Clinical Science and Molecular Medicine (1975) 48, 161-165.
The role of plasma volume in the increase of aldosterone
secretion rate during sodium deprivation
T. G. DALAKOS
AND
D. H. P. STREETEN
Department of Medicine, Section of Endocrinology, State University of New York,
Upstate Medical Center, Syracuse, New York
(Received 3 September 1974)
Summary
1. 24 h aldosterone secretion rates (ASR) have been
measured in six normal volunteers while recumbent
all day and while standing for 12 h, on 200 and 10
mmol/day sodium diets and after salt-poor albumin
infusions (75 g in 150 ml), which significantly expanded plasma volume.
2. The mean ASR on the 10 mmol/day sodium diet,
both without and with the salt-poor albumin infusion, was highly significantly increased above the
mean ASR on the 200 mmol/day sodium diet, both
in the recumbent and in the upright posture.
3. There was no significant difference between the
mean ASR values on the 10 mmol/day sodium diet
alone and after the infusion of albumin either in the
recumbent or in the upright posture.
4. The above observations suggest that sodium
deprivation raises ASR by a mechanism or mechanisms unrelated to plasma volume.
Key words: aldosterone, plasma volume, posture,
albumin infusion.
Introduction
Biglieri, Pronove & Delea (1958) showed that these
volume changes involved mainly the plasma 'compartment', and there is now evidence from many
sources that aldosterone production is increased by
hypovolaemia (Goodkind, Ball & Davis, 1957; Fine,
Meiselas & Auerbach, 1958; Davis, Carpenter, Ayers,
Holman & Bahn, 1961). The potent stimulatory
effect of sodium deprivation on aldosterone secretion
is also well established (Luetscher & Axelrad, 1954;
Hernando, Crabbe, Ross, Reddy, Renold, Nelson &
Thorn, 1957; Bartter, Mills, Biglieri & Delea, 1959),
and has been generally thought to be mediated by
activation of the renin-angiotensin-aldosterone system (Davis, Ayers & Carpenter, 1961; Davis, Hartroft, Titus, Carpenter, Ayers &Spiegel,1962; Veyrat,
de Champlain, Boucher & Genest, 1964; Brown,
Davies, Lever & Robertson, 1964; Binnion, Davis,
Brown & Olichney, 1965). There are few, if any,
direct observations to show whether or not hypovolaemia is part of the mechanism whereby sodium
deprivation leads to hyperaldosteronism. It was the
purpose of this study to determine whether changes
in plasma volume playa role in the increase in aldosterone secretion which follows restriction of
sodium intake in man.
It has long been recognized that changes in the vol-
ume of body fluids can produce important increases
or decreases in aldosterone production (Muller,
Riondel & Mach, 1956; Bartter, Liddle, Duncan,
Barber & Delea, 1956). The studies of Bartter,
Materials and methods
Subject material
Six healthy volunteers were studied, four females
and two males, aged 22-31 years. They took no
antiovulatory or other drugs for at least 6-12
months before the present observations. Consent
Correspondence: Dr T. G. Dalakos, Section of Endocrinology, State University of New York, Upstate Medical
Center, 750 East Adams Street, Syracuse, New York 13210,
U.S.A.
161
T. G. Dalakos and D. H. P. Streeten
162
final eluate in a Packard Tricarb liquid-scintillation
spectrometer. Urinary 17-hydroxycorticosteroid excretion was determined by the method described
by Silber & Porter (1954) on 24 h urine collections
obtained from all subjects. Statistical computations
were done with standard procedures (Croxton,
1953).
was obtained from each subject after full explanation
of the purpose and nature of all procedures used.
Plan 0/ study
The subjects were studied for 3 weeks on constant
weighed diets, prepared in the Clinical Research
Center of the Upstate Medical Center. The daily
procedures (see Table 1) were similar in each of the
3 weeks, except that: (1) sodium intake was 200
mmol/day in the first week and 10 mmol/day during
the second and third weeks; (2) the second and third
weeks were separated by 5-6 days of uncontrolled
TABLE
Constant diet
Body weight
Plasma volume and electrolytes
Aldosterone secretion rate
Na, K, creatinine excretion
Recumbent 24 h
Upright 12 h
Results
Plasma volume (Table 2)
The change in sodium intake from 200 to 10 mmol/
day caused no consistent change in plasma volume.
1. Sequence of studies
Day I
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
diet at home; (3) salt-poor albumin, 75 g (150 ml)
was infused intravenously over a period of 45-60
min, starting at 08.00 hours on days 5 and 7 of the
third week. Potassium intake was kept constant in
each subject at 80-100 mmol/day, and the fluid intake was 1500-2500 ml daily.
Techniques used
Body weights were measured in the mornings before breakfast and after voiding, on a balance which
was accurate to 100 g. Plasma volume was determined with 125I-labelledserum albumin, ±2'0 }lCi,
with a Volemetron (Ames Co.). These determinations were made between 08.00 and 09.00 hours
before subjects had eaten or got out of bed. Sodium
and potassium concentrations were measured on
heparinized samples of plasma and on aliquots of
24 h urine collections, with an AutoAnalyzer flame
photometer. Aldosterone secretion rates were
measured on aliquots of 24 h urine collections by the
double isotope dilution derivative method of Kliman
& Peterson (1960), using [3H]aldosterone and [14C]_
acetic anhydride obtained from the New England
Nuclear Corp., and counting the radioactivity in the
X
X
X
X
TABLE
2. Plasma volumes in six normal subjects
Plasma volume (rnlrkg)
Subject
M.B.
L.S.
J.C.
M.K.
L.R.
H.H.
Mean
SEM
Age
200
(and sex) mmolof
Na/day
22 (F)
22 (F)
23 (F)
24 (F)
31 (M)
28 (M)
10
mmolof
mmolof Na/day
Na/day +albumin
10
46·3
45'6
43·2
42·9
40·5
35'1
48'6
46'6
43-8
46'8
34·2
31'9
51'9
52'6
48'7
50'6
36'6
33-6
42'3
±1'5
42'0
±2'7
45'7
±3'1
However, the intravenous infusion of 75 g of albumin expanded the plasma volume in all subjects, the
mean change being highly significant when analysed
by the t-test for non-independent variables (P<
0'(05).
Aldosterone secretion rate
Aldosterone secretion rate (ASR) rose in every
subject when sodium intake was reduced from 200 to
Hyperaldosteronism in sodium deprivation
10 mmol/day, the mean (± SEM) values being 0'28 ±
0·06 jlIl1ol/day (100±20 pg/day) and 1-15±0·15
pmol/day (414±54 pg/day) on the high and low
sodium diets in recumbency, and 0·52±0·09 pmol/
day (188 ± 33 pg/day) and 2'26 ± 0·47 pmol/day
(813 ± 170 ltg/day) on the high and low sodium diets
in the upright posture (P< 0·001 and < 0·01 for the
effectsof sodium intake in each posture respectively).
The infusion of albumin had no detectable effect on
the ASR when the subjects were either recumbent or
upright (Table 3). The mean values were still significantly higher on the day of albumin infusion both
in the upright and in the recumbent posture, than
when the subjects received the 200 mmol/day sodium
diet (P< 0·001 and < 0·001 respectively). On the
recumbent and upright (days 5 and 7) respectively
(P < 0'01), 26 ± 7 and 3 ± 0·5 mmol/day on the 10
mmol/day sodium diet recumbent and upright
(P< 0'05) and 33 ± 11 and 7 ±2 mmol/day on the
days of albumin infusion recumbent and upright
respectively (P ~ 0'05). The sodium excretion during
albumin infusion was not significantly different from
that on the 10 mmol/day sodium diet without the
infusions.
Urinary excretion ofpotassium
Urinary potassium excretion was 67'9 ±4·5 and
82·0±7·5 (SEM) mmol/day on the 200 mmol/day
sodium diet in the recumbent and upright postures
3. Aldosterone secretion rates in six normal subjects
TABLE
Recumbent posture
Upright posture
10
200
Subject
M.B.
L.S.
r.c,
M.K.
L.R.
H.H.
Mean
SEM
163
mmolof
10
10
mmolof
200
10
mmolof
mmolof Na/day
Na/day +albumin
mmolof
mmolof
Na/day
Najday
Na/day
Na/day
+albumin
0'16
0·15
0'16
0'32
0'36
0'53
0·28
±0'06
1·36
0'78
0'89
0'92
0'94
Jo87
1-15
±0'15
0'78
0·38
0'36
0'19
0·68
0·75
0'52
±0'09
4'72
1-64
1-60
1·19
2-40
2·40
2'26
±0·47
Jo45
1'39
1'36
0·87
0·99
1·93
1·33
±0'14
other hand, there was no significant difference when
ASR after albumin infusion was compared with ASR
on the 10 mmol/day sodium diet alone (P>O'l and
> 0'1 respectively).
Plasma sodium and potassium concentrations
There was no significant change in the mean
plasma sodium concentrations, which were 142 ± 1'0
(SEM) mmol/l on the 200 mmol/day sodium intake,
141± 1·4 mmol/l on the 10 mmol/day sodium intake
and 144± 1·2 mmol/l on the day of albumin infusion.
Mean plasma potassium concentrations were 4·8 ±
0'1,4'6 ±0'1 and 4·8 ±0·2 (SEM) mmol/l in these three
situations respectively.
3044
2'09
2-49
1'28
Jo82
2·23
2'23
±0'27
respectively. On the 10 mmol/day sodium diet urinary
excretion of potassium was 63'3 ± 5·1 and 70'2 ±4'1
mmol/day recumbent and standing respectively; on
the same diet but after salt-free albumin infusions,
urinary potassium excretion was 64·2 ± 3·9 and 68'7 ±
9'3 mmol/day respectively. None of these differences
was statistically significant.
Details of the plasma sodium and potassium and
the urinary potassium changes have been deposited
as Clinical Science and Molecular Medicine Tables
74/12 and 74/13, with the Librarian, the Royal
Society of Medicine, 1 Wimpole Street, London
W1M 8AB, from whom copies may be obtained on
request.
Urinary excretion of sodium
Urinary Yl-hydroxycorticosteroids
Urinary sodium excretion was 221 ± 21 and 134 ± 15
(SEM) mmol/day on the 200 mmol/day sodium diet
Urinary excretion of these steroids was not increased by sodium depletion either in the recumbent
164
T. G. Dalakos and D. H. P. Streeten
or in the upright posture in the present experiments.
Mean urinary excretion of 17-hydroxycorticosteroids
on the 200 mmol/day sodium diet recumbent and
upright was 5'3 ±0·81 and 5·03 ±0·88 (SEM) mg/day
respectively and on the 10 mmoljday sodium diet in
the recumbent and upright postures was 4·82 ± 0'73
and 5·40 ± 0'76 mg/day respectively.
Discussion
The present studies have shown that a reduction in
sodium intake from 200 to 10 mmol/day in normal
human subjects increased the aldosterone secretion
rate without any demonstrable reduction in plasma
volume. ASR was as much increased by sodium
deprivation when plasma volume remained unchanged as when plasma volume was actually increased by the administration of albumin solution.
It seems clear therefore that although sodium deprivation sometimes does decrease plasma volume in
human subjects (Streeten, Schletter, Clift, Stevenson
& Dalakos, 1969),reduction in plasma volume is not
the mechanism whereby sodium restriction stimulates an increase in aldosterone secretion.
These results do not preclude the possibility that
sodium deprivation might increase aldosterone production by raising plasma angiotensin concentrations
in spite of the absence of hypovolaemia or by increasing the sensitivity of the aldosterone response to
circulating angiotensin (Oelkers, Brown, Fraser,
Lever, Morton & Robertson, 1974). However, the
observations of others (Best, Coghlan, Bett, Cran &
Scoggins, 1971; Boyd, Adamson, Arnold, James &
Peart, 1972; Blair-West, Coghlan, Cran, Denton,
Funder & Scoggins, 1973)make it unlikely that hyperangiotensinaemia is the sole means whereby sodium
restriction raises aldosterone concentration in man.
This view is supported by other studies, which have
shown that plasma aldosterone concentration increases in response to sodium depletion induced by
haemodialysis, even in anephric human subjects
(McCaa, McCaa, Read, Bower & Guyton, 1972;
Weidmann, Horton, Franklin, Fichman, Graz, Lupu
& Maxwell, 1972). Such findings in nephrectomized
subjects clearly indicated that the stimulus to increased concentrations of aldosterone did not necessarily require increased renin release, but they could
not be interpreted to exclude a contributory role of
hyperangiotensinaemia in the increased aldosterone
production that follows sodium depletion or orthostasis in intact humans.
The absence of plasma sodium or potassium
changes during sodium deprivation, together with
other evidence in the literature (Luetscher & Axelrad,
1954; Duncan, Liddle & Bartter, 1956; Best et aI.,
1971; Oelkers et al., 1974), make it unlikely that
changes in plasma electrolyte concentration stimulated increased aldosterone secretion. Similarly, the
lack of a rise in urinary excretion of 17-hydroxycorticosteroids during sodium depletion either in the recumbent or in the upright posture in the present
studies constitutes evidence against ACTH release
as the mechanism of the rise in aldosterone production. There may therefore be an additional stimulus
to hyperaldosteronism in individuals deprived of
sodium.
As early as 1962, Peterson & Muller reported the
presence of an aldosterone-stimulating substance in
the urine of sodium-depleted humans and rats. Their
most highly purified fractions showed a good doseresponse effect on aldosterone production by adrenal
cells in vitro. The substance which stimulated
aldosterone release in these experiments was not
angiotensin because it had no pressor effect when
administered to rats. More recently McCaa, Young,
Ott, Guyton & McCaa (1973) have shown that in
nephrectomized dogs, subjected to acute sodium
depletion without change in total body fluid volume
or plasma potassium concentration, the usual rise of
plasma aldosterone was prevented by decapitation.
There is thus evidence that the action of sodium
deprivation on aldosterone production is mediated
by a mechanism, the exact nature of which is unknown, but which is unrelated to changes in plasma
volume.
Acknowledgments
This work was supported by a Graduate Training
Grant in Endocrinology, AM 05252, from the
National Institute of Arthritis and Metabolic
Diseases, and Clinical Research Center Grant, RR
00229, from the Division of Research Facilities and
Resources, USPHS.
The authors wish to thank the nurses ofthe Clinical
Research Center, and Mrs Carol Lynch for her technical assistance. We are also grateful to Miss Judy
Spaulding for typing assistance. The statistical
analyses were performed by the Department of Bioelectronics and Computer Sciences, supported by a
Special Research Resource Grant, FR 00353, from
the USPHS.
Hyperaldosteronism in sodium deprivation
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