Clinical Science (1984)66,427-433
427
Blood pressure and intra-erythrocytesodium during normal
and high salt intake in middle-agedmen: relationship to
family history of hypertension, and neurogenic and hormonal
variables
OTTAR GUDMUNDSSON, HANS HERLITZ, O L O F JONSSON, THOMAS HEDNER,
OVE ANDERSSON A N D GORAN BERGLUND
Department of Medicine I and Department of S u r g q , Sahlgren’s Hospital, University of Gateborg, Goteborg, Sweden
(Received 31 December 198215 September 1983; accepted 18 October 1983)
S-w
1. During 4 weeks 37 normotensive 50-year-old
men identified by screening in a random population sample were given 12 g of NaCl daily, in
addition to their usual dietary sodium intake.
Blood pressure, heart rate, weight, urinary
excretion of sodium, potassium and catecholamines, plasma aldosterone and noradrenaline and
intraerythrocyte sodium content were determined
on normal and increased salt intake. The subjects
were divided into those with a positive family
history of hypertension (n = 11) and those
without such a history (n = 26).
2. Systolic blood pressure and weight increased
significantly irrespective of a positive family
history of hypertension.
3. On normal salt intake intraerythrocyte
sodium content was significantly higher in those
with a positive family history of hypertension.
During high salt intake intra-erythrocyte sodium
content decreased significantly in that group and
the difference between the hereditary subgroups
was no longer significant.
4. In the whole group urinary excretion of
noradrenaline, adrenaline and dopamine increased
whereas plasma aldosterone decreased during the
increased salt intake.
5. Thus, in contrast to some earlier studies
performed in young subjects, our results indicate
that moderately increased sodium intake acts as a
pressor agent in normotensive middle-aged men
Correspondence: Dr Ottar Gudmundsson, Department of Medicine I, Sahlgren’s Hospital,
S-41345 Goteborg, Sweden.
whether there was a positive family history of
hypertension or not. We c o n f m that men with
positive family history of hypertension have an
increased intraerythrocyte sodium content, and
that an increase in salt intake seems to increase
overall sympathetic activity.
Key words: aldosterone, blood pressure, catecholamines, epidemiology, intra-erythrocyte sodium.
salt intake.
Introduction
Based on both between-population studies [ 1, 21
and within-population relationships [3-51 the high
sodium, low potassium diet in industrialized
countries has been suggested to be a causative or
permissive factor in the development of hypertension.
Studies in which salt intake has been manipulated have been performed to investigate the
relationship between changes in salt intake and
blood pressure, but the conclusions drawn vary,
some claiming a pressor effect of increased salt
intake [6, 71, others being unable to verify this
[8, 91. The reported amounts of NaCl needed to
increase blood pressure vary between studies, but
only small alterations in blood pressure are noted
even after drastic changes of dietary sodium in
ymng normotensive men [6, lo]. The effect of
increased salt intake on blood pressure of middleaged subjects has not been studied. This is
astonishing in hght of the fact that essential
hypertension is a disease of the middle-aged and
elderly population.
428
0. Gudmundsson et al.
The mechanisms by which sodium influences
blood pressure are unknown. In recent years
evidence has accumulated that erythrocytes from
patients with hypertension and their relatives have
a higher intracellular sodium content and abnormalities of the transmembrane transport systems
for sodium [l l-161. The higher intra-erythrocyte
sodium content is assumed to reflect a higher
intracellular sodium content in the smooth muscle
cells of the resistance vessels, leading t o an
increased vascular reactivity to neurogenic or
hormonal vasoconstrictor activity. The defect,
postulated to be genetic, has by some been
claimed t o be due to decreased active transport of
sodium out of the cell [16], and a high sodium
intake has been suggested to unmask this
hereditary defect [15].
The present study was designed to determine
the response to a high salt intake during a period
of 4 weeks in non-hypertensive middle-aged men
of the same age, intended to be randomly derived
from the total population. We report on the
effects on blood pressure and on neurogenic and
hormonal variables and intracellular sodium
content. The influence of a positive family history
of hypertension on the response is also analysed.
Subjects and methods
Subjects
The subjects were 68 men, 50 years of age,
randomly selected from the population of Goteborg, who attended a screening examination that
included a thorough interview with regard to
family history of hypertension and cardiovascular
diseases, other previous diseases, current medication, smoking and alcohol habits.
A physical examination was performed and
blood pressure, weight and height were measured.
Blood pressure was measured after a few minutes
rest in the sitting position. Subjects with blood
pressure below 170/105 mmHg not taking drugs
of any kind were asked to participate in a study
during the following 4 weeks. Forty-nine subjects
were willing to participate and met our criteria. Of
the remaining 19 men, six subjects were excluded
because of blood pressure above 170 and/or 105
mmHg or ongoing antihypertensive treatment; ten
subjects were not interested and two were
excluded because of difficulties with the language
and one because of a mental handicap. Of the 49
men taking part, 37 completed the study and 12
dropped out; four subjects claimed after starting
the high salt intake that they did not have time to
complete the time-consuming study; five did not
feel well o n hgh salt diet and three did not give a
reason for dropping out. A positive family history
of hypertension as defined below was found in the
same percentage within the drop-outs as within
those completing the study.
A positive family history of hypertension was
defined as mother or father hospitalized for stroke
before the age of 65 years or with known treatment for hypertension before the same age. The
age limit of 65 was used to decrease the possibility
of old age strokes not related to hypertension. We
excluded those whose parents had died of cerebral
haemorrhage as a consequence of an arterial
aneurysm. When these criteria were applied 1 1 of
our subjects had a positive family history for high
blood pressure and the remaining 26 were without
such history.
Methods
The general outline of the study is given in Fig.
1. On normal salt diet the subjects collected two
consecutive 2 4 h urine samples for the determination of sodium, potassium and hormones. Blood
pressure and heart rate were also recorded twice
during this week and blood samples for the determination of intraerythrocyte sodium, catecholamines and aldosterone were collected. The
subjects then received NaCl tablets (0.5 g) and
were instructed to eat 12 g daily in addition t o
their normal dietary intake. They were advised to
otherwise keep their usual dietary and salt-adding
habits. In this way we doubled their salt intake.
They continued the high salt intake for 4 weeks,
returning each week to the hospital for blood
pressure measurements and delivery of a 24 h
urine sample for determination of sodium and
potassium. At the end of the fourth week blood
samples were again taken for the determination of
the same variables as initially. All subjects returned
again after 3 weeks for blood pressure control and
information about the study results.
Blood pressure was measured in the right arm,
after 10 min supine rest, with an ordinary
sphygmomanometer with a 35 cm long and 12 cm
wide cuff. The diastolic blood pressure was
recorded when the Korotkoff sounds disappeared
(phase 5). The blood pressure was determined t o
the nearest 2 mm to avoid digital preference. All
measurements were made by the same observer
to avoid interobserver variation. Heart rate was
determined by pulse palpation for 1 min. Weight
was determined with a lever balance to the nearest
0.1 kg. Height was determined without shoes to
the nearest 1 cm. Urinary electrolytes were determined by flame photometry. For week 0 the
means of two measurements were used for blood
pressure, heart rate and all urinary data.
Blood pressure response to high salt intake
Week 0
Week 1
Week 4
Ordinary diet plus 12 g of NaCl daily
Ordinary diet
BPX 2
U-Na X 2
U-K X 2
U-NAD X 2
U-AX 2
U-DAX 2
leNa
P-Ald
P-NAD
Week 3
Week 2
429
BPX 1
U-Na X 1
U-K X 1
BPX 1
U-Na X 1
U-K X 1
BPXl
U-Na X 1
U-K X 1
BPX 1
U-Na X 1
U-K X 1
U-NAD X 1
U-AX 1
U-DA X 1
leNa
P-Ald
P-NAD
FIG. 1. Outline of the study, showing measurements and laboratory determinations
made. BP, Blood pressure measurement; U, urinary excretion (U-Na, of sodium; U-K,
of potassium; U-A, of adrenaline; U-NAD, of noradrenaline; U-DA, of dopamine);
IeNa, intraerythrocyte sodium content; P-NAD, plasma noradrenaline; P-Ald, plasma
aldosterone.
Erythrocyte sodium content was determined in
venous blood (10 ml) collected in heparinized
tubes and immediately placed in an ice-water bath
(0°C). They were then centrifuged at 4°C (3000 g,
5 min). One volume of packed cells was washed
twice with 3 vol. of MgC12-Tris solution (pH 7.2).
A portion ( 5 0 ~ 1 ) of the washed erythrocyte
suspension was added to a tube containing 200 pl
of concentrated nitric acid, as well as to a small
cup. The cups were dried at 40°C for 1 week,
whereafter the tissue was weighed on a torsion
balance and dissolved in 2 0 0 ~ 1of concentrated
nitric acid. The rest of the washed erythrocyte
suspension was used for determination of packed
cell volume. Sodium contents of the dried and the
wet samples were determined together in triplicate with a flame photometer, and means of these
six measurements are expressed as mmol/lM)O ml
of erythrocytes. Cell water content was calculated
from the weight of a blood sample with known
packed cell volume, before and after 1 week’s
drying at 40°C.
Samples for plasma catecholamines and aldosterone were taken at approximately 08.00 hours
after 30 min rest. Urinary and plasma catecholamines were determined by using a high performance liquid chromatography method with
electrochemical detection [17].
Aldosterone was measured with an antiserum
from New England Nuclear (Worcester, MA,
U.S.A.) raised in sheep against aldosterone-l8,21dihemisuccinyl-bovine serum albumin. The radioimmunoassay was performed after purification on
an LH-20 Sephadex column. In 16 consecutive
double determinations on the same plasma samples
the error of a single measurement was 12% of the
mean values. For technical reasons these measurements were obtained in only 30 subjects.
Statistical method
S G d a r d methods we^ used for calculation of
mean and standard deviation (sD). The hypothesis
of no difference in means between two groups was
tested by using Student’s t-test. Only two-sided
paired and unpaired tests were used. Values of
P < 0.05 were regarded as statistically significant.
Results
Blood pressure and heart rate (Table I )
During the period of high salt intake the
systolic blood pressure increased significantly in
the whole group. No significant changes in
diastolic blood pressure or in heart rate were
noted. When the influence of family history of
hypertension was considered no significant
difference between the two hereditary subgroups
was seen. Blood pressure had returned to normal
pre-salt values 3 weeks after the study finished.
Weight and electrolyte excretions (Table I )
The weight increased significantly for the whole
group, as did the urinary sodium excretion. The
mean sodium excretion during high salt intake
corresponded roughly to the sum of the ordinary
intake plus the added 1 2 g daily. The potassium
excretion did not change significantly. No
differences between the two hereditary subgroups were noted.
Indices of neurogenic and hormonal activity
(Table 2 )
Plasma noradrenaline remained unchanged
throughout the study. Urinary excretions of
0. Gudmundsson et al.
430
TABLE 1. Systolic and diastolic blood pressure, heart rate, b o d y weight and urinary excretion o f sodium
and potassium on normal salt intake (week 0 ) and during 4 weeks of high salt intake (weeks 1-4) in
normotensive middle-aged men
Means 5 SD are shown (n = 37). *P < 0.05 compared with week 0.
Weekno. ..
..
Blood pressure (mmHg)
systolic
diastolic
Heart rate (beats/min)
Weight (kg)
Na excretion (mmo1/24 h)
K excretion (mmo1/24 h)
0
1
2
3
4
130k13
89 ?;9
72 * 3
83.1 *10.6
192 *31
78 k29
137 *13*
91 k10
69 *6
84.2+10.7*
340 f 116*
80.7 f 30
135 *14*
90t10
71 i8
84.1 f10.8*
326 * 109*
83.3 f 34
136 f 15*
90f11
73 *11
84.0*10.4*
303 f 139*
78.3 *34
137 *13*
91 i l l
73 r 9
84.2*10.6*
366 f 179*
90.4 t 36
TABLE 2. Neurogenic and hormonal variables on
normal salt intake (week 0) and during the fourth
week of high salt intake
Means f SD are shown ( n = 30). * p 0.05 cornpared with week 0.
<
Neurogenic and
hormonal variables
Urinary noradrenaline
@mo1/24 h)
Urinary adrenaline
@mo1/24 h)
Urinary dopamine
@rno1/24 h)
Plasma aldosterone
(nmol/l)
Plasma noradrenaline
(nmol/l)
PHT
Week
0
Week
4
439 * 180
679* *202
46 232
62* *50
2410 k593
3570* + I 4 4 0
0.50 k0.2
0.40* kO.1
1.36 t0.42
1.48 k0.42
PNT
T.
noradrenaline, adrenaline and dopamine increased
significantly during high salt intake with no
significant differences between the hereditary
subgroups. Plasma aldosterone decreased significantly in the whole group during high salt intake
but there was no difference in this respect between
the hereditary subgroups.
Intra-erythrocyte sodium (Fk. 2 )
On normal salt intake intra-erythrocyte sodium
content was significantly higher among those with
a positive family history of hypertension than in
the group without such family history (1 1.4 f 2.7
vs 9.8 f 1.7 mmol/l of erythrocytes) (Fig. 2, P <
0.05). After high salt intake intra-erythrocyte
sodium decreased in the group with a positive
family history, but no significant change was
observed in the group without such a history. The
difference noted between the groups when on
normal salt intake had disappeared after the period
of increased salt exposure (9.3 f 1.6 vs 9.2 f 1.7
mmol/l of erythrocites respectively). The cell
water content before salt loading was 61.7k3.2
m1/100 ml in the non-heredity group and 60.9 f
3.6 and 62.5k3.3 and 61.3f3.1 m1/100ml respectively). None of the differences was statistically
significant.
Correlations between changes in blood pressure
and other variables
0
FIG. 2. Intraerythrocyte sodium before (stippled
column) and after (open column) high salt intake
in the two hereditary groups: PHT, at least one
parent hypertensive (n = 11); PNT, parents
normotensive ( n = 2 6 ) . Mean values f SD. * P <
0.05.
Correlations are calculated between the blood
pressure change from base-line to week 4 and the
corresponding changes in intra-erythrocyte sodium
content, urinary noradrenaline, adrenaline, dopamine and sodium excretion. No significant
correlation coefficients were found in the study
groups as a whole or in the two hereditary subgroups.
Blood pressure response to high salt intake
Discussion
Several salt loading studies varying in design and
experimental procedure have been reported with
varying conclusions. In some the participants have
been healthy young volunteers, often recruited by
advertisement [18], medical students [19],
prisoners [8] or borderline hypertensive subjects
[7], not representative of the population at large.
The present study aimed to investigate a random
sample of the non-hypertensive 50-year-old male
population in order toshed light on the sensitivity
to increased salt intake in such a population. In a
study of this kind, involving behavioural changes
during a relatively long time period, a high dropout rate might be expected. Several participants
also dropped out during the study. Those who
remained in the study were well motivated and
adhered closely to the prescribed salt intake as
judged by their urinary sodium excretions. They
should constitute a reasonably good representation
of the middle-aged normotensive male population.
At the fvst screening examination we chose a high
cut-off point for blood pressure, 170/105 mmHg,
without prior rest, which corresponds to recommendations by the Medical Board of Health in
Sweden. The blood pressure used during the study
was taken after at least 10 min rest. As can be seen
in Table 1 these pressures were well within normal
limits.
The subjects were divided into two groups
according to their family history of hypertensive
disease. The validity of hereditary data is as usual
questionable, owing to uncertainties about the
cause of death and to the large proportion of
undetected hypertension in the population. The
prevalence of parental hypertension is thus
probably underestimated [20]. Furthermore, a
proportion of those hereditarily predisposed to
hypertension might already have become hypertensive at the age of 50 years. These subjects
would, according to our inclusion criteria, not
have entered the trial. A prospective study has,
however, shown that the vast majority of those
becoming hypertensive do so after the age of 50
years [Zl]. According to another study those with
heredity for hypeItension did not seem to have a
higher incidence of hypertension before the age of
50 than those without such history [22]. There is
thus no reason to believe that a substantial proportion of those prone to develop hypertension
during their lifetime have been excluded in the
present study.
Former studies have been short-term, with the
increased salt intake period ranging from a few
days to a few weeks. Sometimes the amount of
dietary salt was changed several times during the
43 1
experimental period [8, 101. The effect of
increased salt intake on blood pressure may take
a long time to develop. We continued during 4
weeks with a constantly increased salt intake. This
is probably too short to enable us to determine the
chronic effects but practical difficulties in motivating the subjects to continue for longer time
periods limited the duration of the trial. However,
the 4 weeks of high salt intake enables most
compensatory mechanisms to have come into
play before our final assessment of blood pressure
and the other factors studied.
This study has four main findings. Firstly,
moderate increase in intake of sodium acts as a
pIessor agent in this unselected group of normotensive 50-year-old men, thereby contradicting the
results of most previous studies of young normotensives [8, 91. To our knowledge the only two
studies showing a pressor effect of a moderate
increase of salt intake in normotensive young men
are the studies by Sullivan et al. [7] and Parfrey
et al. [19], later analysed again by Holly et al.
~231.
Sodium may act as a pressor agent through
volume expansion at high salt intake [24] or
through augmentation of the effects of sympathetic nervous activity [25,26]. Our study was not
designed to elucidate mechanisms and the data
give no clues to how the high sodium intake
increases blood pressure in certain individuals. It is
a point of interest that our subjects increased their
weight during high salt intake. A similar study
done on 30-year-old men with the same amount
of salt consumed during an equally long period
(0. Gudmundsson et al., unpublished work)
showed that young men neither increased their
weight nor their blood pressure. Thus, our results,
like those of Luft et al. [27], indicate that the
renal handling of a salt load is in some way age
dependent.
Secondly, the urinary excretion of noradrenaline, adrenaline and dopamine increased during
the study. The increase in dopamine is in accordance with findings in other studies [28, 291,
suggesting that an intrarenal natriuretic system is
stimulated when subjects increase their salt intake.
There are conflicting findings with regard to
changes in noradrenaline and adrenaline in
response to changes in salt intake. The data by
Luft et al. and Romoff et al. [30,31], suggest that
the levels of catecholamines are higher during very
low sodium intake than during normal and high
sodium intake. Nicholls et al. [32] also found
the lughest levels of plasma noradrenaline during
severely restricted salt intake and lowest levels
when the urinary sodium excretion was in the
normal range; on higher salt intake plasma nor-
43 2
0.Gudmundsson et al.
adrenaline rose again. Our findings are in accordance with the findings of Nicholls et d. and with
findings in animal experiments where moderate
increases in urinary excretion of noradrenaline and
adrenaline were noted after a period of high salt
intake [33, 341. This indicates that the level of
salt intake may be of importance for the activity
of the sympathetic nervous system. One investigator has suggested that increasing the concentration of sodium in the medium results in faster
efflux of noradrenaline from platelets [35].
Thirdly, we found that on normal salt intake
those with a positive family history had a significantly higher intra-erythrocyte sodium content
than those without a family history of hypertension. Many groups have shown an increased
intraerythrocyte sodium content in hypertensive
patients and their offspring [ll-131, whereas
others have found normal sodium content [36,
371. We conclude, as did L o s e et al. [38] and
other investigators [ l l , 131, that those with a
positive family history of hypertension have
significantly higher intra-erythrocyte sodium
content on normal salt intake than those without
such history. Our subjects were all normotensive
and 50 years old, and thus considerably older than
groups studied formerly. Our data and the abovementioned studies [ l l , 13, 141 suggest that alterations in intracellular sodium content and transmembrane fluxes are present in the normotensive
offspring of hypertensive parents, indicating that
the defect is genetic rather than acquired. Whether
these offspring with heredity for hypertension and
a high intraerythrocyte sodium content will
develop hypertension can only be studied prospectively.
It has been claimed that the renal arteries as
well as other blood vessels in patients and animals
with high blood pressure contain increased
amounts of sodium [39, 401. It is difficult to determine the sodium content in complex tissues
such as the arterial wall but this can be done
accurately in isolated cells such as erythrocytes
and leucocytes. We do not know whether the
intraerythrocyte sodium content reflects the
intracellular sodium content of the smooth muscle
cells of the arteriolar wall. At present we can only
assume a relationship between the sodium content
of the cells of the arteriolar wall and that of
erythrocytes.
Fourthly, during the period of high salt intake
intraerythrocyte sodium content decreased significantly in those with a positive family history. Our
results do not lend support to the notion that
intracellular sodium should increase when normal
man is subjected to a salt load. The significant
increase in body weight during the high salt intake
suggests volume expansion. Both in animal experiments [41] and in human studies [42] volume
expansion through high salt intake has been proposed to increase the level of a circulating natriuretic factor inhibiting Na+,K+-dependent
ATPase activity and, hence, suppressing the
pumping of sodium out of cells, leading to
increased intracellular sodium. Our fmdings of a
decrease in intraerythrocyte sodium content
during high salt intake oppose the hypothesis that
volume expansion secondary to a high salt intake
increases the level of such an ouabain-like factor.
Acknowledgments
The authors thank Inger Olander for expert
technical assistance. This investigation was supported by grants from the Swedish Medical
Research Council.
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