Clinical Science (1970) 39, 641-651.
T H E EFFECTS O F P R O L O N G E D A D M I N I S T R A T I O N
O F VASOPRESSIN A N D OXYTOCIN ON R E N I N ,
ALDOSTERONE A N D S O D I U M BALANCE I N N O R M A L
MAN
F. J . GOODWIN*, J . G . G. L E D I N G H A M
AND
J . H. L A R A G H
Department of Medicine, Columbia University, College of Physicians and Surgeons
and the Presbyterian Hospital in the City of New York, New York
(Received 21 July 1970)
SUMMARY
1 . Vasopressin was administered to normal men in metabolic balance for periods of
5-10 days under conditions of water restriction or overhydration. Likewise, oxytocin
was administered to two normal men for 10 days.
2. The effects of both neuropeptides on plasma renin activity, aldosterone excretion
rate and sodium balance were observed.
3. In the absence of overhydration, vasopressin had no demonstrable effect upon
plasma renin activity, aldosterone excretion rate or sodium balance. During overhydration body weight gain and plasma dilution were followed by natriuresis; the
associated changes in plasma renin activity and aldosterone excretion, however, were
unimpressive.
4. The prolonged administration of oxytocin for 10 days under conditions of
normal hydration failed to influence sodium excretion, plasma renin activity or
aldosterone excretion.
5. It is concluded that in normal man changes in circulating levels of vasopressin
or oxytocin do not play a physiological role in the control of sodium excretion.
The regulation of extracellular fluid volume is complex: both aldosterone and vasopressin
have been shown to be important factors in its control. The increased secretion and excretion
of aldosterone which follow dietary sodium deprivation (Ulick, Laragh & Lieberman, 1958 ;
Axelrad & Luetscher, 1954) or haemorrhage (Farrell, Rosnagle & Rauschkolb, 1956) are
mediated, at least in part, by stimulation of the renin-angiotensin system (Laragh, Angers, Kelly
& Lieberman, 1960; Biron, Koiw, Nowaczynski,Brouillet & Genest, 1961 ;Brown, Davies, Lever
& Robertson, 1963).However, aldosterone secretion is also controlled by other factors, including
dietary potassium intake (Laragh & Stoerk, 1955, 1957) and ACTH (Liddle, Duncan &
Bartter, 1956; Tucci, Espiner, Jagger, Pauk & Lauler, 1967; Newton & Laragh, 1968). Further-
* Present address: The Medical Unit, The London Hospital, Whitechapel, London, E.l.
Correspondence: Dr J. H. Laragh, Department of Medicine, Columbia Presbyterian Medical Center, 630,
West 168th Street, New York, N.Y. 10032, U.S.A.
64 1
642
F. J. Goodwin, J . G. G. Ledingham and J . H . Laragh
more, the demonstration that some patients with primary aldosteronism have bilateral adrenal
hyperplasia without evidence of stimulation by either angiotensin or ACTH, has suggested the
existence of some other, as yet unidentified, trophic stimulus to aldosterone secretion (Laragh,
Ledingham & Sommers, 1967; Davis, Newsome, Wright, Hammond, Easton & Bartter, 1967).
Vasopressin release also appears to be governed by multiple factors and is influenced not
only by changes in osmolarity of the body fluids (Verney, 1947), but also by changes in blood
volume. Ginsburg & Heller (1953) demonstrated that haemorrhage in the rat resulted in an
increase in circulating antidiuretic material and Weinstein, Berne & Sachs (1960), studying
haemorrhage in the dog, showed that this substance was in fact vasopressin. Share (1961)
subjected dogs to peritoneal dialysis with hypertonic solutions, thereby producing small gradual
decreases in blood volume without affecting mean arterial blood pressure, and demonstrated a
six-fold increase in the circulating level of vasopressin. The mechanism whereby the secretion
of this hormone is influenced by volume changes is as yet ill-defined, although volume receptors
in the left atrium of the heart (Henry, Gauer & Reeves, 1956; Henry, Gupta, Meehan, Sinclair
& Share, 1968) and baroreceptors in the region of the carotid arteries have been implicated in
the control of its release.
Bartter, Liddle, Duncan, Barber & Delea (1956) produced expansion of body fluid volume
in normal man by means of administered vasopressin and water-loading, and caused aldosterone
excretion to diminish despite the accompanying dilution of extracellular sodium concentration. However, evidence is lacking about the possibility of a direct effect of prolonged administration of vasopressin on aldosterone secretion in man, occurring in the absence of changes in
body fluid volume. By means of direct arterial perfusion of the adrenal gland of the hypophysectomized dog Hilton (1960) showed that lysine vasopressin stimulated hydrocortisone
secretion, and that the synthetic analogue acetyl arginine vasopressin stimulated aldosterone ;
however, the latter finding was demonstrated in one animal only and the effect of arginine
vasopressin itself, the naturally occurring hormone in man, was not investigated. Furthermore,
vasopressin is known to stimulate ACTH release (McCann, 1957) and, in view of the known
transient effect of the latter upon aldosterone secretion, it seemed possible that aldosterone
might be stimulated indirectly by vasopressin.
It has been shown in dogs that vasopressin, as well as possessing marked antidiuretic activity,
is also markedly natriuretic during water diuresis : conversely, oxytocin is natriuretic during
antidiuresis (Brooks & Pickford, 1958; Chan & Sawyer, 1961). A further implication that
vasopressin may be involved in sodium metabolism is the report by Bunag, Page & McCubbin
(1967) of its action in dogs of suppressing the rise in renal venous renin activity which normally
occurs in response to lowering renal perfusion pressure.
In the present experiments, therefore, we have studied in normal man the effects of the
prolonged administration of vasopressin, associated with and in the absence of an increase in
total body water, and of oxytocin upon aldosterone excretion, peripheral venous plasma renin
activity and sodium excretion.
METHODS
The studies were made on seven normal male volunteers, to whom the purpose and nature of
the experiment had been fully explained and from whom consent had been obtained. All
were maintained in the Metabolic Ward of Presbyterian Hospital, New York, on a constant
Neurohypophyseal peptides and sodium balance
643
diet containing approximately 100 mEq of sodium and 100 mEq of potassium daily. All urine
was collected for determination of daily excretion rates of electrolytes, aldosterone, and 17ketogenic steroids. Normal activity was permitted throughout the studies. Blood was taken at
noon, after the subject had been ambulant for at least 4 h, for measurement of plasma electrolyte and cortisol concentrations and plasma renin activity: for the latter 20 ml of venous blood
were drawn rapidly into a tube containing either 250 units of thrombin to hasten clotting, or
20 mg of disodium EDTA, and renin activity was determined by a method described previously
(Newton & Laragh, 1968). Plasma cortisol was measured by a modification of the method of
Silber & Porter (1954), and both urinary and plasma electrolytes by flame photometry. Faecal
electrolyte content was not measured. Osmolarity of plasma and urine was measured using a
freezing-point osmometer (Advanced Instruments, Inc.). Aldosterone excretion rate was measured by a double isotope dilution technique (Laragh, Sealey & Klein, 1965; Laragh, Sealey &
Sommers, 1966), and urinary 17-ketogenic steroids by a modification of the method of Few
(1961). In certain of the studies measurements of plasma volume were made using 1311-labelled
serum albumin. Vasopressin was given as Pitressin tannate in oil (PTO) or as aqueous Pitressin
(Parke, Davis and Company) ; oxytocin was given as the synthetic preparation, Pitocin (Parke,
Davis and Company) : both hormones were given by intramuscular injection. Each subject
received the constant diet for 5 days, at the end of which period control observations were made
before either hormone was administered.
Vasopressin studies
Water restriction. In four subjects (D.G., P.K., W.M.and P.W.), following control observations, fluid intake was restricted, usually to less than 1000 ml daily, in order to maintain body
weight, measured twice daily, constant, and urine specific gravity, measured at each voiding,
above 1.020. In one subject (P.K.) 5 units of aqueous Pitressin were given five times daily,
but in the remainder 5 units of PTO and 10 units of aqueous Pitressin were given on the first
day and the same dose repeated only when urine specific gravity fell below 1.020. Each of the
four subjects was studied for 5 days. It was assumed that this procedure ensured high circulating
levels of either endogenous or exogenous vasopressin in each subject throughout the study.
Dosage schedules appear in the Figures.
A further two subjects (W.C. and P.J.) were studied in greater detail and for a longer period.
After control measurements 5 units of aqueous Pitressin were given 4-hourly for 10 days.
During the waking hours body weight was recorded 2-hourly and fluid intake restricted so as to
prevent a gain in body weight. In addition, plasma volume was measured on the first, fifth and
tenth days of vasopressin administration.
Water expansion. In three subjects (D.G., P.K. and W.M.),
following control observations,
between 10 and 30 units of vasopressin as PTO and aqueous Pitressin were given daily for
5 days, and fluid intake increased such that each subject gained approximately 3 kg in body
weight. In two of the subjects mild symptoms of water-intoxication occurred, following which
vasopressin was omitted for 1 day.
Oxytocin studies
The effect of prolonged and regular administration of oxytocin on plasma renin activity,
aldosterone excretion and sodium balance was studied in two subjects (W.C.
and P.J.).
Following control observations 5 units of Pitocin were given 4-hourly for 10 days, during which
F. J. Goodwin, J. G . G . Ledingham and J. H. Laragh
644
period fluid was allowed ad libitum. Measurements of plasma volume were made on the first,
fifth and tenth days of oxytocin administration.
RESULTS
Vusopressin
The metabolic data for the studies in which vasopressin was administered with concurrent
restriction of water intake are shown in Figs 1 and 2. In the absence of body fluid expansion,
PK
DG
30
oc
-I
-1000
lntaket
+
output
+moo
1 +3000
- 50
[
_-_---
H
Intak!
+4r
Na Balance (mEq)
A Weight (kg)
Y
Plasma cartisal
(pg/IOOml)
Urinary 17- KGS
(mgld)
Plasma renin activity
(ng ml-1 h-1)
2t 4
0
Aldosterone excretion
rate (wg/d 1
-
0
5-0
5
Days
FIG.1 . Effect of the administration of vasopressin to normal subjects with restricted fluid intake.
vasopressin had no significant effect upon plasma renin activity, aldosterone excretion or
sodium balance. In D.G., body weight rose when vasopressin was given, with an associated
increase in urinary sodium excretion : this increase was not associated with any significant
change in plasma renin activity or aldosterone excretion. In P.K., W.M. and P.W., weightgain was satisfactorily prevented by restriction of fluid intake; in these three subjects no significant changes in sodium excretion, plasma renin activity or aldosterone excretion rate occurred.
Neurohypophyseal peptides and sodium balance
Subject
P. J.
W.C.
645
m
Vasopressin
-1ooo r
H 2 0 Balance (rnl)
3000
-50r
No Balance (mEq1
AWeight (kgl
290
,*OF
270L
+0.5r
+0.25t
0
Plasma osrnolarity
(rnOsrn/l)
T
A Plasma volume I
A
Plasma ccrtisol
(pg/IOO ml)
Urinary 17-KGS
(rng/d)
Urine osrnolarity
(mOsmol/ll
Plasma renin activity
(ng ml-1 h-1)
- -
0
5
0
10
5
Aldosterono excretion
rate (pg/d)
10
Days
FIG.2. Effect of the prolonged administration of vasopressin to normal subjects with restricted
fluid intake.
Subjects W.C. and P.J. were studied for 10 days. Both received 30 units of vasopressin daily and
body weight gain was satisfactorily prevented in each by water restriction : throughout the
studies urinary osmolarity remained above 750 mosmol/l in W.C. and above 500 mosmol/l
in P.J., plasma osmolarity remaining unchanged. In P.J.a marked natriuresis occurred on the
third to sixth days of vasopressin administration, following which sodium excretion fell
considerably. Although in this subject body weight remained fairly constant, plasma volume
had expanded by 340 ml at the time of natriuresis; on the tenth day of vasopressin administration, when sodium excretion had fallen below control levels, plasma volume had returned to its
F. J. Goodwin, J. G. G. Ledingham and J. H. Laragh
646
original value. These changes in sodium excretion occurred despite the continued administration of vasopressin throughout the study.
The metabolic data for the three studies in which vasopressin was administered without
concurrent restriction of water intake are shown in Fig. 3. In each subject body weight rose by
Subject
Vasopressin units
30
OC
-4000
-2OOOF
H,O
Balance (ml)
I
clutput +4000
-100
Intake
Outbut
Na Balance ( m E q )
+50
A Weight ( k g )
145
I25
20
Plasma cortisol
(pq/IOO m I )
40
Urinary 17-KGS
(mg/d)
Plasma renin activity
(ng ml-1 h-1)
:I[
0
-
0
Aldosterone excretion
rate (CLq/d)
5
Days
FIG.3. Effect of the administration of vasopressin to normal subjects with water-loading.
approximately 3 kg and plasma sodium concentration fell by at least 10 mEq/l. In each a
natriuresis occurred during volume expansion : the accompanying changes in plasma renin
activity and aldosterone excretion rate were, however, unimpressive. The marked rise in
aldosterone excretion rate occurring on the fifth day in P.K., following the withdrawal of
vasopressin, was associated with striking falls in both body weight and sodium excretion.
Neurohypophyseal peptides and sodium balance
647
In none of the studies in which vasopressin was given did significant or consistent changes in
plasma cortisol or 17-ketogenic steroid excretion occur, thereby excluding any marked effect
of vasopressin in the dosages employed upon ACTH release.
--
Oxytocin
The metabolic data for the two studies in which oxytocin was given are shown in Fig. 4.
Both subjects were given 30 units of the hormone daily in divided doses for 10 days. In neither
wc
33
-50
Intoke
+5z[
1
output+100
+iE
-I
~
P.J.
-
-
"g -v$-
Subject
oxytocin units
No Bolonce (rnEq)
A Weight ( k g )
Plasma osmolority
( m Osrn/l)
290
+0.25
L
-0.25
A Plasma volume I
Plasma renin activity
(ng mi-1 h-1)
0
- I-
0
5
10
0
5
A ldosterone excretion
rate (pg/d)
10
Days
FIG.4. Effect of the administration of oxytocin to normal subjects with unrestricted fluid
intake.
were any significant or consistent changes in plasma renin activity, aldosterone excretion rate
or sodium excretion observed. Although measurements of plasma cortisol and urinary 17ketogenic steroids were made in these studies, they failed to show significant changes following
oxytocin and have not been presented here.
DISCUSSION
In these studies the physiological role of vasopressin in the control of aldosterone, plasma renin
activity and sodium metabolism was investigated in normal man. In those subjects to whom
vasopressin was given for 5 days only and in whom water intake was restricted, it may be
assumed that high circulating levels of vasopressin were present throughout the studies in view
I;. J. Goodwin, J. G . G. Ledingham and J. H. Lmagh
of their persistently high urine specific gravities. The remaining two subjects, W.C. and P.J.,
who were studied for 10 days, received constant doses of vasopressin which were appreciably
above the physiological requirement of normal man. That in each case antidiuretic doses of
vasopressin were given was demonstrated by the tendency for water to be retained. When
expansion of body fluid volume was prevented, the administration of vasopressin in doses
sufficient to produce marked antidiuresis failed significantly to affect aldosterone excretion,
plasma renin activity or sodium balance. The absence of changes in plasma cortisol levels or in
17-ketogenic steroid excretion is not surprising, since the dose of vasopressin required to
stimulate ACTH release greatly exceeds that necessary for antidiuresis (Nichols & Guillemin,
1959). Furthermore, the role of ACTH in controlling aldosterone secretion in normal man is of
doubtful significance, since the rise in aldosterone excretion which follows ACTH administration (Liddle et al., 1956; Tucci et al., 1967; Newton & Laragh, 1968) is only transient and
occurs only in response to large unphysiological doses. The latter objection obtains in the acute
experiments of Hilton (1960) in which hydrocortisone was released from the isolated perfused
adrenal gland of the dog by lysine vasopressin and aldosterone by acetyl arginine vasopressin.
In the present studies we have demonstrated in normal man that antidiuretic doses of vasopressin influence neither hydrocortisone nor aldosterone secretion in the absence of changes in
body fluid volume.
The studies in which water-retention was permitted during vasopressin administration
confirm the observations of Leaf, Bartter, Santos & Wrong (1953) who showed that physiological doses of the hormone produced in normal subjects on unrestricted fluid intakes,
prompt water retention with weight gain and serum dilution, followed by a delayed marked
increase in sodium and chloride excretion on the second or third day. These changes, like
those observed in our own experiments, were prevented by water restriction and led to the
conclusion that the increased sodium chloride excretion was a result of water retention and not
a direct effect of vasopressin per se. Bartter et al. (1956) expanded normal subjects on low
sodium diets with vasopressin and water for several days and observed that the accompanying
increase in urinary sodium excretion was associated with a marked fall in aldosterone excretion;
it was concluded that the natriuresis was due to the decrease in aldosterone secretion, especially
since urinary potassium excretion fell at the same time. In our own studies, however, aldosterone
excretion fell only slightly in response to water-retention : when volume expansion was prevented, vasopressin had no consistent effect upon aldosterone secretion. That suppression of
mineralocorticoid secretion is not essential for the natriuresis occurring after water-loading has
been shown by Jones, Barraclough & Mills (1963), who demonstrated in normal subjects and
in patients without functioning adrenal glands that the urinary sodium loss which followed the
acute administration of vasopressin and large intravenous loads of 23% dextrose in water
was not prevented by prior administration of large doses of 9a-fluorohydrocortisone, suggesting
that in the state of acute volume expansion at least, factors other than aldosterone may be
operative in causing sodium rejection. Further evidence suggesting that changes in sodium
excretion occurring in response to changes in fluid volume are not related to changes in
vasopressin levels was obtained from the study of subject P.J. (Fig. 2) in whom urinary sodium
excretion rose with expansion of plasma volume and fell with its contraction, despite the high
levels of vasopressin maintained throughout the study.
These studies are also relevant to experiments by Newsome & Bartter (1968) who investigated
the relative effects of changes in body fluid volume and serum sodium concentration as stimuli
Neurohypophyseal peptides and sodium balance
649
for the release of renin. When normal subjects were overhydrated with vasopressin and water,
plasma renin activity decreased significantly despite a marked fall in plasma sodium concentration. The possibility that vasopressin had a specific inhibitory effect on renin release, occurring
even in the absence of volume expansion, was not investigated by these workers; however, our
own studies, which demonstrated no such specific effect of vasopressin on plasma renin activity,
exclude this possibility. Furthermore, although Bunag et al. (1967) have demonstrated in dogs
that vasopressin,given in larger doses than employed here, inhibits the release of renin normally
induced by lowering renal perfusion pressure, the present studies have shown no effect of
vasopressin, given in antidiuretic doses, upon renin release in normal man.
The discovery by de Wardener, Mills, Clapham & Hayter (1961) in dogs that the increase in
sodium excretion which followed an acute intravenous infusion of saline was largely independent of changes in glomerular filtration rate and mineralocorticoid secretion led to the suggestion
that another, as yet unidentified, factor may be involved in the control of sodium excretion.
The transmission of the natriuretic response from the saline-infused animal to another by
cross-circulation suggested the existence of a humoral agent. The site of production and
chemical identity of this postulated factor are therefore of utmost importance, and interest in
the former has centred upon the hypothalamus and the pituitary gland. Earlier studies in the
dog (Brooks & Pickford, 1958; Chan & Sawyer, 1961) showed that natriuresis could be produced by vasopressin during water diuresis and by oxytocin during water restriction : in the
rat, oxytocin caused a marked natriuresis (Chan, 1965). These findings led to the speculation
that the two peptides might play a physiological role in the control of sodium excretion. However, the natriuresis during saline loading in dogs occurred in de Wardener’s experiments
independently of the administration of large doses of exogenous vasopressin. Furthermore,
Cort, Hagemann & Lichardus (1965) showed in cats that infusion of vasopressin did not alter
the natriuresis occurring after carotid occlusion, a response which these authors believed to be,
at least in part, humorally-mediated and independent of changes in steroid secretion. The
present experiments in normal man confirm that prolonged administration of vasopressin
exerts no significant influence upon sodium excretion, at least under the condition of water
restriction. De Wardener, Fabian, Lee, Schrier & Verroust (1968) found no increase in plasma
oxytocin levels in dogs undergoing saline infusion :furthermore, a constant infusion of oxytocin
had no effect on the associated natriuresis: when the rate of saline infusion was increased,
sodium excretion rose despite a fall in plasma oxytocin levels due to dilution of extracellular
fluid. Our own studies, in which oxytocin was given for a prolonged period in normal man in a
state of moderate hydration, failed to show any significant effect of the hormone upon plasma
renin activity, aldosterone excretion rate or sodium balance.
ACKNOWLEDGMENTS
We wish to acknowledge grants HE41275 and HE45741 from the National Institutes of
Health, United States Public Health Service. F.J.G. was the holder of a Lilly International
Fellowship during the performance of this work.
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