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PATHOPHYSIOLOGY AND NATURAL HISTORY
HYPERTENSION
Transient enhancement of sympathetic nervous
system activity by long-term restriction of sodium
intake
MASSIMO VOLPE, M.D., FRANCO B. MULLER, M.D.,
AND
BRUNO TRIMARCO, M.D.
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ABSTRACT To further investigate the relationship between salt intake and sympathetic nervous
system activity, the short- and long-term effects of a low-salt diet (40 meq/day) were assessed in 10
normal subjects. Measurements of hemodynamic, hormonal, and other parameters were obtained on
the day preceding institution of the low-salt diet (day 0) and on days 4, 7, 30, and 60 of the diet. Urinary
sodium excretion was 178 1 0 meq/24 hr on day 0 and 31 ± 4, 38 4, 45 ± 6, and 47 + 7 meq/24
hr on days 4, 7, 30, and 60, respectively (all p < .001 compared with day 0). Blood pressure, urinary
potassium, serum electrolytes, and cardiac function (as assessed by echocardiography) were not
modified by the 2 month low-salt diet. Plasma renin activity and plasma aldosterone were significantly
elevated above control values throughout the entire period of the low-salt diet. In contrast, plasma
norepinephrine concentration increased significantly only on days 4 and 7 (from 253 ± 20 pg/ml on
day 0 to 495 ± 32 pg/ml, p < .001, and 347 + 22 pg/ml, p < .05, respectively), returning to baseline
at days 30 (280
18 pg/ml) and 60 (262 + 18 pg/ml). Changes in plasma epinephrine paralleled those
observed for norepinephrine. Similarly, resting heart rate and the blood pressure response to isometric
exercise were significantly increased only on days 4 and 7 of the low-salt diet. These results suggest
that sympathetic nervous system activity is enhanced only transiently during a sustained reduction in
sodium intake.
Circulation 72, No. 1, 47-52, 1985.
±
IT HAS LONG been hypothesized that the level of
sodium intake affects sympathetic nervous system activity both in normal and in hypertensive subjects.
There have been several reports that circulating catecholamines increase during dietary sodium restriction'`8 and decrease upon sodium loading,3' 6-9 although some conflicting data exist.'102 There have
been contradictory reports on the influence of sodium
intake on vascular reactivity and total peripheral resistance. Sullivan et al.'3 reported an increase in total
peripheral resistance during sodium depletion in borderline hypertensive subjects, whereas Takeshita et
al.'4 observed an increase in forearm vascular resistance during salt loading in subjects with hypertension.
Other authors have reported that salt loading induces
vasodilatation in normotensives'5 16 and vasoconstriction in hypertensive subjects. '7 Finally, it has been
reported that high sodium intake increases the vascular
From Clinica Medica 1, 2 Facolta di Medicina, Universitai di Napoli,
Naples, Italy, and the Cardiovascular and Hypertension Center, Cornell
University Medical Center, The New York Hospital, New York.
Address for correspondence: Massimo Volpe, M.D., Via Tasso 179,
80127 Napoli, Italy.
Received Feb. 20, 1985; accepted March 22, 1985.
Vol. 72, No. 1, July 1985
sensitivity to norepinephrine while it decreases the
basal plasma concentration of norepinephrine, ' but
others have found no change in renal vascular reactivity to norepinephrine during acute sodium repletion.'9
These discrepancies could be ascribed to differences
in the experimental protocols used in the studies, such
as differences in animal species used or clinical characteristics of the population studied (e.g., with respect to
age, blood pressure) and differences in the duration
and degree of the changes in salt intake.
The purpose of the present study was to assess the
time course of the humoral and hemodynamic responses to a moderate reduction in sodium intake, particularly as related to sympathetic nervous system activity, in a homogeneous group of normal human
subjects.
Methods
Twelve normal volunteer subjects from 23 to 39 years old
(mean + SEM = 35 ± 3.5 years) were enrolled in the study.
As a group they had no history of serious illness and no family
history of hypertension. Informed written consent was obtained
from each and they took no drugs for the duration of the study.
To achieve an equilibrium on a standardized diet for baseline
measurements, the subjects were admitted to our metabolic
47
VOLPE et al.
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ward and were maintained on a daily diet containing 200 meq
sodium, 70 meq potassium, 60 g protein, 50 g fat, 280 g carbohydrate, and 400 mg calcium, for 1 week after their entry into
the study. Each subject consulted with the research dietician
before the study and personal food preferences were allowed as
much as possible. After 7 days on this diet (day 0), the following
baseline measurements were obtained: body weight, supine and
upright heart rate and blood pressure, 24 hr urinary sodium and
potassium excretion, 2 hr supine plasma renin activity, aldosterone, epinephrine and norepinephrine levels, peripheral venous
hematocrit, creatinine clearance, and serum sodium and potassium. Resting M mode echocardiographic and blood pressure
and heart rate responses to isometric exercise were determined
after the humoral measurements. Blood samples for catecholamine measurement were drawn with the subject in the supine
position on a comfortable bed at least 30 min after the insertion
of a 20-gauge butterfly needle into a forearm vein. The room
was kept quiet, darkened, and warm for the entire study. Subjects avoided caffeine, smoking, and strenuous physical exercise for the 24 hr preceding the sampling.
Subsequently, the subjects were prescribed a diet containing
identical quantities of potassium, protein, fat, carbohydrate,
and calcium, but only 40 meq of sodium, and were followed in
the outpatient clinic for 60 days. The diet was reinforced periodically by reconsulting the dietician. Measurements of the
above-mentioned parameters were repeated on days 4, 7, 30,
and 60 of the diet. In addition, 24 hr urinary electrolytes were
measured on day 1.
Plasma concentrations of norepinephrine aad epinephrine
were measured by a radioenzymatic method.20 Plasma renin
activity and aldosterone levels were measured by radioimmunoassay,21, 22 and sodium and potassium concentrations in serum
and urine were determined by flame photometry. Adequacy of
24 hr urine collection was evaluated by measurement of urinary
creatinine. Blood pressure was measured by mercury sphygmomanometer according to the recommendations of the American
Heart Association.23
The isometric muscular exercise consisted of sustained handgrip in the supine position on a hydraulic adjustable dynamometer. After the subjects had become familiar with the technique,
maximum voluntary contraction of the dominant hand was assessed 15 min before the start of the actual experiment. After a
15 min period of supine rest, blood pressure and heart rate
measurements were obtained each minute for 5 min in the nondominant arm and averaged to obtain the baseline value. The
subjects then performed 75% maximum contraction handgrip
for 1 min. Blood pressure and heart rate were measured during
the last 15 sec of the effort. Percent changes in mean blood
pressure and heart rate in response to handgrip were used for
statistical comparisons.
M mode echocardiography was performed with the patient in
left lateral position after 30 min of supine rest with use of an Irex
system 2 echocardiograph with a 2.25 MHz, 15 mm diameter
transducer. All tracings for left ventricular dimensions were
recorded at the level of the tips of the mitral valve. The dimensions measured in each tracing, using the leading-edge technique and following the recommendations of the American Society of Echocardiography,24 were ventricular septal thickness,
left ventricular posterior wall thickness, and left ventricular
diameter, with each dimension measured at both end-diastole
and end-systole. The readings were performed by two observers
in a double-blind fashion. Three beats were measured routinely;
as many as 5 were measured if the recording was not easy to
read. (Agreement between the two observers and reproducibility of the readings by the same observer were within 1 mm.)
Heart rate values were obtained from a simultaneously recorded
electrocardiogram. Echocardiographically measured volumes
48
in end-diastole and end-systole were derived with the cube
formula. Echocardiographic left ventricular mass index was
calculated as the difference between total left ventricular enddiastolic volume (including muscle shell) and the inner left
ventricular volume multiplied by effector 1.05 (the specific
weight for heart muscle) and divided by body surface area.25
Stroke volume was derived as the difference between end-diastolic and end-systolic volume, and cardiac output by multiplying stroke volume by heart rate. Mean blood pressure was obtained by adding one-third of the pulse pressure to diastolic
blood pressure. Total peripheral resistance (dynes x sec x
cm- 5) was calculated by dividing mean blood pressure by cardiac output and multiplying by 80. The mean velocity of circumferential fiber shortening (sec- 1) was calculated as the percent
change in left ventricular dimension divided by the left ventricular ejection time.
Statistical analysis was performed by one-way analysis of
variance (ANOVA). Differences were considered statistically
significant at a level of p < .05. Data are expressed as mean
SEM.
Results
Two of the 12 enrolled subjects were excluded during the course of the study because their 24 hr urine
creatinine and sodium excretion indicated inaccuracy
in urine collection and/or noncompliance with the lowsodium diet. Therefore, data from only 10 subjects
were considered in further analysis.
Urinary sodium excretion was 178 ± 10 meq/24 hr
on the last day of the normal sodium diet (day 0) and
fell to 122 ± 20 meq/24 hr after 1 day on the lowsodium diet. Three more days were then allowed to
achieve equilibrium on the new sodium regimen before
the first humoral and hemodynamic measurements
were obtained. Urinary sodium fell to 31 + 4 meq/24
hronday4,to38 ± 4meq/24hronday7, to45 + 6
meq/24 hr on day 30, and to 47 ± 7 meq/24 hr on day
60 (p < .001 for all as compared with the control
value) (figure 1). There were no significant differences
among the urinary sodium values obtained on days 4,
7, 30, and 60 of the low-sodium diet.
Table 1 shows the effects of the low-sodium diet on
the different humoral and hemodynamic parameters.
Blood pressure was not significantly altered. Both supine and upright heart rate increased modestly but significantly on days 4 and 7, returning to baseline thereafter. Supine plasma renin activity and aldosterone
concentrations were significantly increased by day 4 of
low sodium intake and remained significantly above
baseline at days 7, 30, and 60. Body weight decreased
significantly by day 7, whereas no significant change
was detectable in urinary potassium excretion, creatinine clearance, or hematocrit.
Figure 1 illustrates the changes in plasma epinephrine and norepinephrine as related to the concurrent
values for urinary sodium excretion. Plasma concenCIRCULATION
PATHOPHYSIOLOGY AND NATURAL HISTORY-HYPERTENSION
The reliability of the catecholamine pattern found
during the low-salt diet is supported by data obtained
c
0)CY
from four normal subjects given a 200 meq sodium diet
v~
identical to our control diet for 2 months. In these
0._
subjects, plasma norepinephrine and epinephrine conLLI
centrations measured on days 0, 4, 7, 30, and 60 were,
50
respectively, 272 ± 20, 252 21, 295 + 26, 249
28 pg/ml for norepinephrine (all NS
18, and 279
550
15, 57
17, 67
compared with 0 control) and 61
*l
-450
10 pg/ml for epinephrine (all
54
10,
and
66
8,
CaE
c)
NS compared with 0 control). No significant change
350
C.
from control in urinary sodium excretion could be de0)
II
tected during the 2 months of the diet in these subjects.
250
Table 2 summarizes the hemodynamic response to
the low-salt diet as assessed by echocardiography and
200 r
responses to isometric exercise. No significant change
in any of the resting cardiovascular parameters was
C s
150
z n
detected by echocardiography. In contrast, the per100
centage of increase in mean blood pressure induced by
C cr
W~
isometric exercise was significantly greater on days 4
E 50
._
*~~~~~~~
I
:
and 7 compared with that under control conditions.
n
30
0 47
This effect of sodium restriction was no longer apparTime (days)
ent on days 30 and 60 of the diet. The heart rate
to exercise was not significantly affected by
response
FIGURE 1. Time course of catecholamine plasma levels in subjects on
diet.
the
low-salt
the low-salt diet. *p < .05; **p < .001.
100
n
-10
*
'
0)
c-
0.
±
±
±
c
±
±
±
a.
z
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c
_--
J
trations of both catecholamines were significantly increased on days 4 and 7 of the low-sodium diet, whereas by days 30 and 60 their values were no longer
different from those obtained during the normal sodium diet.
Discussion
The evaluation of sympathetic nervous system activity has long been difficult and controversial. However, with the introduction of sensitive radioenzymatic
assays for measurement of circulating catecholamines,
TABLE 1
Time course of effects of the low-salt diet (40 meq/day) on different
hemodynamic and humoral parameters (n
=
10)
Days on diet
Supine BP
Systolic (mm Hg)
Diastolic (mm Hg)
Upright BP
Systolic (mm Hg)
Diastolic (mm Hg)
Supine HR (beats/min)
Upright HR (beats/min)
PRA (ng/mllhr)
PAC (pg/ml)
UKV (meq/24 hr)
Hct (%)
CrCl (ml/min)
Weight (kg)
BP
=
blood pressure; HR
excretion; Hct
=
0
4
7
30
60
128 7
76 +5
125 + 4
78 ±4
124 ±4
75 + 3
120 +4
76 ± 5
120 + 6
75 ± 4
129 ± 5
79 + 5
65 ± 2A
80 ± 3A
2.95 ± 0.5A
174+ 16A
122 + 5
81 ± 6
57 ± 3
78 ± 5
2.86± 0.6A
191 ± 16A
55±7
44±0.9
124 ± 5
81 ± 5
55 ± 2
72 + 4
2.62 ± 0.6A
167+±OA
58±7
130+12
134±13
70 2A
136 ±4
82 ± 5
59 ± 2
72 + 4
1.42 ±0.2
130±9
50±3
42±0.8
131±10
72 ± 3
=
126 ± 3
79 ±4
65 ± 2A
88 ± 7A
4.42 ±0.7A
260+35A
43+0.8
41+5
43+0.8
124±14
72 ± 3
116±13
71 ± 3A
45±4
heart rate; PRA = plasma renin activity; PAC
= creatinine clearance.
=
71
2A
44+0.3
plasma aldosterone; UKV - urinary potassium
hematocrit; Cr Cl
Ap < .05.
Vol. 72, No. 1,
July
1985
49
VOLPE et al.
TABLE 2
Time course of effects of the low-salt diet (40 meq/day) on cardiac anatomy and hemodynamics and on cardiovascular
response to isometric exercise (n = 10)
Days on diet
0
Echocardiography
LVID (cm)
Diastole
5.0+0.2
Systole
3.4+0.2
LVV (cm3)
Diastole
126+10
Systole
49+6
LVMI (g/m2)
96+4
1.1 0.05
VCF (sec- 1)
CO (1/min)
6.6+0.7
TPR(dynes x sec X cm-5) 1240+208
Isometric exercise
+ 22.3 4
%A MBP
+42±10
%A HR
4
7
30
60
5.0+0.2
5.0+0.2
3.5+0.2
5.1+0.1
3.6+0.2
5.1+0.2
127+10
51+6
97+5
130+12
50+7
98+5
130+12
1.08 ± 0.05
6.6±0.3
1.03 0.04
6.3±0.3
1255+198
1200+78
1198+55
1241 85
+ 41 + A
+ 40 5A
+ 28 4
+43+7
+52±8
+50±9
+ 23 3
+40±7
3.5+0.2
127+11
50+6
96+5
1.08 0.05
6.4+0.6
3.6+0.2
52+8
98+5
1.05 0.05
6.3+0.3
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
LVID = left ventricular internal diameter; LVV = left ventricular volume; LVMI left ventricular mass index; VCF
mean velocity of circumferential fiber shortening; CO = cardiac output; TPR = total peripheral resistance; HR = heart rate;
MBP = mean blood pressure.
Ap <
.05.
a number of recent studies have indicated that such
measurements can provide a reliable index of sympathetic activity under certain conditions, 1-12 particularly
when factors such as body posture,26 age,27 smoking,28
caffeine consumption,29 stress,30 exercise,- medications, salt intake,'1 31 and blood pressure8 32 are taken
into account. Much care was thus devoted in the present study to control of the blood sampling procedure,
and only normal subjects falling into a restricted age
range were studied. In addition, hemodynamic parameters that, at least in part, reflect neural sympathetic
discharge were also monitored to further validate plasma catecholamine levels as a measure of sympathetic
nervous system activity.
In keeping with most previous observations,'-8 our
results show that plasma catecholamine levels increase
when sodium intake is decreased. However, in the
present study, the increase in plasma catecholamines
was detectable only in the early period of the low-salt
diet. Measurements obtained after 30 and 60 days of a
continuous low-salt diet showed that both plasma epinephrine and norepinephrine concentrations were no
longer different from those obtained during the control
period.
Consistent with the trend observed in plasma catecholamine levels are two additional findings of our
study. First, the small but significant increases in heart
rate (mostly in the upright position) paralleled those
observed in plasma catecholamine levels, since they
50
were restricted to the observations made on days 4 and
7. Similarly, the blood pressure response to isometric
exercise was significantly enhanced only in the early
period of the low-salt diet.
Taken together, these findings indicate that, in normotensive subjects, a sustained and protracted reduction in salt intake enhances sympathetic activity only
transiently. A few earlier observations are consistent
with our findings. For example, Carroll et al. 1 l reported that long-term sodium depletion in dogs did not
alter plasma catecholamine concentration despite a
fourfold increase in plasma renin activity. Fujita et al.4
reported that in salt-sensitive hypertensive patients
switched from a low- to a high-salt diet, plasma norepinephrine decreased initially but then increased toward control values. These findings are compatible
with the hypothesis that the catecholamine response to
a change in sodium intake is transient.
Although we found that a transient increase in plasma catecholamines was associated with increases in
heart rate and blood pressure responses to exercise, we
failed to detect a significant effect of the low-salt diet
on resting cardiac output or peripheral resistance, as
evaluated by echocardiography. This contrasts in part
with some earlier findings. '3 However, in most studies
showing changes in local or systemic vascular resistance or contractility during a low-salt diet,'3 18 the
responses to far more drastic sodium restriction were
evaluated principally in patients with borderline or esCIRCULATION
PATHOPHYSIOLOGY AND NATURAL HISTORY-HYPERTENSION
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tablished hypertension who might have different
hemodynamic responses than the normal subjects studied herein.
Another important finding of our study is that, unlike the parameters reflecting sympathetic function,
both plasma renin activity and plasma aldosterone remained elevated for the duration of the low-salt diet.
This is not surprising, given the known complexity of
the control of renin secretion by the kidney. Thus,
although the transient stimulation of sympathetic activity may have contributed to the initial rise in plasma
renin, other mechanisms (such as stimulation via the
macula densa) appear able to sustain the stimulation of
the renin-angiotensin system despite waning of the
sympathetic response. It must be pointed out that,
since hormonal measurements were made only in the
supine position, we may have underestimated the degree of stimulation of the renin-angiotensin system (as
well as of the sympathetic nervous system) during
long-term sodium depletion. It thus remains possible
that some degree of sympathetic activation might persist in the upright posture, although our data on exercise responses are evidence against this. Whatever the
case, the present findings demonstrate a dissociation
between the long-term responses of the renin-angiotensin and sympathetic nervous systems.
The mechanisms responsible for the initial stimulation of sympathetic function induced by sodium restriction and for the waning of this response over the
long term are not elucidated by the present study. It is,
of course, possible that angiotensin II itself plays a role
in stimulating the sympathetic nervous system, since
several mechanisms have been proposed whereby this
could occur.33-" If so, it is difficult to understand why
the sympathetic response would fade despite maintained activation of the renin-angiotensin system; however, there is evidence that long-term angiotensin infusion appears to only transiently increase arterial
epinephrine levels.38 Other mechanisms are possible,
such as initial changes in blood volume followed by
redistribution of volume, but further work is needed to
clarify this point.
In conclusion, our findings indicate that the duration
of the change in salt intake has to be taken into account
in evaluating the sympathetic nervous system responses to a reduction in sodium intake. They also
support the hypothesis that long-term blood pressure
homeostasis in normal subjects is accomplished mainly through the kidney and its control mechanisms, as
indicated by the more sustained response of the reninangiotensin system, whereas the autonomic nervous
control of the circulation principally contributes to the
Vol. 72, No. 1,
July
1985
short-term control of blood pressure homeostasis during long-term changes in sodium intake.
We thank Linda Stackhouse for preparation of the manuscript.
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CIRCULATION
Transient enhancement of sympathetic nervous system activity by long-term restriction
of sodium intake.
M Volpe, F B Müller and B Trimarco
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Circulation. 1985;72:47-52
doi: 10.1161/01.CIR.72.1.47
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