Clinical Science and Molecukar Medicine (1976) 51, 267-274.
The response of arginine vasopressin and plasma renin to
postural change in normal man, with observations on syncope
ROY DAVIES, J. D. H. SLATER, MARY L. FORSLING A N D NADIA PAYNE
The Cobbold Laboratories, Sir Jules Thorn Institute of CIinicaI Science, and Departmentsof Medicine andPhysiology,
The Middlesex Hospital Medical School, London
(Received 30 December 1975)
summary
1. Fourteen mildly hydropenic normal volunteers
were slowly tilted at a constant rate from the
horizontal to the 85" head-up position in order to
study the interrelationship between plasma arginine
vasopressin concentration, plasma renin activity
and the change of plasma volume.
2. Nine subjects did not develop vaso-vagal
symptoms and were studied for 45-60 min. Arginine
vasopressin rose biphasically in all subjects: a
small initial rise, which was seen at 3 rnin and persisted for 30 min, was followed by a striking rise
between 30 and 45 min, when the fall of plasma
volume had reached its maximum (17%).
3. Plasma renin activity reached a maximum at
30 min but fell by 45 min, as plasma concentration
of arginine vasopressin rose.
4. Five subjects developed vaso-vagal symptoms
4-24 min after reaching 85" when the study was
terminated. A strikig increase of arginine vasopressin concentration was seen within 4 min of
syncope, but there was no change of plasma osmolality, cortisol concentration or renin activity.
in man. The circulatory responses to the upright
posture have been well documented (McMichael &
Sharpey-Schafer, 1944; Tuckman & Shillingford,
1966) but less is known about the changes and
interrelationship between the two major hormonal
mechanisms concerned with the homeostasis of
salt and water, namely the renin-aldosterone system
and vasopressin. The object of our study was to
relate orthostatic changes of plasma renin activity
and plasma arginine vasopressin concentration
both to each other and to the fall of plasma volume.
Despite attempts to minimize the incidence of
syncope, a well-known hazard of head-up tilt
(Brigden, Howarth & Sharpey-Schafer, 1950), we
are able to report metabolic and hormonal changes
occurring within 4 min of syncope in five normal
young people.
Some of the data described in this paper were
presented at the Society for Endocrinology, November 1974 (Davies & Forsling, 1975).
Materials and methods
Ten normal men and four normal women (aged
22-26 years) were studied at 10.00 hours. They
were not receiving any medication and had been
asked to abstain from drink and food for 12 h.
The subjects wore light indoor clothing and the
ambient temperature was maintained at 15-18°C.
After 90 min of supine rest, the subjects were
tilted to an angle of 85" on an electrically operated
tilt bed (model 83000, Nesbit-Evans, Wednesbury,
Staffs,U.K.) at a constant rate over 90 s. Each
subject was familiarized with the procedure by a
Key words: plasma volume, posture, renin, syncope,
tilt, vasopressin.
Introduction
The mechanisms for preserving plasma volume
during orthostasis are necessarily highly developed
Correspondence: Dr Roy Davits, The Middlesex Hospital,
London, W.1.
267
268
R. Davies et al.
or actual syncope when the tilt was immediately
preliminary 'dummy run'. No restraining straps
terminated.
were used and the subjects were encouraged to
make such use of their antigravity muscles as to be
consistent with comfort. An 18G cannula (Argyle,
Subjects without syncope
Medicut) was inserted into a left antecubital fossa
Heart rate and arterial pressure. The heart rate
vein at the beginning of the rest period. During
rose
from a mean supine value of 64 beatslmin k 3
blood sampling the subjects were made to avert
to 85 5 3 (P<OOOl, t = 5.45, n = 9) within 2
their gaze. Blood was collected without stasis and
min of reaching 85" and the increased rate was
samples for plasma renin activity and arginine
sustained
throughout the study.
vasopressin determination were taken into heparinThe arterial pressure stabilized within 4 min.
ized tubes and cooled at once to 4°C. The plasma
The systolic pressure did not change significantly:
was separated within 5 min and stored at -20°C.
e.g. the mean supine value was 109 mmHg f6 and
Samples for osmolality and cortisol were taken into
the value at 10 min was 109k3. Diastolic pressure
heparinized tubes and centrifuged at room temrose consistently and significantly from a mean
perature, and samples for peripheral venous packed
supine value of 71 k 7 to 83 f3 (P <0001, t = 3.9,
cell volume were taken into sequestrene tubes.
n = 9). The systolic and diastolic pressures reThe sampling needle was kept open by a slow
mained unchanged thereafter.
infusion of sodium chloride solution (150 mmol/l;
Change of plasma volume. The change of plasma
saline). During each experiment a volume of saline
volume was measured indirectly from the change
was infused which was appIoximately equal to the
of the peripheral venous packed cell volume in
sodium content of the blood lost (about 150 ml).
seven subjects according to the following formula:
Arterial pressure was measured sphygmomanometrically, Korotkoff sounds I and IV being used to
indicate the systolic and diastolic pressure respectively. Blood sampling and arterial pressure
determination were carried out with the arm at the
where P = % fall in plasma volume, H1 = the
level of the heart. Plasma renin activity was deterinitial, and H z the final, packed cell volumes
mined by radioimmunoassay (M6nard & Catt,
(modified from LeQuesne, Hobsley & Hand, 1960).
1972) of angiotensin I generated by incubation for
Themean packed cell volumes were: supine, 41.0% k
3 h at pH 5.5 in the presence of EDTA and 80.4; 15 min, 44-7%+0.5; 30 min, 455Xk1.2;
hydroxyquinoline. Arginine vasopressin was mea45 min, 45.5zk1.3. From the formula above,
sured by bioassay in ethanol-anaesthetized, waterthe mean reduction of plasma volume was 13.9% k
loaded rats, after extraction from plasma (Forsling,
23, 16.6zk2.1 and 16.8Xk1.5 at 15, 30 and 45
Jones & Lee, 1968; Forsling, 1974). Cortisol was
min respectively (Fig. lc). The fall of plasma volume
measured by a protein-binding technique (Murphy,
between 15 and 30 min was small but an increase of
1967). Osmolality was measured by a freezing-point
packed cell volume was observed in six of the seven
depression method (Osmometer model 3L, Adsubjects. However, the variance of the response was
vanced Instruments Inc., Massachussetts, U.S.A.).
considerable so that the mean values are not
Peripheral venous packed cell volume was estimated
significant when Student's t-test is applied, although
from the haemoglobin concentration and mean
it becomes significant ( t = 2.7, P(O.025) when the
corpuscular volume (Coulter-S model 1034, Coulter
single anomalous subject is omitted. With the
Electronics Ltd).
x 2 distribution test, the difference between 15 and
Results are expressed as the m e a n k ~and
~ ~ 30 min is significant at the 5 % level ( x 2 = 14.09)
analysed by Student's t-test for paired data, unless
when all the data are analysed.
otherwise specified.
Arginine vasopressin. The changes of plasma
arginine vasopressin concentration are shown in
Table 1 and summarized in Fig. l(a). The mean
Results
arginine vasopressin concentration rose slightly
Nine subjects did not develop vaso-vagal symptoms;
within 3 min of reaching 85" from 0.97 ,uunit/ml
four of them were studied for 45 min and five for 60
k0.2 to 1.9 punitslmlrt0.3. This only just reached
min. Five subjects developed presyncopal symptoms
significance at the 5 % level (P<0.05,I = 2.23,
Vasopressinand renin in tilt and syncope
6-
T
5-
4-
=
<
:3 B
3
2-
I-
Time (min)
FIG.I . (a) Plasma arginine vasopressin (AVP) concentration,
(b) plasma renin activity (PRA), and (c) the change of plasma
volume after an 85' head-up tilt (7) in normal people. Note
that between 30 and 45 min there is a considerable rise of
arginine vasopressin concentration but a fall of plasma renin
activity at a time when the plasma volume has reached its
minimum. Mean valuesf SEM are shown.
269
n = 6). The mean values at 7 , 15 and 30 min did in
fact remain at 1.6-1.9 times the supine value and the
mean value at 15 rnin was again just significantly
different from the supine value, whereas the mean
values at 7 and 30 rnin were not. When the fluctuations were smoothed by taking the mean of the
3, 7 , 15 and 30 rnin values, significance was not
enhanced (P<0.05, t = 2.13, n = 8), although the
application of Wilcoxon's non-parametric test
gives P<O-02. However, at 30-45 min, there was a
striking rise of plasma concentration of arginine
vasopressin to reach a mean value of 5.1 pnitslml
f0.7 or 3-15 times the supine value (P<O-OOl,
t = 6.67, n = 8).
Plasma renin activity. The changes are summarized
in Fig. l(b). The mean supine value was 1.96 pmol
h - l ml-l k0.12, and this rose to 3.14 pmol h-l
ml-' f 0 . 1 6 at 15 rnin and 3.33 pmol h - l ml-l
f 0 . 1 2 at 30 min. The values at 15 and 30 min were
both very highly signscantly greater than the supine
value ( t = 13.8 and 15.8 respectively, P<O.OOl for
each). In eight of the nine subjects, renin activity
fell between 30 and 45 rnin to a mean value of
2.89 pmol h- ml-' f0.08, and this fall was significant ( t = 5-5, 0.01 <P < 0.0125).
Plasma osmolality. Osmolality was measured in
six of the subjects in whom arginine vasopressin
had been determined and it remained unchanged;
the mean supine value was 282 mosmolllrt2 and
subsequent values at 15,30 and 45 min were 281 f2,
281 f 3 and 282 k 2 respectively. These values are
similar to those observed after 12-18 h of strict
fluid deprivation in normal people, in another
study from this group (Khokhar & Slater, 1976).
Plasma cortisol concentration. Cortisol was
estimated in five subjects as a measure of possible
TABLE1. Plasma arginine vasopressin concentrations in subjects tilted for 45-60 nrin
Plasma arginine vasopressin (pnitslml)
Subject
- 5 min
3 min
7 min
I5 min
30min
45 min
60min
1
1.6
1 .o
2.4
2
3
4
5
6
7
8
0.3
1.3
0.4
2.4
0.4
05
0.9
0.97k0.2
2.3
28
1.3
2.7
1.3
-
0.6
1*5
2.7
1*4
2.3
1*4
1*2
5.2
0.7
0.8
1.9
5.2
0.5
3.2
44
43
46
4.6
2.9
-
0.5
1.9f0.3
1*59*0*3
1.93f 0.6
4.1
4.6
4.0
3.7
10
45
6.0
3.7
5.1 & 0.7
~
Meanf
D
SEM
-
0.7
3.8
0.7
1.3
0.5
0.3
1.O
1.69f0.6
-
4.16k0.3
R . Davies et al.
270
changes in adrenocorticotrophic hormone. The
mean supine value was 353 f 7 6 mmol/l and subsequent values at 15, 30 and 45 rnin were 356 ? 78,
317 f 6 9 and 320k64 respectively. None of these
values was significantly different from the others.
Subjects with syncope
Two subjects lost consciousness and three
developed presyncopal symptoms necessitating
termination of the study.
These episodes were accompanied by yawning,
deep respiration, skin pallor and sweating. Syncopal
signs developed 4-24 rnin after reaching 85". The
heart rate fell precipitously from 80-100 beatslmin
to 40-50 beatslmin. When signs of impending
syncope appeared the subjects were laid flat and the
'post-syncopal' blood samples were taken within 4
rnin when bradycardia was still present. Sufficient
blood was available for the measurement of arginine
vasopressin in five subjects and for the measurement
of cortisol and plasma renin activity in three
subjects. Arginine vasopressin rose dramatically
after syncope; the mean supine concentration was
1.1 punits/ml kO.1, and the value 3 min after
reaching 85" was 1.6kO.5 (for subjects without
syncope; supine and 3 rnin values were 0.97k2
and 1.9 f 0.3 respectively). After syncope the mean
concentration of arginine vasopressin was 10.9 k
I
f/*
0
2
*-*
1.8 punitslml. A five- to eight-fold rise was seen in
each of the five subjects (Fig. 2). The mean value
observed after syncope was very highly significantly
greater than any of the mean values up to 30 min
seen in those without syncope (PcOGO1, t = 5.31
to 5.99 at 3,7, 15 and 30 rnin). Even when compared
with the 45 min value in those without syncope, the
value was highly significantly greater (Pc 0.01,
f = 3.39).
After syncope the plasma cortisol concentrations
in the three subjects were 309,408 and 215 mmol/l,
which are not different from the supine values of
320, 340 and 232 mmol/l respectively. Plasma renin
activity values after syncope were 2.76, 3.25 and
2.06 pmol h - ' ml-l and did not differ from the
expected values, relative to the time of syncope
after reaching 85", when compared with the values
observed in non-syncopal subjects at a comparable
interval after assuming the upright posture.
Discussion
Subjects without syncope
Changes of heart rate, arterial pressure andplasma
volrrme. In this study we have minimized the use of
invasive techniques, which, by causing discomfort
and stress, might otherwise influence plasma renin
activity and the plasma concentration of arginine
i
4 4 8 1 2
'
Time (mi;)
FIG. 2. Heart rate and plasma arginine vasopressin (AVP) concentration in the five subjects who developed
syncopal symptoms (onset denoted by upper arrows) 4-24 min after 85" tilt (lower arrows). Note the rapid fall
in heart rate and the striking rise of arginine vasopressin concentration which occurs in all the subjects.
Vasopressin and renin in tilt and syncope
vasopressin and cortisol. The haemodynamic
changes we have observed, as assessed by the change
of heart rate and of arterial pressure, are very
similar to those recorded in studies in which stroke
volume andlor cardiac output were measured
(McMichael & Sharpey-Schafer, 1944; Tuckman
& Shillingford, 1966). Although different angles of
tilt were used in these studies, the hydrostatic
effect of tilt to angles of 60" or more is, for all
practical purposes, the same as the effect of the
erect position (Gauer & Thron, 1965).
In addition to the immediate effects of venous
pooling, there is a gradual fall of plasma volume
due to loss of protein-free fluid through dependent
vascular beds. We have been impressed by the size
of this loss, which occurred consistently in all our
subjects. The fall of plasma volume is rapid initially
and reaches a maximum of about 17% by 30 min.
This confirms earlier studies (Thompson, Thompson
& Daily, 1928; Waterfield, 1931a, b; Nielson &
Mliiller, 1968). As indicated below, the careful
delineation of the size and timecourse of the fall of
plasma volume may be critical for the release of
vasopressin.
Changes of arginine vasopressin Concentration and
of plasma renin activity. We have demonstrated
significant increases in concentration of arginine
vasopressin after postural change. This rise appears
to take place in two phases: there is an initial very
small increase amounting to 1.61.9 times the
supine value, which occurs within 3-7 min of
reaching 85". However, at 3 W 5 min, there is a
striking rise to 3-15 times the supine value. This
rise occurs at a time when heart rate and arterial
pressure are constant, but it coincides with the
maximum fall of plasma volume. Although the
change of plasma volume between 15 and 30 min is
small, we suggest that the fall of plasma volume
may reach a critical value and trigger the second
phase of the response of arginine vasopressin.
Blood volume change provoked by haemorrhage is
well known to lead to release of arginine vasopressin
in animals (Weinstein, Berne & Sachs, 1960;Share,
1961; Gauer, Henry & Behn, 1970; Claybaugh &
Share, 1973). Gauer et al. (1970) have reported a
similar biphasic response after controlled haemorrhage in dogs; the initial increase of arginine
vasopressin was small when up to 10% of the blood
volume was removed, but beyond this critical point
further bleeding provoked a striking rise in arginine
vasopressin.
271
Studies of the effect of real (e.g. haemorrhage)
or apparent (e.g. tilt) fall in blood volume in man are
conflicting. Segar & Moore (1968),using a bioassay
in mildly hydropenic normal volunteers (U/P
osmolar ratio 1.9-3.7) reported mean plasma
arginine vasopressin concentrations of 0.4, 1.4 and
3.1 punitslml in the lying, sitting and standing
positions respectively. In addition, they reported a
threefold rise in arginine vasopressin in normal
subjects after vasodilatation induced by warmth.
This group also reported similar results with
centrifugation (Rogge, Moore, Segar & Fasola,
1967)and with application of negative pressure to the
lower portion of the body in normal man (Rogge &
Moore, 1968). In contrast Norton, Padfield &
Forsling (1975), using a radioimmunoassay for
arginine vasopressin, were unable to demonstrate
any rise after the non-hypotensive haemorrhage over
10 min, nor after tilting to 85".Furthermore Share,
Claybaugh, Hatch, Johnson, Lee, Muirhead &
Shaw (1972), Beardwell, Geelen, Palmer, Roberts
& Salomonson (1975)and Kimura, Minai, Matsui,
Mouri, Sato, Yoshinaga & Hoshi (1976)were all
unable to demonstrate a rise of plasma arginine
vasopressin concentration on standing. From our
data and from those of Robertson (1974), who
describes a small but significant fall of arginine
vasopressin concentration when hydropenic people
lie down but not when normally hydrated people
do so, we suggest that the differences can be explained by differences of the state of hydration, the
extent to which plasma volume falls and the timing
of blood samples. Morton et al. (1975), Beardwell
et al. (1975)and Kimura et al. (1976) used waterloaded or normally hydrated subjects. Share er al.
(1972)did not sample until 4 h in ambulant subjects,
and the fall of plasma volume described by Kimura
et al. was only just over half that seen in the present
study.
We suggest that the increase of plasma arginine
vasopressin concentration is due to the isosmotic
fall of plasma volume but it is possible that emotional
factors may be relevant (Verney, 1947). However,
we minimized discomfort and anxiety, the response
at 30-45 min was consistent both in its extent
and timing and there was no change in plasma
cortisol concentration.
Renin release after postural change has been
extensively studied in man, and in these studies there
is considerablevariation both in the magnitude of the
change of renin activity or renin concentration in
272
R. Davies et al.
response to orthostasis and in the variance of the
change (Cohen, Rovner, Conn & Blough, 1964;
Brown, Davis, Lever, MacPherson & Robertson,
1966; Nielsen & Msller, 1968; Molzahn, Dissman,
Halim, Lohmann & Oelkers, 1972). The change
varied from 5 to 500% above the recumbent value
and this probably reflects different experimental
protocols and different assay methods. In the present
study we have shown that it is possible to reduce
greatly this variability of response. For example,
when the response was at its maximum at 30 min,
the range of response was modest, from 46 to 118%.
From our results it is both clear and noteworthy
that after 30 min of orthostasis plasma renin activity
began to fall, an observation we have made in two
previous studies (Davies, Payne & Slater, 1975;
Khokhar, Slater, Jowett & Payne, 1976). The fall
between 30 and 45 min is significant statistically
and it occurred in all except one subject and at a
time when haemodynamic factors were stable and
when the fall of plasma volume had reached a
maximum. Consideration of current physiological
concepts is unfruitful but a possible explanation is
that this fall of plasma renin activity resulted from
the rapidly rising concentration of circulating
arginine vasopressin which we observed between
30 and 45 min. In experimental animals infusions of
arginine vasopressin in physiological amounts
inhibit renin release (Bunag, Page & McCubbin,
1967), and in humans Khokhar, Slater, Forsling &
Payne (1976) reported an inverse relationship
between plasma renin activity and arginine vasopressin during very low rates of infusion of the
latter to achieve concentrations within the physiological range.
In this study we have interpreted the rise of
renin activity and arginine vasopressin after postural
change as indicating an increase in the rate of
secretion rather than a fall in clearance of these
hormones. Certainly in dogs, hepatic extraction
of renin is not diminished even by severe haemorrhage (Schneider, Johnson, Davis & Baumber,
1971), nor by an 80" tilt in man (Kotot, Kuska &
Czekala, 1968). Furthermore, Culbertson, Wilkins,
Ingelfinger & Bradley (1951) demonstrated that
hepatic blood flow falls only in very severe circulatory embarrassment. Arginine vasopressin is
cleared largely by the kidneys (Lauson, 1974) and
postural change undoubtedly affects renal function;
for example, Brun, Knudsen & Raaschou (1945)
found a 20-25 % fall of glomerular filtration rate in
normal volunteers on 60" head-up tilt. Detailed
studies of the effect of changes in renal function
upon clearance of arginine vasopressin are lacking,
but recent work in this laboratory (Khokhar &
Slater, 1976) has shown a twofold increase in
urinary arginine vasopressin in normal subjects
tilted to 45", a rise similar to that we have observed
in plasma arginine vasopressin, suggesting that
there is no change in the handling of the compound
by the kidney after tilt. A minor increase of plasma
protein concentration may contribute to the rise of
plasma renin activity on tilt to a small extent, but the
plasma protein concentration determined in five
subjects, supine and at 30 min, increased only by a
mean value of 17%, whereas the corresponding
mean increase of renin activity was 73 %.
Subjects with syncope
The symptoms experienced by our subjects and
the accompanying signs corresponded closely with
those described by Lewis (1932). Such attacks are a
well-known hazard of tilting (McMichael & SharpeySchafer, 1944) and of venesection (Poles & Boycott,
1942). Brun et al. (1946) first reported an initial
period of oliguria after syncope, after which a
diuresis supervened, an observation commented
upon earlier by Lewis (1932). Noble &Taylor (1953)
subsequently reported the presence of an antidiuretic
substance in the urine of subjects who had experienced vaso-vagal attack 2 h earlier, but they were
unable to make any direct measurements of arginine
vasopressin. In this study we have observed a
striking rise in plasma arginine vasopressin concentration within 2-4 min of syncope.
Tilt mimics non-hypotensive haemorrhage and the
incidence of syncope after such haemorrhage is proportional to the amount of blood removed. For
example, Poles & Boycott (1942) found an incidence of 3.8% in blood donors who had lost
440 ml of blood, whereas the incidence of syncope
was 8.5% when 540 ml of blood was removed.
To compensate for real or apparent fall of blood
volume, vasoconstriction occurs to reduce the size
of the vascular compartment. Occasionally, this
compensatory mechanism fails and vasodilatation,
particularly of muscle arterioles, occurs (Brigden
et al., 1950), leading to a sudden increase of vascular
capacity. This leads to a sharp hypovolaemic but
isosmotic stimulus to release of arginine vasopressin.
The exact trigger to this release in these circum-
Vasopressin and renin in tilt and syncope
stances is uncertain; it may be via intrathoracic
volume receptors (Henry, Gauer & Reeves, 1956),
or arterial baroreceptors (Robertson, Mahr, Athar
& Sinha, 1973) or, alternatively, it may be a consequence of a brief period of hypoxia. Certainly,
acute hypoxia can lead to an antidiuresis in conscious man (Granberg, 1962) and to vasopressin
release in the sheep (Alexander, Forsling, Martin,
Nixon, Ratcliffe, Redstone & Tunbridge, 1972).
Whatever the exact nature of the final stimulus for
release of arginine vasopressin it may be specific to
the syncopal response rather than a non-specific
response to stress. Thus, in those subjects in whom
measurements were possible, both plasma cortisol
concentration and renin activity did not increase.
It is possible, however, that the time-course of
release of renin and adrenocorticotrophic hormone
differsfrom that of argininevasopressin.Nonetheless,
the increase of plasma arginine vasopressin concentration within 4 min of syncope is striking and
hitherto unrecorded. It seems to underline the
sensitivity of the mechanisms for the preservation
of the circulating volume which appear so well
developed in man, as opposed to other animals.
The upright posture is, after all, a specifically human
attribute.
Acknowledgments
We are indebted to the Special Trustees of The
Middlesex Hospital for essential running expenses,
and to Ciba Laboratories, Horsham, Sussex, for
additional financial support. We are also grateful
to Sister M.Charles and Sister H. Griffin for nursing
assistance and to Ms Kate Fawkes and Mrs N.
Fowler for their secretarial help, and also to Mr H.
Williams for skilful technical assistance. We thank
our colleagues in the Courtauld Institute of Biochemistry and the Bland-Sutton Institute of
Pathology for determinations of cortisol and
packed cell volumes respectively.
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