Plasma and Urinary Norepinephrine Values
at Extremes of Sodium Intake in Normal Man
FRIEDRICH C. LUFT, M.D.,
RICHARD BLOCH, M.D.,
LAURA I. R A N K I N , M.D.,
CLARENCE E. GRIM, M.D.,
RAYMOND H. M U R R A Y , M.D.,
DAVID P. H E N R Y ,
ARTHUR E. WEYMAN,
A N D M Y R O N H. WEINBERGER,
M.p.,
M.D.,
M.D.
SUMMARY To examine the effects of a wide range of sodium intake on plasma and urinary norepinephrine
values in normal man, we studied 14 men at six levels of sodium intake from 10 to 1500 mEq/24 hrs. Mean
blood pressure increased from 83.8 ± 1 (SEM) to 1003 ± 3 mm Hg, while cardiac index increased from
2.6 ± 0.1 to 3.6 ± 0 3 llters/min/m1 (p < 0.001). Upright venous plasma norepinephrine concentration
decreased from 467 ± 6 3 to 67 ± 24 pg/ml, while urinary norepinephrine excretion decreased from
5 4 3 ± 3.4 to 23.4 ± 2.9 Mg/24 hrs. There was no effect of sodium intake on blood pressure responses to
isometric hand-grip contraction. The urinary sodium excretion was inversely correlated with urinary
norepinephrine excretion (r = — 0.46, p < 0.001). There was a significant inverse multiple correlation of mean
blood pressure and plasma and urinary norepinephrine values (correlation coefficient = 0.72, p < 0.001).
These results indicate that sodium homeostasis has a signiflcant effect on plasma and urinary norepinephrine
values. Sympathetic nervous system activity appears to decrease with sodium loading in normal subjects. These
responses may have facilitated the excretion of massive salt loads in normal subjects and may nave modulated
the increases in blood pressure. (Hypertension 1: 261-266, 1979)
KEY WORDS • catecholamines • urinary norepinephrine • plasma norepinephrine
sodium loading • sympathetic nervous system • autonomic nervous system
I
of sympathetic and adrenal medullary activity during
the course of these studies. The purpose of our study
was to delineate the responses of normal subjects and
to provide a basis of comparison for subsequent
studies in hypertensive individuals. Our data suggest
that the state of sodium homeostasis affected the upright venous plasma norepinephrine concentration and
urinary norepinephrine excretion in normal subjects.
Sympathetic nervous system activity as reflected by
our measurements appeared to decrease with salt
loading. A decrease in sympathetic nervous system activity may have facilitated the excretion of massive
salt loads.
NCREASES in arterial blood pressure have
been observed with increases in salt intake
in subjects with diminished renal function since
the report of Ambard and Beaujard in 1904.l Subsequently, similar blood pressure observations have been
made in normal persons subjected to large increases in
salt intake.1"4 We recently reported that increases in
blood pressure occurred in normotensive human
volunteers when they were subjected to a sodium intake in excess of 800 mEq per day.5 The sympathetic
nervous system plays a major role in the blood
pressure regulation of normal persons," and has also
been implicated in the development of experimental
hypertension,7 as well as in certain forms of human essential hypertension.8"10 We therefore observed indices
Methods
Fourteen normotensive, healthy male volunteers
(mean age 32 years, range 18-40) were obtained by
advertisement and were studied at the Indiana University Clinical Research Center. The protocol was approved by the Indiana University Medical Center
Human Use and Clinical Research Center Committees and informed consent was obtained from each
volunteer after detailed explanation of the procedures
to be performed. None had a family history of
hypertension.
From The Renal Section and the Specialized Center of Research
(SCOR) — Hypertension, Department of Medicine, Indiana
University Medical Center, Indianapolis, Indiana.
Supported in part by USPHS Grant HL 14159, Specialized
Center of Research (SCOR) — Hypertension, HL 07181 and RR
00750 (General Clinical Research Center).
Presented in part to the Council for High Blood Pressure
Research, Cleveland, Ohio, 1978.
Address for reprints: Friedrich C, Luft, M.D., Fesler Hall 110,
Indiana University School of Medicine, 1100 West Michigan
Street, Indianapolis, Indiana 46202.
261
262
HYPERTENSION
Sodium Intake Levels
Observations were made after at least 3 days at six
levels of sodium intake, namely: 10, 300, 600, 800,
1200, and 1500 mEq/24 hrs. All 14 subjects were
studied at the 10 and 300 mEq/24 hr levels. Eight subjects then received 800 and 1500 mEq/24 hrs sodium,
while six subjects received 600 and 1200 mEq/24 hrs
sodium. The subjects were given a constant diet containing 10 mEq sodium, 80 mEq potassium, 65 g protein, 50 g fat, 279 g carbohydrate, 400 mg calcium,
and 1000 mg phosphorous daily. All meals were eaten
at the Clinical Research Center. Dietary sodium intake was maintained at 10 mEq/24 hrs for 7 days. For
3 days 290 mEq sodium, in the form of sodium
chloride, was added to the diet (300 mEq sodium diet).
Either 590 or 790 mEq sodium (600 and 800 mEq
sodium diet) was added to the 10-mEq diet for the
next 3 days. In order to achieve these high levels of intake, sodium was given with bouillon between meals
and at bed time. For the final 3 days, the subjects were
hospitalized and received the 600 mEq or 800 mEq
sodium diet. Throughout the night they received 600
or 700 mEq sodium, respectively (1200 and 1500
mEq/24 hr sodium intake) in the form of I.V. normal
saline. Fluid intake (distilled water) was allowed ad
libitum.
Procedures
The subjects were weighed every morning before
breakfast after voiding. Blood pressures were obtained
daily before meals by the indirect auscultatory technique. The same mercury manometers (Baum, Inc.,
New York, NY) and cuffs were employed throughout
the study. The subjects rested supine in a darkened
room for 5 minutes after which blood pressure and
measurements of heart rate were obtained in the nondominant arm each minute for 5 minutes. The same
observers were responsible for these measurements
throughout the study.
Daily 24-hour urine specimens were obtained for
the determination of sodium, potassium, creatinine,
and norepinephrine concentrations. Acetic acid, which
protects against urinary norepinephrine loss during
storage, was used as a preservative. At 8:00 a.m. on
the morning of the final day at each level of sodium intake, venous blood specimens were obtained from the
basilic vein, following 2 hours of ambulation, for
hematocrit, creatinine, sodium, potassium, plasma
renin activity, plasma aldosterone and plasma
norepinephrine concentrations.
Blood Pressure Responses to Hand-Grip
On the morning of the final day at each level of
sodium intake, blood pressure responses to isometric
hand-grip were determined.11 The static muscular
effort consisted of sustained hand-grip on a hydraulic,
adjustable .dynamometer (J. A. Preston, New York,
NY). The subjects were trained in the full experimental procedure before the actual experiments. All subjects were studied in the supine position after
VOL 1, No
3, MAY-JUNE
1979
breakfast, without sedation. Maximum voluntary contraction (MVC) was determined 30 minutes before the
start of the actual experiment. Hand-grip was performed in the dominant hand. During hand-grip the
subjects were urged to breathe as normally as possible
and to relax all muscles not involved in the contraction. After a basal 15-minute relaxation period, blood
pressure measurements were obtained each minute for
5 minutes in the nondominant arm. Thereafter the
subjects were studied during a 30% MVC hand-grip
sustained for 3 minutes. Blood pressure was measured
every 30 seconds during the contraction period. The
change in mean blood pressure in response to handgrip in each subject was calculated by subtracting the
mean value obtained during the 5-minute period
before contraction from the mean value of
measurements obtained during the 3-minute contraction period.
Echocardiograpbic Findings
Cardiac index, stroke index, end-systolic left ventricular volume, and end-diastolic left ventricular
volume were measured noninvasively on the final day
at each level of sodium intake by means of echocardiography." This technique has been intensively
studied and carefully validated in our institution.
Rasmussen et al. u compared Fick stroke volume to
echocardiographically calculated mitral valve stroke
volume in 16 patients with normal left ventriculograms and no angiographic evidence for coronary artery disease. The results of the two techniques were highly correlated (r = 0.95).
Initially, left ventricular diastolic and systolic internal dimensions (LVIDd and LVIDs) were determined.
The left ventricular end-diastolic dimension (LVIDd)
was measured from the leading edge of the left septal
surface to the leading edge of the posterior wall endocardium at the peak of the R wave. The end-systolic
dimension (LVIDs) was measured from similar points
at the peak of anterior position of the posterior left
ventricular wall. End-systolic and diastolic volumes
were determined by cubing the respective internal
dimensions. The cube method was utilized since the
subject group could be assumed to have symmetrically
contracting, normally shaped left ventricles. Stroke
index was estimated from the formula:
. . .
c
Str0kemdeX =
(LVIDd)' - (LVIDs)'
"
BSA(M')
and cardiac index was estimated with the formula:
„ ,. . ,
(LVIDd)' - (LVIDs)' X HR
Cardiac index = J
'
B S A ( M ' )
where HR = heart rate and BSA = body surface area.
All echocardiograms were recorded by the same technician and were evaluated independently by two
observers.
Laboratory Methods
The concentration of norepinephrine in plasma and
urine was measured using a radioenzymatic assay.14
NOREPINEPHRINE VALUES WITH SALT LOADING/Lu/i et al.
TABLE 1.
263
The Effects of Sodium Loading on Variables Interacting Significantly with Sodium Intake (mean ± SEM).
10
Subjects (no.)
14
A Weight (kg)
—
UN.V (mEq/24 hrs)
15 ± 4
UKV (mEq/24 hrs)
63 =*= 5
MABP (mm Hg)
Cardiac index (liter/min/m 1 )
300
Sodium intake (mRq/24 hrs)
600
800
1200
6
1.500
6
8
0.8 ± 0.2
0.7 ± 0.3
2.5 ± 0.4
2.5 ± 0.5
278 ± 18
543 ± 61
706 ± 24
1122 ± 68
71 ± 4
132 ± 13
142 ± 7
150 ± 11
189 ± 14
83.8 ± 1.3
85.8 ± 1.5
86.8 ± 1.0
91.1 ± 2.8
93.1 ± 1.5
100.3 ± 3.1
2.6 ± 0.1
2.8 ± 0.2
2.6 ± 0.2
2.9 ± 0.1
3.0 ± 0.2
3.6 ± 0.3
14
8
5.5 ± 0.6
1443 ± 36
P N . (pg/ml)
467 ± 63
272 ± 41
260 ± 24
136 =*= 64
160 ± 19
67 ± 24
UN. (Mg/24 hrs)
.54.3 ± 3.4
39.1 ± 2.6
40.1 ± 4.1
31.6 ± 6.7
42.5 ± 5.0
23.4 ± 2.9
PRA (ng AI/ml/3 hrs)
11.9 * 2.3
2.6 ± 0.5
1.8 ± 0.4
1.3 ± 0.4
0.6 ± 0.5
0.7 ± 0.1
PA(ng/100ml)
43.9 ± 6.9
8.7 ± 1.8
6.3 ± 1.5
4.6 * 1.6
2.8 ± 1.0
1.5 ± 0.2
Abbreviations: UNHV = urinary sodium excretion; UKV = kaliuresis; MABP = mean arterial blood pressure, PN» = plasma
norepinephrine concentration; U N . = urinary riorepinephrine excretion; PRA = plasma renin activity; PA = plasma aldosterone
concentrations.
Norepinephrine was converted to radiolabeled
epinephrine using partially purified bovine adrenal
phenylethanolamine-N-methyl-transferase and tritiated S-adenosylmethionine. The epinephrine formed
was isolated by batch alumina adsorption chromatography. Residual unreacted S-adenosylmethionine was
precipitated with phosphotungstic acid and the epinephrine was finally extracted by bis-ethylhexylphosphoric acid in toluene and quantified using liquid
scintillation spectrophotometry.
Sodium and potassium concentrations in plasma
and urine were measured by flame photometer
(Instrumentation Laboratories, Boston, MA).
Creatinine was measured by an automated technique
(Technicon, Chauncey, NY). Plasma renin activity
and plasma aldosterone were measured by previously
reported radioimmunoassay methods.18 The data were
analyzed statistically by analysis of variance (repeated
measures when indicated), t test, and multiple regression analysis, where appropriate.1"1 " The relationship
between urinary sodium excretion and blood pressure
was also subjected to quadratic regression analysis.
The 95% limits of probability were accepted as significant.
Results
Table 1 outlines the effect of sodium intake on
variables which by repeated measures analysis of
variance interacted significantly with sodium intake
(p < 0.05). The observations were obtained on the
final day at each level of sodium intake. Weight increased in significant increments from the 10 mEq/24
hr level. The urinary sodium excretion (U Na V) approached the total sodium intake at each level. A
significant kaliuresis (U K V) occurred above a sodium
intake of 300 mEq/24 hrs. Increases were observed
between both the 300 and 600 mEq/24 hrs, and
between the 1200 and 1500 mEq/24 hr levels of
sodium intake (p < 0.05). No consistent effects on
plasma sodium and potassium were observed. Mean
blood pressure (MABP) increased significantly
between the 10 and 800 mEq/24 hr levels and again
between the 1200 and 1500 mEq/24 hr levels of
sodium intake (p < 0.05). The relationship between
U Na V and mean blood pressure is depicted in figure 1.
Quadratic regression analysis revealed a significant
relationship with a correlation coefficient of 0.50
(p < 0.001). The relationship is defined by the expression: y = 84.6 + 0.000398 X + O.OOOOO387 X2.
Figure 2 outlines each individual's blood pressure
responses to the salt loads. There was considerable
variability in the responses. Two subjects failed to
develop an increase in blood pressure. The change in
mean blood pressure for the subjects between the
lowest and highest level of sodium intake was correlated with the cumulative increase in total body
sodium as calculated from urinary values (r = 0.52,
p < 0.03).
Mean blood pressure increased in response to
isometric hand-grip contraction by 21.4 ± 2.4 (SEM)
mm Hg at the 10 mEq/24 hr level of sodium intake.
Responses of similar magnitude were observed at the
five higher levels of sodium intake. No significant interaction between blood pressure responses to
isometric hand-grip contraction and sodium intake
was identified {p > 0.05).
Cardiac index (table 1) increased significantly
between the 10 and 800 mEq/24 hr levels of sodium
intake [p < 0.05). An additional increase was
observed between the 800 and 1500 mEq/24 hr levels
of sodium intake (p < 0.05). Throughout the range of
sodium intake mean blood pressure and cardiac index
were directly correlated (r = 0.49, p < 0.001).
Significant decreases (p < 0.05) in plasma
norepinephrine concentration (P Ne ) w cre observed
between the 10 and 300, 600 and 800, and 1200 and
1500 mEq/24 hr levels of sodium intake. The change
in plasma norepinephrine concentration between the
10 and 1500 mEq/24 hr levels of sodium intake was
264
HYPERTENSION
1979
*
"1:-
i
0
VOL 1, No 3, MAY-JUNE
100
200
300
400
<
i
WO
*
i
<
i
gOO
<
700
U
N j
V
i
>
800
(mEq/24
i
MO
>
1000
1100
1100
1300
1400
1500
hr)
FIGURE 1. Relationship between urinary sodium excretion (UNlV) and mean blood pressure (MABP), as
defined by a quadratic expression.
inversely correlated with the change in mean blood
pressure (r = -0.61, p < 0.05) and with the
cumulative increase in total body sodium as calculated
from urinary values (r = -0.75, p < 0.05).
Urinary norepinephrine excretion (UNe) decreased
(p < 0.05) between the 10 and 300, and 1200 and 1500
110 —I
105
-
100 —
1
e
u
K
S
m
m
H
B
95 —
a
D
o
o
-1
a
2
86 -
80 —
75 •
10
S00
SODIUM
800
INTAKE
800
1200
1500
mEq/day
FIGURE 2. Individual mean blood pressure values in
response to extremes in sodium intake.
mEq/24 hr levels of sodium intake. Urinary
norepinephrine excretion, which was measured daily,
was inversely correlated (r = —0.46, p < 0.001) with
urinary sodium excretion (fig. 3). The relationship is
defined by the expression y = -0.0174 X + 48.4.
Urinary norepinephrine excretion was also inversely
correlated with mean blood pressure (r = —0.21,
p < 0.01). No correlation between the change in
urinary norepinephrine excretion and cumulative increase in total body sodium was identified (r = —0.46,
p > 0.05).
Plasma renin activity (PRA) decreased significantly
between the 10 and 300 mEq/24 hr levels of sodium
intake (p < 0.05), and again between the 300 and 800
mEq/24 hr levels (p < 0.05). Plasma aldosterone
(PA) decreased between the 10 and 300, and 300 and
800 mEq/24 hr levels of sodium intake (p < 0.05).
Mean blood pressure was inversely correlated with
PRA (r = -0.38, p < 0.001) and plasma norepinephrine concentration (r = —0.40, p < 0.001).
Plasma norepinephrine concentration and PRA were
correlated (r = 0.52, p < 0.001), as were urinary norepinephrine excretion and PRA (r = 0.41, p < 0.001).
A multiple regression analysis was performed with
mean blood pressure as the dependent variable and
cardiac index, renin, aldosterone, norepinephrine
values in plasma, and urinary norepinephrine excretion as independent variables. Plasma norepinephrine
concentration and urinary norepinephrine excretion
entered the equation. The addition of the remaining
independent variables failed to improve the correlation. The expression defining the relationship among
mean blood pressure, plasma norepinephrine concentration and urinary norepinephrine excretion is as
follows: MABP= 105.1 - 0 . 0 3 (PNe) -0.24 (UNe)
(multiple correlation coefficient = 0.72, p < 0.001).
265
NOREPINEPHRINE VALUES WITH SALT LOADING/Lu// et al.
Discussion
The autonomic nervous system plays a major role in
the regulation of arterial blood pressure.18 Short-term
autonomic control of blood pressure is vested
primarily in baroreceptor reflexes, chemoreceptors
within the walls of great vessels, and receptors within
the vasomotor center." In addition, a number of
studies suggest that the autonomic nervous system influences long-term arterial blood pressure regulation
at least in part by modulating the excretion of salt and
water by the kidney." The autonomic nervous system
also participates in the control of renin release.20"" In
addition, direct adrenergic innervation of glomerular
arterioles and proximal tubules has been demonstrated by histochemical techniques and by electron microscopy." In the dog, baroreceptor reflex
stimulation of renal sympathetic nerves produces an
increase in renal tubular sodium reabsorption without
changes in glomerular filtration rate, renal blood flow,
or intrarenal distribution of blood flow.*4 Furthermore, it has been shown that cardiopulmonary receptors exert a tonic inhibition on both renal nerve
activity and renin release." The magnitude of the inhibition was directly related to blood volume.
In the present study, a sodium intake of 800 mEq/
24 hrs, which is twofold greater than that consumed by
even the most salt-gluttonous societies," resulted in
increases in weight and cardiac index, and a modest
increase in blood pressure. The increase in blood
pressure is most readily explained by the increase in
cardiac index resulting from an increase in extracellular fluid volume. Increasing the sodium intake
still further to 1500 mEq/24 hrs amplified the effects;
however, the increase in blood pressure was still
relatively modest. Obviously, important adjustments
accompanied the increases in sodium intake which
facilitated the renal excretion of the massive sodium
load.
The upright plasma norepinephrine concentration,
which provided a means for assessing sympathoadrenal medullary function," decreased with sodium
loading" and was directly correlated with plasma
renin activity. Both were inversely correlated with
urinary sodium excretion and blood pressure. Changes
in both were correlated with calculated changes in
total body sodium. These relationships provide
evidence that not only were these two pressor substances not directly responsible for the increases in
blood pressure, but also that their prompt suppression
may have ameliorated the effects of sodium loading.
Urinary norepinephrine excretion decreased in our
subjects with sodium loading. The urinary norepinephrine excretion was inversely correlated with the
urinary sodium excretion, but it was not correlated
with the calculated increase in total body sodium. Although the urinary norepinephrine excretion may
represent in part norepinephrine released into the cardiovascular system, it is likely that a considerable contribution comes from the kidneys themselves.2*- M A
previous study from our laboratory has shown that the
clearance of norepinephrine increases with standing
100
25
1
600
800
1000
1200
U N a V ( m E q / 2 4 hr)
1400
FIGURE 3. The relationship between urine sodium excretion (UNmV) and urinary norepinephrine excretion (UNt).
and exceeds the clearance of creatinine in that
position.*0 Since with upright posture the amount of
norepinephrine excreted in the urine exceeded the
amount filtered, it is likely that the urinary
norepinephrine excretion is at least in part related to
the activity of the adrenergic renal nerves.
In addition to the relationship between mean blood
pressure and urinary sodium excretion in the present
study, mean blood pressure was also directly correlated with cardiac index, and inversely correlated
with plasma renin activity, plasma aldosterone concentration, plasma norepinephrine concentration, and
urinary norepinephrine excretion. Multiple regression
analysis revealed a close correlation of mean blood
pressure with plasma and urinary norepinephrine
values, which was not improved by the addition of
other variables. This regression, which in no way implies cause and effect, provides an additional
demonstration of the close relationship between mean
blood pressure following sodium loading and norepinephrine in plasma and urine of normal subjects.
A number of previous studies has raised the
possibility that sodium may alter vascular reactivity to
humoral vasoactive substances.'1"" Since hemodynamic responses to static effort are related to a
powerful activation of the sympathetic nervous
system, 44 '" and occur even in the face of betablockade," isometric hand-grip contraction might be
expected to result in augmented responses under the
condition of a high sodium intake. In the present
study, no interaction between the blood pressure
responses to hand-grip contraction and the level of
sodium intake were identified. Thus, the present study
fails to show evidence of an enhanced pressor response
to stimuli known to increase adrenergic activity.
Our subjects were faced with excreting massive salt
loads. Even at the highest level of sodium intake,
homeostasis was achieved in a relatively short period
266
HYPERTENSION
of time. The urinary sodium excretion approached the
sodium intake after 72 hours. Presumably our subjects
were able to excrete such large salt loads not only by
an increase in glomerular filtration rate5 and blood
pressure, and by decreases in plasma renin and
aldosterone, but also by tonic inhibition of the sympathetic nervous system, either via baroreceptor
responses" or via some other influence upon the renal
nerves." Although these acute studies were performed
at levels of sodium intake well outside those at which
sodium is considered a necessary constituent of the
diet, they may nevertheless have relevance to the study
of hypertension. Subtle aberrations in autonomically
mediated sodium excretory mechanisms may contribute to elevation of blood pressure in some individuals when they indulge in the high salt intake
characteristic of our society.
Acknowledgments
We arc grateful to the nurses of the Clinical Research Center,
Rosemary Bagnato, the research dietitian, and Rebecca Sloan, who
assisted in these studies. Drs. James Norton and Naomi Fineberg
provided expertise in statistics.
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