Age, Race, Diagnosis, and Sodium Effects on the
Pressor Response to Infused Norepinephrine
JOEL E. DIMSDALE, ROBERT M. GRAHAM, MICHAEL G. ZIEGLER,
RANDALL M. ZUSMAN, AND CHARLES C. BERRY
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SUMMARY We studied the blood pressure responses to infused norepinephrine in 34 normotensive
and 21 unmedicated subjects with essential hypertension. The two groups were similar in age, relative
body weight, and urinary electrolyte excretion. Patients were studied on two extremes of dietary salt
(200 mEq Na and 10 mEq Na per day). The dose-response curves were highly linear (p<0.00001) for
both systolic and diastolic blood pressures. There was no evidence for an increased sensitivity to
infused norepinephrine among the hypertensive subjects. On the other hand, older subjects had
steeper slopes ( p < 0.005). Subjects on a high salt diet had steeper slopes than those on low salt diets
(p<0.0025); this trend was especially apparent among blacks (p<0.005). Black and white hypertensive subjects responded to the high salt diet in opposite fashion: The blacks showed an increased
pressor sensitivity (p<0.05), whereas the whites demonstrated a nonsignificant decreased pressor
sensitivity. These results indicate that age, race, and salt effects must be meticulously controlled in
studies of sympathetic nervous system physiology. (Hypertension 10: 564-569, 1987)
KEY WORDS
• norepinephrine
• sodium
• hypertension
I
N 1948, Goldenberg et al.1 made the intriguing
observation that hypertensive patients seemed
unusually sensitive to the blood pressure (BP)elevating effects of infused norepinephrine (NE).
Since then, many investigators have studied the slope
of this relationship, comparing hypertensive and normotensive subjects. Since BP is elevated in many essential hypertensive patients because of increased peripheral resistance, many researchers have expected
that hypertensive patients would demonstrate an increased vascular sensitivity (or steeper dose-response
slopes) to infused NE. 2 Over the years, however, this
hypothesized increased sensitivity has not been replicated consistently. Although no one has reported that
hypertensive subjects are less sensitive than normotensive subjects to infused NE, the findings are mixed,
• race • age • hostility
with some studies reporting increased sensitivity
among hypertensive subjects3"7 and other studies failing to find such increased sensitivity.8"17
In reviewing these studies, we have been struck by
their frequent reliance on small sample size and their
failure to control for possibly confounding factors. In
some early studies, virtually all hypertensive subjects
were grouped together, regardless of subtype, for contrast with normotensive subjects. Other differences in
the studies concern the severity of hypertension: Some
investigators examined moderately hypertensive subjects, whereas others examined mildly hypertensive
subjects. Any of these differences may account for the
divergent findings. Finally, a sound, quantitative basis
for establishing a dose-response curve is absent in
many of the studies. Many studies infused only one or
two doses of NE, and from these administrations inferred a linear relationship, despite the fact that the
proposed difference in sensitivity could just as well be
curvilinear (e.g., apparent principally at low doses of
infused NE).
Curiously, many of these studies neglected to examine age effects even though older subjects have decreased clearance of NE from the circulation.18 Additionally, differences in sodium intake were similarly
ignored in many studies, although salt has major actions on sympathetic nervous system activity. For instance, salt depletion shortens the prolonged half-life
From the Departments of Psychiatry (J.E. Dimsdale), Medicine
(M.G. Ziegler), and Community and Family Medicine (C.C. Berry), University of California, San Diego, La Jolla, California; and
the Department of Medicine (R.M. Graham, R.M. Zusman), Massachusetts General Hospital, Boston, Massachusetts.
Supported by Grants HL36005, HL350I8, and RROO827 from
the National Institutes of Health.
Address for reprints: Joel E. Dimsdale, M.D., UCSD Medical
Center, University of California, San Diego Medical Center, 225
Dickinson Street, San Diego, CA 92103-9981.
Received January 12, 1987; accepted June 22, 1987.
We are grateful to Dr. Stevo Julius for acting as guest editor in the
evaluation of this manuscript.
564
PRESSOR RESPONSE TO INFUSED NOREPlNEPHRINE/Dims^a/e et al.
of NE in hypertensive subjects." A number of other
factors related to BP might confound studies contrasting normotensive and hypertensive subjects; for example, family history, obesity, and race are clearly related to BP. Two psychosocial factors — depression and
hostility — have also been suggested as related to
g p 20.21 jf a n y o f m ese many factors were unequally
represented across hypertensive and normotensive
subjects, one would have reason to doubt the validity
of attributed slope differences across the diagnostic
groups. We have examined this topic anew, trying to
take into consideration these various methodological
criticisms.
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Subjects and Methods
Subjects were recruited from community BP screening or by word of mouth. We studied 34 healthy men
and 21 untreated hypertensive men. All subjects (hypertensive and normotensive) were free from any
medication for at least 3 weeks before participation in
the study. Subjects were classified as normotensive if
systolic BP was below 140 mm Hg and diastolic BP
was below 90 mm Hg. Hypertensive subjects were
defined as having systolic BP above 140 mm Hg or
diastolic BP above 90 mm Hg. BPs were taken with a
mercury sphygmomanometer after the subject had
been seated quietly for at least 5 minutes. Three BP
values were obtained, and subjects were classified on
the basis of the average of these readings. The subjects
returned for a repeat BP screening approximately 1
week later. Subjects were enrolled in the study only if
they remained in the same BP group on repeat testing.
The mean BPs for the normotensive and hypertensive
groups were 120/73 and 144/95 mm Hg, respectively.
Subjects' ratings on the Beck Depression Inventory22 and the Buss-Durkee Hostility Scale23 were obtained before the infusions. A family history was considered positive for hypertension if the subject
indicated that a parent had high BP. Relative obesity
was calculated using Metropolitan Life Insurance
tables.24
Subjects were admitted twice to the Clinical Research Center and randomized to either a high sodium
diet (200 mEq/day) for 4 days or a low sodium diet (10
mEq/day) for 5 days. The opposite diet was used during the second admission. Both diets were isocaloric
and contained potassium, 100 mEq/day. An interval of
approximately 1 week separated the hospitalizations.
Four subjects completed only one hospitalization.
Twenty-four-hour urine samples were obtained for
electrolytes.
The NE infusions were performed in the early afternoon of the final day of each hospitalization. All subjects had been caffeine-free for at least 16 hours before
the infusion studies and had been asked to refrain from
cigarette smoking for at least 7 hours before the infusion studies.
The subjects were tested in the supine position. A
D5W drip (5% dextrose in water) at the rate of 180
ml/hr was administered in the subjects' nondominant
565
arm, and BPs were taken repeatedly during a half-hour
period while the subject became acclimated to the infusion and the repeated BP measurements. At the end of
the 30-minute interval, three more BPs were taken,
and their average was used as the subject's baseline
BP. After the baseline period, the NE solutions were
added to the sustaining infusion. A freshly constituted
solution of NE in D5W was infused at the rate of 0.01
/Ltg/kg/min for 10 minutes. Subsequent doses were
0.025, 0.05, and 0.10 pig/kg/min, each given for 10
minutes. The infusion was stopped if systolic BP increased by 30 mm Hg, diastolic BP increased by 25
mm Hg, or if premature ventricular contractions occurred. Throughout the infusion, BP was taken by a
mercury sphygmomanometer every minute after the
start of each infusing dose and continued until the BP
plateaued for 3 successive minutes at that given dose.
The data were initially examined with a repeatedmeasures analysis of variance (ANOVA) and an orthogonal polynomials decomposition to determine whether the increase of BP with increased amounts of
infused NE was linear. The linear term was found to be
highly significant (p< 0.00001) for both systolic and
diastolic BPs, while the higher order terms were not
significant. Moreover, the higher order effects accounted for only a small portion of the total variance.
Because of our safety precautions for stopping the NE
infusion (see the preceding paragraph), there were
some missing data; as a result, we could not rely on a
repeated-measures ANOVA as the fundamental tool
for analysis. Rather, we used a least-squares analysis
for each subject to quantitate the slope of the line
relating infused NE and BP. Unpaired t tests were used
to contrast the hypertensive and normotensive subjects
in terms of the average slope and intercept of such
dose-response curves. We examined other variables to
ascertain whether they were significantly related to the
slope of the dose-response curve. For continuous variables (age, relative obesity, depression, hostility), we
calculated Pearson correlation coefficients with slope.
For categorical variables (race, family history of hypertension), we employed unpaired / tests to contrast
the slopes. Finally, we examined the effect of dietary
salt by employing a paired t test.
Results
The hypertensive and normotensive groups did not
differ in age or relative obesity. Analysis of 24-hour
urine samples obtained the day before the study revealed no significant differences in urinary sodium or
potassium excretion (Table 1).
As a result of hospitalization, the BP in both groups
fell. Diastolic BP of most of the subjects who were
originally classified as hypertensive on two separate
occasions decreased below 90 mm Hg after 4 days of
hospitalization and rest, but overall BP in this group
remained 10/10 mm Hg higher than that of the control
group. There were no untoward effects of the NE
infusion.
Figure 1 portrays the relationship between infused
HYPERTENSION
566
TABLE 1.
Characteristics of the Sample
Variable
Race (black/white)
Age (yr)
Relative body weight
High Na admission electrolytes
Urinary Na (mEq/24 hr)
Urinary K (mEq/24 hr)
Low Na admission electrolytes
Urinary Na (mEq/24 hr)
Urinary K (mEq/24 hr)
Normotensive Hypertensive
(" = 34)
(i = 21)
8M3
19:15
32±6
35±7
l.l±0.1
1.1 ±0.2
214±87
62 ±20
217±52
66±17
22 ±10
57 ±22
Values, except for race, are means ± SD. There were no significant differences between groups.
29 ±25
69 ±19
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60
50
140
SYSTOLIC
130
120
VOL
10,
No
6,
DECEMBER
1987
NE and BP for the normotensive and hypertensive
subjects. Despite the relative normalization of BP in
the hypertensive group, there was still a significant
difference (/?<0.001) in the overall BP (or intercept)
between the hypertensive and the normotensive groups
0 = 3.90 systolic; f = 4.24 diastolic). However, the
amount of that difference was consistent at all dose
increments. In other words, the slopes of the relationship were not different for the hypertensive and normotensive groups (t = 1.29 systolic; t = 0.37 diastolic).
We examined whether other variables would influence the slope of the dose-response curve (Table 2).
Relative obesity, family history of hypertension, depression, and hostility were unrelated to slope. On the
high salt diet, older subjects had a greater BP response
to infused NE (p< 0.005; Figure 2).
Race and diet powerfully affected slope (Figure 3).
The slope was steeper on the high salt diet than on the
low salt diet for all the subjects and for the normotensive group (p<0.0025). This salt effect was not observed among the hypertensive group because the hypertensive blacks and hypertensive whites responded
in opposite fashion. The blacks had steeper slopes on
the high salt diet (p<0.05), whereas the whites had a
nonsignificant decrease in slope in response to the high
salt diet.
no
100 aASTOUC
90 80
— - —
70
——
Hypertv&vt
Hormottmn*
60
0
025
05
075
10
N0REP1NEPHRIC INFUSED (>iQ/kg)
FIGURE 1. Dose-response curve relating BP to infused norepinephrine during high salt diet (200 mEqlday). Similar linearity
was observed during low salt diet (10 mEqlday).
Discussion
This research was undertaken to clarify the relationship between infused NE and resulting BP. This technique does not measure only a-adrenergic receptor
sensitivity, because the pressor response to NE is
modulated by a reflex bradycardia that is mediated by
the vagus.23 By assessing the change in heart rate per
millimeter-of-mercury increase in BP over the range of
the dose-response curve, we obtained an index of
baroreceptor activity. This activity was not significantly different in subgroups by race or diagnosis on
either diet (by one-way ANOVA). As a result, we
doubt that vagal activity differences in our subgroups
could be obscuring our index of a-adrenergic receptor
sensitivity.
TABLE 2. Variables Associated with Slope (Systolic BP)
Total (r, = 55)
Normotensive (« = 34)
Hypertensive (" = 21)
Low Na
High Na
Low Na
High Na
Low Na
High Na
r = -0.017
r = 0,297
r = 0.407t
r= -0.004
r= 0.475*
r= 0.017
r = 0.212
r= 0.108
r = 0.100
r= 0.206
r= 0.195
r= 0.240
t= 0.64
/= 0.36
t = 0.96
/= 0.15
r=-0.22
/= 0.89
r = 0.025
r = 0.075
r=-0.022
r= -0.106
r= 0.157
r = 0.231
r=-0.154
r = -0.226
r= 0.054
r = 0.418
r = -0.132
r = -0.131
t = +0.60
r= +2.51$
/= +0.01
/= + 1.24
»=-0.12
/= -0.46
t=
2.23*
t= 3.47§
t= 2.78*
(= 1.62
/= 1.39
t= 3.48§
Subjects were studied during high salt (200 mEq/day) and low salt (10 mEq/day) diets.
*p<0.05, t p < 0.005, tp< 0.025, §p< 0.0025. For r values, p indicates the strength of association; for rvalues,/? indicates the degree of
difference between subgroups in terms of slope.
Variable
Age
Relative obesity
Family history of hypertension
Beck depression score
Buss-Durkee total hostility score
Black vs white race
High Na vs low Na diet
PRESSOR RESPONSE TO INFUSED NOREPINEPHRINE/D/mst/a/e et al.
IOOO
800
600
J
400
i
200
0
-200 15
20
25
30
35
AGE
40
45
50
FIGURE 2. Effect of age on systolic pressor sensitivity during the high salt diet (200 mEqlday).
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ALL SUBJECTS
500
55
An additional issue concerns the variable rate of
clearance and half-life of plasma NE across individual
subjects.26-27 A dose-response calculation employing
blood levels, as opposed to infused doses, would allow
a more accurate estimation of receptor sensitivity and
would eliminate the confusing factor of different rates
of NE clearance in different subjects. We did draw a
baseline plasma NE level before beginning the infusion and observed no significant overall correlation
between resting NE and slope for systolic or diastolic
BP on either diet. Future studies will examine NE
levels at each step of the NE infusion. Predictably, NE
levels increased in response to the low salt diet; however, the degree of increase was unrelated to the
change in slope of the dose-response curve (r = 0.005
for systolic slope, r = 0.195 for diastolic slope).
Despite these caveats, we believe these data lead to
NORMOTENSIVE
HYPERTENSIVE
r
400
300
x
p
200
100
rri
<n
0
5
100
-
200
-
567
3C0
Wh
FIGURE 3. Effect of salt on pressor sensitivity. The slope of the BP dose-response curve to infused norepinephrine
was calculated, and the slope on the low salt diet was subtracted from the slope on high salt diet for each subject.
The mean, SE, and individual points are portrayed for different groups according to race and diagnosis. Single
(p < 0.05), double (p < 0.025), triple (p < 0.005), and quadruple (p < 0.0025) asterisks denote the significance of
the salt effect in each group (obtained by paired t tests). All = all subjects; Bl = blacks; Wh = whites.
568
HYPERTENSION
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an important and clear conclusion. There is a disagreement in the literature about the relationship between
infused NE and the resulting BP in normotensive and
hypertensive subjects. Our data argue against a difference in sensitivity across the two groups. It is possible
that subjects with moderate to severe hypertension
could be more sensitive than normotensive subjects,
but in comparing values for normotensive subjects
with those for mildly hypertensive subjects, there was
no difference in slope. Our methodology was designed
explicitly to control for factors that might influence the
dose-response relationship. When we examined such
factors, we found that they could have marked effects
on slope, thus possibly confounding the relationship
between diagnosis and slope.
There is some evidence that older subjects have a
reduced clearance of NE from the circulation.l8 In addition, there is some evidence that the pressor response
increases with age6; however, not all groups have observed such an effect.28 Even across our modest age
span (19—48 years), we found that older subjects on the
high salt diet had steeper slopes relating BP to infused
NE. If previous studies did not meticulously control
for dietary salt and age differences, their comparisons
of hypertensive and normotensive subjects would thus
be of diminished value.
Since weight loss is associated with a decrease in
adrenergic activity,29 it is possible that obese hypertensive persons have a steeper slope; however, Boehringer et al.30 found no difference in NE sensitivity
among obese patients. In our study as well, relative
obesity was not related to slope. However, our obesity
range was quite circumscribed (91 -151 % of ideal body
weight).
We could not reconfirm the observation by Bianchetti et al.31 that a family history of hypertension was
related to slope. We relied on unverified self-report of
family history; thus, these data are subject to question.
There is a growing psychiatric literature about possible sympathetic dysregulation in depressed patients.3233 In addition, depression has long been
known to increase BP.20 Our tool for depression was a
self-reported demoralization measure that is related to
but not identical to a formal psychiatric diagnosis of
depression. We found no association between slope
and the Beck Depression Inventory. If there is a slope
effect, it may be evident only in clinically depressed
patients. Abnormalities in regulation of hostility have
also been related to hypertension,21 but they were unrelated to slope in this study. Taken together, these two
findings suggest that no confounding of diagnosis and
slope occurred because of these psychosocial factors.
We know of no study that has explicitly compared
black and white dose-response curves. As race was
rarely discussed in previous studies, no information
was available about possible differences in the racial
composition of the hypertensive or control groups. In
our study we found a significant difference across the
races. On the high salt diet, black hypertensive subjects had steeper slopes than white hypertensive subjects (p < 0.025); there was no racial difference for the
normotensive subjects.
VOL. 10, No 6, DECEMBER 1987
We reconfirmed the observation by Rankin et al.34
of a steeper dose-response curve on high salt diets.
Rankin et al.M contrasted sodium diets of 800 and 10
mEq/day; as our work demonstrates, the salt sensitization is apparent even at a dietary sodium intake of 200
mEq/day (p<0.0025). In addition, we again found a
race effect: In general, blacks were particularly sensitive to salt loading (p< 0.005); whereas whites had a
nonsignificant response to salt loading. However, in
the diagnostic subgroups, the pattern of sensitization
was exactly opposite: There was salt sensitization
among the normotensive whites and hypertensive
blacks (see Figure 3). Using diet as a within-subject
measure and race and diagnosis as between-subjects
measures, we employed a repeated-measures ANOVA
to examine the role of salt, race, and diagnosis. The
analysis revealed a significant three-way interaction
among salt, race, and diagnosis (p<0.02). These racial and salt response differences are new observations. However, they must be tempered by the small
sample size in the subgroups.
A final observation relates to our method of data
analysis. We used each subject's total data to generate
a dose-response curve rather than rely on only one or
two points. At the doses infused, this relationship was
highly linear, suggesting that elaborate data transformations are not necessary.
At first glance, our findings may seem primarily
negative in nature. We are yet another research group
that has failed to replicate observation of an increased
sensitivity to NE infusions among hypertensive subjects. However, the reasons for such confusion are
now clearer. Age, dietary salt intake, and race all impinge rather clearly on the sensitivity of the dose-response curve. Few reported studies controlled for one
of these factors, let alone three. Our findings point to
the importance of meticulous care in controlling for
these factors in studies of sympathetic nervous system
physiology. These data also suggest a basic difference
between black and white subjects' pressor sensitivity
in the face of increased dietary salt.
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J E Dimsdale, R M Graham, M G Ziegler, R M Zusman and C C Berry
Hypertension. 1987;10:564-569
doi: 10.1161/01.HYP.10.6.564
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