Definitions and Characteristics of Sodium
Sensitivity and Blood Pressure Resistance
MYRON H. WEINBERGER, JUDY Z. MILLER, FRIEDRICH C.
CLARENCE E. G R I M , AND NAOMI S.
LUFT,
FINEBERG
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SUMMARY Sensitivity and resistance to the effects of sodium were evaluated in normotensive and
hypertensive humans by two approaches. Blood pressure was measured after an intravenous infusion
of 2 L of normal (0.9%) saline and after sodium and volume depletion induced by a low sodium diet
and furosemide administration in 378 normal volunteers and 198 subjects with essential hypertension.
Those in whom mean arterial blood pressure decreased by at least 10 mm Hg after sodium and volume
depletion were considered sodium-sensitive, and those with a decrease of 5 mm Hg or less (including
an increase in pressure) were considered sodium-resistant. The second study utilized the blood
pressure response to modest dietary sodium restriction in 74 normotensive subjects to identify sodium
sensitivity and resistance. In both studies the responses were heterogeneous. In the first study significantly more hypertensive subjects were sodium-sensitive, as compared with those in the normotensive
group (p<0.001). Plasma renin activity (low, normal, or high) did not predict sodium responses. In
both groups sodium-sensitive individuals were significantly older (p<0.001) and had lower baseline
renin values than sodium-resistant subjects. Factors related to the change in mean arterial blood
pressure after sodium and volume depletion included baseline pressure ( r = —0.54, p < 0.001) and
age ( r = —0.16, p = 0.002 in the normotensive group; r= - 0 . 2 8 , p < 0.001 in the hypertensive
group). The response to dietary sodium restriction was also correlated with baseline pressure
(r = 0.61, p<0.001) and the initial urinary sodium excretion (r = 0.27, p<0.01). These two different
studies demonstrate that sensitivity and resistance exist in normotensive as well as hypertensive
subjects and that this phenomenon may be associated with the change in blood pressure with age.
(Hypertension 8 [Suppl II]: II-127-11-134, 1986)
KEY WORDS
• hypertension
• salt
• race • age • renin
S
UBSTANTIAL epidemiological evidence implicates sodium indirectly in the prevalence of hypertension and its cardiovascular sequelae.1
Although the beneficial effects of severe sodium restriction in the treatment of hypertension have long
been recognized, 2 ' 3 evidence of blood pressure reduction with modest degrees of sodium restriction is relatively recent.4"8 Considerable debate has been engendered regarding the role of sodium in the pathogenesis,
maintenance, and treatment of hypertension.9"13
Studies in normotensive subjects have demonstrated
a blood pressure rise with massive sodium loading14
From the Indiana University School of Medicine, Indianapolis,
Indiana.
Supported in part by Grants HL14159 and HL27398 from the
U.S. Public Health Service.
Address for reprints: Myron H. Weinberger, M.D., Hypertension Research Center, Indiana University School of Medicine, 541
Clinical Drive, Indianapolis, IN 46223.
11-127
and a decrease in blood pressure with a modest reduction in sodium intake,15 indicating that the blood pressure response to sodium is heterogeneous. The concepts of sodium sensitivity and resistance of blood
pressure have been advanced by several investigators
using different techniques and studying different populations.16"20 However, the characteristics and mechanisms involved in these responses remain unclear.
We have utilized a standardized protocol of rapid
intravascular volume expansion21 and contraction22 for
clinical and investigative purposes in a large population of normotensive and hypertensive subjects.23"30 In
addition, we have examined the effect of modest dietary sodium restriction in a number of normotensive
families.l5 These two studies provided a unique opportunity to examine sodium sensitivity and resistance of
blood pressure in different ways in a large number of
carefully characterized normotensive and hypertensive
subjects.
11-128
1985 BLOOD PRESSURE COUNCIL
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Methods
All studies described below were approved by the
Indiana University School of Medicine Human Use
and Clinical Research Center Committees. Informed
consent was duly documented. The designs of the studies have been described in detail previously. "• 21~30 The
rapid volume expansion and contraction protocol was
performed in 378 normotensive subjects and in 198
subjects with essential hypertension in whom secondary forms of hypertension had previously been excluded.2122 Antihypertensive medications had been
withdrawn for 2 weeks or more, and oral contraceptives or estrogens (in normal volunteers) for at least 3
months. All normotensive subjects had blood pressure
readings under 140/90 mm Hg at every outpatient visit
and throughout hospitalization. All hypertensive subjects had three or more readings above that level, including at least one while they were hospitalized.
Briefly, after a 1-day period of hospital acclimatization, subjects underwent blood sampling, blood pressure measurement, and urine collection beginning at
0800. At that time, they received an intravenous infusion of 2 L of normal (0.9%) saline at a rate of 500
ml/hr.21 At the end of the saline infusion (noon), blood
was again sampled, urine collection terminated, and a
new collection begun, which lasted until midnight. A
third urine collection occurred during the sleep period
and ended at 0800 the following morning. On the day
after the saline suppression maneuver, sodium and volume depletion was induced by a 10-mEq sodium diet
and three doses of oral furosemide (40 mg) given at
1000, 1400, and 1800.22 The stimulatory effect of sodium and volume depletion was assessed in blood samples obtained at 0800 the following morning, after
2 hours of ambulation. The normotensive subjects
served as age-, race-, and sex-matched controls for the
hypertensive subjects. The protocol also permitted
subdivision of the hypertensive group on the basis of
plasma renin activity (PRA) as follows: high renin
(PRA >2.5 ng/ml/3 hr after saline), low renin (PRA
^4.0 ng/ml/3 hr after sodium and volume depletion
and upright posture), and normal renin (normal suppression anu stimulation of PRA). Subjects with primary aldosteronism were identified by failure of plasma aldosterone to be suppressed normally (< 10 ng/dl)
after saline infusion,21 as well as failure of PRA to be
stimulated normally ( s 4 ng/ml/3 hr) after the sodium
and volume depletion maneuver.22 Trained and certified nurses measured blood pressure.
The purpose of the second study, conducted in normotensive volunteer families, was to examine the feasibility of, and blood pressure response to, modest
dietary sodium restriction (^80 mEq/day) in ambulatory subjects living at home. The details of subject
recruitment15 and dietary instruction31 have been described previously. In brief, during a baseline period of
1 month, 74 adults each collected five 24-hour urine
samples and subsequently received individualized dietary instruction from a research dietitian. During the
next 3 months, their adherence to dietary sodium restriction was evaluated by 24-hour urine collections
SUPPL
II HYPERTENSION, VOL 8, No 6, JUNE 1986
Salno
Infusion
Sodkfn and
VoUns Depletion
-10L p-co.001 J
-16
FIGURE 1. Changes in mean arterial blood pressure in response to saline infusion and sodium and volume depletion in
normal (open bars) and hypertensive subjects (stippled bars).
every 2 weeks. Blood pressure was measured in the
home by trained and certified individuals on the days
of urine collection, during the baseline and sodium
restriction phases. At each visit three measurements
were made while the subjects were seated; an average
of the second and third measurements was used for
data analysis.
PRA,32 aldosterone,33 and norepinephrine34 were
measured by radioassay techniques. Sodium, potassium, and creatinine were measured by established
automated techniques. After coding, entry into a computer, and verification, data were analyzed with paired
and unpaired / tests, chi-square comparisons, repeated
measures analysis of variance and covariance, and
multiple regression analysis. Differences were considered to be significant at the level of p<0.05, except
when a two-tailed paired t test was used, in which case
p<0.1 was considered to be significant.
Results
The mean blood pressure responses to the saline
infusion and to the sodium and volume depletion maneuver in hypertensive and normotensive subjects are
depicted in Figure 1. Although a significant increase in
mean arterial blood pressure (MABP) after saline infusion was seen in both groups (p <0.001), there was no
significant difference in the magnitude of the response
between normal and hypertensive subjects. As seen in
Figure 1, both groups had a decrease in blood pressure
after sodium and volume depletion. The response of
the hypertensive group was significantly (p<0.001)
greater than that of the normotensive group.
For purposes of further investigation, the MABP at
the end of the saline infusion was compared with that
observed during upright posture the morning after the
sodium and volume depletion maneuver. Individuals
with a decrease in MABP of at least 10 mm Hg were
designated as sodium-sensitive, and those with less
than a 5 mm Hg decrease (including those with an
increase in MABP) were considered to be sodiumresistant. Individuals with an intermediate change in
SODIUM SENSITIVITY AND RESISTANCE/Weinberger et al.
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MABP ( < 10 mm Hg but s 5 mm Hg) were considered
to have indeterminate sodium sensitivity. Figure 2
shows the distribution of normotensive and hypertensive individuals on the basis of their MABP response
to rapid expansion and contraction of sodium and extracellular fluid balance. Data in both groups demonstrated a Gaussian distribution. The curves were significantly different (p< 0.001) when compared by the
Kolmogorov-Smirnov test.35 The hypertensive subjects were more sensitive to sodium than the normotensive subjects, but striking heterogeneity was evident in
both populations. Table 1 indicates the proportionate
responsiveness in the two groups. More than half the
normotensive subjects demonstrated sodium resistance, and one fourth were sodium-sensitive. Half the
hypertensive subjects were sodium-sensitive, and one
third were sodium-resistant. The same proportion
(16%) of both groups had an indeterminate response.
The sodium-sensitive and sodium-resistant subgroups within each population were compared on the
basis of various characteristics, shown in Table 2. In
both groups sodium-sensitive subjects were significantly older than those in whom MABP was resistant
to sodium (p<0.001).
Sodium-sensitive subjects
within both populations had significantly lower PRA
values at baseline (p<0.0l). Since neither PRA nor
plasma aldosterone values were normally distributed,
a square root transformation was utilized before analy-
RESISTANT( < 5 mmHg)
58. « %
33. 3 %
25 -1
11-129
TABUE 1. Proportionate Responsiveness to Rapid Sodium and
Volume Expansion and Contraction in Normotensive and Hypertensive Subjects
SodiumSodiumSubjects (n)
sensitive
Indeterminate resistant
Normotensive (375)
26.0%
15.7%
58.4%
Hypertensive (192)
51.0%
15.7%
33.3%
Sodium sensitivity was defined as a change of at least 10 mm Hg
in mean arterial blood pressure (MABP), and sodium resistance as a
change of less than 5 mm Hg; indeterminate responses were defined
as values falling in between (< 10 mm Hg but &5 mm Hg).
sis to provide a more normal distribution and to facilitate data analysis. After the saline infusion, the magnitude of PRA suppression did not differ between the
sodium-sensitive and sodium-resistant normotensive
subjects, but sodium-resistant hypertensive individuals had significantly higher PRA values at every measurement than did their sodium-sensitive counterparts
(/?<0.001). After stimulation of the renin-aldosterone
system by sodium and volume depletion, significantly
lower PRA was seen in sodium-sensitive subjects,
or hypertensive
whether normotensive (p<0.05)
(p<0.00l), than in those who were sodium-resistant.
To examine the relationship between age, PRA, and
sodium sensitivity or resistance, we performed an
analysis of covariance, as well as matching subjects in
(5-10)
15.7%
15.7%
- SENSITIVE ( > ! 0 mcnHcj)
26.0%
51.0%
NORMOTENSIVE (375)
20 -
HYPERTENSIVE (192)
z
o
D
a.
O
a.
hZ
15 ~
10 -
5-
-27.5
-17. 5
-7. 5
37.5
17.5
CHANCE IN MEAN ARTERIAL PRESSURE (mmHg)
(Saline Infusion-Low Sodium • Furosemide)
FIGURE 2. Blood pressure responses to the maneuvers in normotensive and hypertensive subjects, according to
their sensitivity or resistance to sodium. The hypertensive subjects were significantly (p< 0.001) more sensitive to
sodium than the normotensive subjects. I = indeterminate response to sodium.
11-130
1985 BLOOD PRESSURE COUNCIL
SUPPL
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HYPERTENSION, VOL
8, No 6,
JUNE
1986
TABLE 2. Differences between Sodium-Sensitive and Sodium-Resistant Subjects
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Measurements
Age (yr)
PRA (ng/ml/3 hr)
Baseline
Suppressed
Stimulated
Plasma aldosterone (ng/dl)
Baseline
Suppressed
Stimulated
Serum creatinine (mg/dl, baseline)
Plasma norepinephrine (/xg/ml)
Baseline
Suppressed
Stimulated
Normotensive
Sensitive
Resistant
35.3±1.8
26.9 + 0 8*
2.3±0.09
1.1 ±0.04
4.7+0.19
2.6 + 0.06t
1.2 ±0.03
5.2 + O.1U
Hypertensive
Sensitive
43.8+ 1.4
Resistant
35.5+1.7*
1.8+0.11
1.0±0 05
3.1±0.17
2.9±O.I5*
1.4 ±0.07*
4.8±0.21*
5.4 + 0.2
1.8±0.1
7.7±0.3
1.02 ±0.02
5.4±0 1
1.7 + 0.04
7.6±0.2
1.01 ±0.01
5.1 +0.2
2.0±0.1
7.4 + 0.3
l.04±0.03
6.0±0.4
1.8±0.l
8.4±0.5
1.15±0.04+
0.32±0.04
0.14±0.02
0.59±0.08
O.22±O.O2*
0.14 + 0.01
0.45 ±0.03
0.31 ±0.05
O.15±O.O3
0.43 + 0.08
0 29 ±0.07
0.13 ±0.03
0.68±0.12
Values are means ± SEM. PRA = plasma renin activity.
0 0 1 , tp<0.01, t 0 0 5
both groups for age. After adjustment for age in the
normotensive group, there was no difference in PRA.
However, when the sodium-sensitive and sodium-resistant subgroups were separated into those 40 years of
age or under and those who were over 40, the sodiumsensitive subjects in the older group had significantly
lower PRA (p<0.00l). In the hypertensive group,
correction for age did not change the significant difference (p<0.001) in PRA.
Although differences in PRA were observed between the sodium-sensitive and sodium-resistant
groups, no differences in plasma aldosterone levels
were discernible, at baseline or after the suppressive or
stimulatory maneuvers. Sodium-resistant hypertensive
subjects had higher baseline serum creatinine values
than did their sodium-sensitive counterparts (p < 0.05,
see Table 2). No differences were seen in the serum
creatinine values in normotensive subjects. At baseline, sodium-resistant normotensive subjects had lower levels of plasma norepinephrine (/?<0.05) than
those who were sodium-sensitive. Such differences
were not observed after saline suppression or volume
depletion or in the hypertensive subjects. Urinary norepinephrine excretion did not differ among any of the
groups at any point in the study.
To determine whether demographic characteristics
influenced sodium sensitivity or resistance, subjects
were subdivided on the basis of race and sex. The
results of this analysis are shown in Figure 3. Among
normotensive subjects, there were no differences in the
responses of any group during the study. Among hypertensive subjects, black women had a significantly
greater blood pressure increase with saline infusion
than did white women (p<0.05), but no other differences were seen. Hypertensive subjects were noted to
have a significantly greater change in blood pressure
after the sodium and volume depletion maneuver than
the normotensive subjects (p<0.001), except for
black women (who had the greatest change in blood
pressure among the normotensive subgroups), in
whom the difference was of borderline significance
(p = 0.07, see Figure 3). Sensitivity of blood pressure
to sodium was more likely to be observed among hypertensive subjects than among their race- and sexmatched normotensive counterparts (p<0.025, Table
3). There were significant differences in the distributions of sodium-sensitive and sodium-resistant
subjects in the four demographic groups, as shown in
Table 3. Among whites, normotensive subjects were
more apt to be sodium-resistant, whereas sensitive
and resistant responses were more evenly distributed
among hypertensive subjects. Among blacks, however, those with hypertension were more frequently
sodium-sensitive.
When the hypertensive subjects were compared on
the basis of their PRA values (Figure 4), the low-renin
group was found to have a significantly greater blood
pressure response to saline infusion (p<0.02) and to
sodium and volume depletion (p<0.05) than the normal- or high-renin subgroups. However, as shown in
Table 4, sensitivity of blood pressure to sodium was
also observed among individuals in the normal- and
high-renin hypertensive subgroups, and resistance was
seen in some subjects in the low-renin group. Significantly more hypertensive subjects in the low-renin
group were sodium-sensitive than in the other two
groups (p<0.01), when compared by chi-square analysis. Conversely, fewer hypertensive subjects in the
low-renin group were sodium-resistant than in the other two groups. No differences were observed between
the distributions of sodium-sensitive and sodium-resistant subjects in the normal- and high-renin subgroups.
SODIUM SENSITIVITY AND RESISTAHCEIWeinberger et al.
~
a
15 T
I
10H
11-131
I I Normotensive
fri Hypertensive
w
DC
5 -
a.
a
O
O
LJJ
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W
41
-5-
-15"
C3
-p<o 001 J
z
X
o
_2Oj
WM
L p <o 001 J
WF
L
BF
BM
FIGURE 3. Changes in mean arterial blood pressure in white male (WM), white female (WF), black male (BM),
and black female (BF) subjects in the normal and hypertensive groups.
The relationship between baseline (supine) MABP
and the change in blood pressure after furosemideinduced sodium and volume depletion was similar
( r = —0.54, p<0.001) in the hypertensive and normotensive groups. The relationship with age was
weaker but highly significant for both normotensive
subjects (r = — 0.16, p = 0.002) and hypertensive
subjects ( r = - 0 . 2 8 , p < 0 . 0 0 1 ) . In the hypertensive
group the most important predictor of the magnitude of
blood pressure change after sodium and volume depletion was baseline PRA (p< 0.002).
The preliminary results of the second study, which
measured the blood pressure response to dietary sodium restriction in normotensive adults, have been re-
15-
?
Black
White
Subjects
Normal
Hypertensive
Normal
Hypertensive
42
104
32
29
9
23
12
4
NRH
" 1
10
HRH
I
5-
rri
2
|
-5-
-10-
-15-
-20-
TABLE 3. Comparison of Sodium Sensitivity and Resistance
among Demographic Groups
LRH
1
1
' T
.
^r
1
''V
T
i
l_ p •• aoe —
FIGURE 4. Comparison of changes in mean arterial blood
pressure between the low-renin hypertensive (LRH) group and
hypertensive subjects with normal (NRH) or high (HRH) renin
responses to saline infusion (open bars) and sodium and volume
depletion (hatched bars).
Male
Sodium-sensitive
Sodium-resistant
X2 = 9.5, p = 0.002
2
X = 7.7, p = 0.006
Renin subgroup
Female
Sodium-sensitive
Sodium-resistant
TABLE 4. Proportionate Incidence of Sodium Sensitivity and Resistance among Hypertensive Renin Subgroups
31
73
X 2 =13.6, /J =
34
23
0.001
14
18
20
8
X2 = 5.1, p = 0.025
Low
Normal
High
Sodiumsensitive
Indeterminate
68%
53%
28%
20%
12%
39%
Sodiumresistant
12%
35%
33%
1985 BLOOD PRESSURE COUNCIL
11-132
-14
-11
-8
- 5 - 2
1
4
Change In MABP ( i n Hg)
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FIGURE 5. Changes in mean arterial blood pressure (MABP)
in normotensive adults after dietary sodium restriction. Sodium
sensitivity was defined as a decrease of at least 3 mm Hg, and
sodium resistance as an increase of at least 3 mm Hg.
ported previously. 15 Figure 5 depicts the distribution of
the change in MABP for the study population. We
have reexamined the heterogeneous blood pressure responses observed in that study and devised an arbitrary
definition of blood pressure sensitivity and resistance
to sodium, in order to compare responses to dietary
sodium restriction with those to saline infusion and
volume depletion. We defined sodium sensitivity as a
decrease in MABP of at least 3 mm Hg after dietary
sodium restriction, and resistance as an increase of at
least 3 mm Hg. Although these changes in blood pressure are small, the multiple precise measurements
made in the home, by the same observer using the
same Hawksley (Lancing, England) Random Zero
sphygmomanometer, and compared by repeated measures analysis of variance provide confidence in the
significance of even small changes in MABP. The
sodium-sensitive subjects (n = 31) had a significantly
higher ( p < 0 . 0 0 1 ) baseline MABP (89.01 ± 1 . 5
[SEM] mm Hg) than did those resistant to sodium
restriction ( n = 1 3 , MABP = 74.5 ± 1.4 mm Hg).
The mean age of the sodium-sensitive group
(39.8 ± 1.5 yr) was not significantly different from
that of the sodium-resistant group (36.3 ± 1.5 yr).
There were no significant differences between the two
groups in weight or in sodium or potassium excretion
at baseline or after the low-sodium diet. However, the
change in MABP during the low-sodium diet was correlated with age (r = 0 . 1 9 , p < 0 . 0 5 ) , baseline sodium
intake (r = 0.34, p<0.00l),
and baseline MABP
(r = 0.61, p < 0 . 0 0 1 ) . There were no differences in
renal function, as judged by serum creatinine levels,
between the two groups.
Discussion
These studies represent two novel approaches to the
assessment of sodium sensitivity and resistance of
blood pressure in humans. Kawasaki and colleagues16
compared the blood pressure changes when sodium
SUPPL
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HYPERTENSION, VOL
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JUNE
1986
intake was changed from 9 mEq/day to 249 mEq/day
in hypertensive subjects, and arbitrarily separated
them into sodium-sensitive and sodium-resistant responses. They observed less sodium excretion during
the high-sodium intake in the sodium-sensitive subjects than in the sodium-resistant group. They did not
examine normotensive subjects in a similar fashion.
Neither did they identify characteristics associated
with sodium sensitivity or resistance. Many studies
have demonstrated that dietary sodium restriction lowers blood pressure in hypertensive persons, but the
heterogeneous nature of responses to sodium restriction has only recently been emphasized, by Longworth
et al.36 Lever and associates37 have reported a significant correlation between total body sodium and blood
pressure in hypertensive but not normotensive subjects. They also noted a closer correlation between
sodium and blood pressure in older hypertensive subjects than in younger subjects.
The heterogeneity of blood pressure responses to
sodium depletion alone or followed by increased sodium intake prompted us to investigate possible characteristics associated with these responses. The lack of
information regarding similar responses in the normotensive population provided an additional challenge.
Using a consistent procedure of intravenous saline administration and rapid diuretic-induced sodium and
volume depletion, we were able to examine both hypertensive and normotensive subjects carefully. Although MABP rose in both groups, the increase did not
differ between them. However, the hypertensive subjects had a significantly greater fall in blood pressure
after sodium and volume depletion. Utilizing an arbitrary definition of sodium sensitivity and resistance of
blood pressure, we were surprised to note the Gaussian
distribution of responses in both normal and hypertensive populations. The significant shift toward the sodium-sensitive pole in the hypertensive group was not so
surprising in view of the representative nature of our
population and the responsiveness of average American hypertensive populations to diuretic therapy.
These studies are the first, to our knowledge, that
demonstrate the heterogeneity of sodium sensitivity
and resistance of blood pressure in normotensive as
well as hypertensive subjects and that apply the same
procedures and criteria to both populations.
The characteristics that we found to be associated
with sodium sensitivity — increased age and decreased
PRA — were also not surprising in view of our previous report of the association between these factors
and sodium excretion in normal and hypertensive subjects.29 Other investigators have also reported that diuretic-responsive hypertensive persons tend to be older
and to have lower renin levels than those in whom
diuretic therapy does not decrease blood pressure.38
However, to our knowledge, this study is the first to
confirm similar characteristics among normotensive
subjects. No discernible differences in renal function
between sodium-sensitive and sodium-resistant subjects were observed in our normotensive group. In the
hypertensive group, however, sodium resistance was
associated with significantly higher serum creatinine
SODIUM SENSITIVITY AND RESIST ANCEJWeinberger et al.
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levels than sodium sensitivity. This suggests that more
sodium-resistant hypertensive persons have intrinsic
renal disease, with the associated increased renin release and vasoconstrictor predominance of angiotensin
II affecting their blood pressure elevation. Alternatively, it is conceivable that mild renal impairment, manifested by the modest increase in serum creatinine,
prevented these individuals from responding to
furosemide appropriately. The efficacy of furosemide
in patients with moderate renal impairment makes the
latter possibility unlikely.
Plasma norepinephrine levels did not differ significantly between sodium-sensitive and sodium-resistant
normotensive subjects, and both sodium-sensitive and
sodium-resistant normotensive and hypertensive subjects had the expected decrease in plasma norepinephrine with saline infusion and the expected increase with
sodium and volume depletion, as previously observed.30 However, sodium-sensitive hypertensive
subjects in this study had significantly higher plasma
norepinephrine levels at baseline than did those who
were sodium-resistant. Since the sodium-sensitive hypertensive subjects had a greater urinary sodium excretion during the saline load, we cannot invoke a-adrenergic-mediated sodium reabsorption as an explanation
for the blood pressure response. On the other hand,
sodium sensitivity may be associated with a chronic
increase in sodium balance, which is consistent with
the lower PRA observed in this group. Thus, the subtle
increase in sodium balance could have enhanced the
pressor effects of norepinephrine39 and thus contributed to sodium sensitivity. Alternatively, a mechanism
of increased norepinephrine activity, similar to that
which others40'4I have reported in subjects with labile
hypertension and which we have found to be associated with an exaggerated natriuretic response to a saline
load in such subjects,42 may also have been operative
in the sodium-sensitive hypertensive subjects.
A variety of studies have identified individuals at
increased risk for the development of hypertension.
Black subjects are more likely to develop hypertension
than are whites. We examined both populations on the
basis of sex and race to discern any differences in
sodium sensitivity or resistance. Among the normotensive subjects, we found no demographic differences in
blood pressure responses. Among the hypertensive
subjects, black women had a greater increase in blood
pressure after saline infusion than did white women.
All hypertensive subjects had greater decreases in
blood pressure after sodium and volume depletion than
did their normotensive counterparts, except for the
black female subjects, who had the greatest blood pressure responses among the normotensive subjects. Furthermore, we observed that sodium sensitivity was
more common among the hypertensive subjects in all
four demographic groups. Thus, the differences in sodium sensitivity and resistance could not be explained
on demographic grounds.
Substantial data from a variety of studies indicate
that hypertensive persons with low PRA are more apt
to be responsive to diuretic therapy than their counterparts with normal or high PRA. Indeed, some investi-
11-133
gators have proposed that the decision to institute antihypertensive therapy be based on a patient's renin
status.36-M Although the present study confirms the
increased frequency of sodium sensitivity among hypertensive persons with low renin, it is important to
emphasize the heterogeneity of blood pressure responses that we observed in all three renin subgroups.
Sodium resistance was seen in hypertensive subjects
with low renin, as well as sodium sensitivity in subjects with high or normal renin. Thus, sensitivity of
blood pressure to sodium cannot be predicted by renin
levels alone.
Although the data from the normotensive adults participating in the 3-month study of dietary sodium restriction are less comprehensive than those obtained
with the more rapid protocol, and the number of subjects was considerably smaller, the implications of our
observations deserve emphasis. These studies demonstrate compliance with moderate dietary sodium restriction during a 3-month period by normotensive
adults living at home. They also demonstrate that modest sodium restriction can lower blood pressure in normotensive persons. The heterogeneity of blood pressure responses observed in this study, which utilized a
different intervention, confirms the concept of heterogeneity of blood pressure sensitivity and resistance
among normotensive persons. Despite the differences
in both the population and the study design, sodium
sensitivity was again correlated with age. Within this
normotensive population, subjects with higher baseline blood pressure were more apt to be sodium-sensitive than those with lower pressure. These results support the concept that the increase in blood pressure
with age, even in the normotensive range, appears to
be dependent on sodium.
These observations provide new information concerning two different approaches to the definition of
sodium sensitivity and resistance. In addition to confirming previous observations concerning certain subgroups or aspects of the sodium sensitivity phenomenon in hypertension, we have provided new evidence
of a spectrum of responses to sodium in normotensive
subjects. We have also identified similarities and differences between different populations studied in similar ways, which should be helpful in further investigations. As always, these studies pose myriad questions
to be answered. The need for specific markers of
sodium sensitivity and resistance is obvious. Their
identification would provide a major advance in the
investigation, treatment, and ultimate prevention of
sodium-sensitive hypertension. Finally, these studies,
conducted as long as 12 years ago, provide a new
opportunity to examine the contribution of sodium sensitivity or resistance to changes in blood pressure with
age.
Acknowledgments
The authors wish to acknowledge the important contributions of
many individuals in these studies. Expert secretarial support was
provided by Ms. Sandra Wilson and Ms. Uma Richmond. Ms. Julie
Ellison and Ms. Mary Anne Wagner provided help in data handling
and analyses. Technical support for the measurement of peptides,
11-134
1985 BLOOD PRESSURE COUNCIL
hormones, and electrolytes was provided by Ms. Mary Wade, Ms.
Ann Haddix, Ms. Nancy McAllister, and Mr. Charles Hancock.
Dr. J. Howard Pratt helped in the recruitment and study of some
patients.
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M H Weinberger, J Z Miller, F C Luft, C E Grim and N S Fineberg
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Hypertension. 1986;8:II127
doi: 10.1161/01.HYP.8.6_Pt_2.II127
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