopa excretion to salt loading. Urinary dopa
excretion during the first 3 days of salt loading was
related to the magnitude of the pressor response.
Since patients with salt-sensitive hypertension had a
low ratio of dopamine to dopa in urine, regardless of
dietary salt intake, a high urinary excretion of dopa
and a low urinary dopamine/dopa ratio may indicate
salt-sensitive hypertension.
Acknowledgment
We acknowledge the technical assistance of
Robin Stull.
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KEY WORDS • dopamine • salt • sodium • norepinephrine
• salt-sensitive hypertension • dopa
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High urinary dopa and low urinary dopamine-to-dopa ratio in salt-sensitive hypertension.
J R Gill, Jr, E Grossman and D S Goldstein
Hypertension. 1991;18:614-621
doi: 10.1161/01.HYP.18.5.614
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
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