Clinical Science (2001) 101, 313–319 (Printed in Great Britain)
Haemodynamics of the pressor effect of oral
water in human sympathetic denervation
due to autonomic failure
P. CARIGA and C. J. MATHIAS
Neurovascular Medicine Unit, Imperial College School of Medicine at St. Mary’s Hospital, Praed Street, London W2 1NY, U.K.,
and Autonomic Unit, National Hospital for Neurology and Neurosurgery, Institute of Neurology, University College London,
Queen Square, London WC1N 3BG, U.K.
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Oral water ingestion increases blood pressure in normal elderly subjects and in patients suffering
from autonomic failure, but the time course of the haemodynamic changes is not known. We
therefore studied 14 subjects with documented sympathetic denervation due to pure autonomic
failure, with continuous haemodynamic recordings obtained before and after ingestion of 500 ml
of distilled water at room temperature. The time course of changes in values of systolic and
diastolic beat-by-beat finger blood pressure, heart rate, stroke volume, cardiac output, ejection
fraction and total peripheral resistance were analysed. Systolic blood pressure rose from
115p8 mmHg (meanpS.E.M.) to 133p8 mmHg (P 0.001), and diastolic blood pressure
from 64p4 to 73p4 mmHg (P 0.001), with the pressor response beginning a few minutes after
water ingestion, plateauing between 10 and 35 min (peak at 14 min), and returning to baseline
at 50 min. Heart rate fell from 71p2.5 to 67p2 beats/min (P 0.001), and total peripheral
resistance increased from 1.31p0.19 to 1.61p0.24 m-units (P 0.001). There were no significant
changes in ejection fraction, stroke volume or cardiac output. This study confirmed a pressor
response to oral water in subjects with sympathetic denervation. The temporal profile of the
response did not favour reflexly mediated sympathetic activation. As subjects with autonomic
failure are prone to salt and water depletion, and since blood pressure is exquisitely sensitive to
such changes, it may be that the observed response is due to repletion or restoration of
intravascular and extravascular fluid volume.
INTRODUCTION
In 1999, Jordan et al. [1] reported that oral ingestion of
tap water increased systolic blood pressure (SBP) in
elderly normal subjects, with an even greater increase
(33 mmHg) observed in subjects with autonomic failure
(AF) who had sympathetic denervation. In a later paper
they extended these observations and, using mainly a
combination of pharmacological approaches and neurohormonal measurements, concluded that water drinking
raises sympathetic neural activity significantly and rapidly [2]. In both of these studies, the composition of tap
water was not provided, and limitations in the latter
study included the degree of sympathetic denervation of
Key words : arterial blood pressure, autonomic failure, distilled water.
Abbreviations: AF, autonomic failure ; BP, blood pressure ; CO, cardiac output ; DBP, diastolic blood pressure ; EF, ejection
fraction ; HR, heart rate ; MSA, multiple-system atrophy ; SBP, systolic blood pressure ; SV, stroke volume ; TPR, total peripheral
resistance.
Correspondence : Dr Pietro Cariga (e-mail p.cariga!ic.ac.uk).
# 2001 The Biochemical Society and the Medical Research Society
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P. Cariga and C. J. Mathias
the AF subjects, as some had pressor responses to
physiological stimuli ; no details of haemodynamic
changes were provided. Furthermore, in a subsequent
study utilizing a similar protocol in subjects with AF
associated with Parkinson’s disease, the pressor responses
to oral water were not reproduced [3].
The objectives of our present study included the
following : to confirm in subjects with clearly defined
sympathetic denervation as a result of AF that a similar
amount of water had a pressor effect ; to exclude the
possible contribution of chemicals and electrolytes by
using distilled water ; and to characterize the haemodynamic factors responsible for the pressor response by
using continuous recording of cardiovascular variables.
METHODS
A total of 14 subjects (four male and ten female ; age range
39–78 years ; average 64 years) with sympathetic denervation due to pure AF took part in the study. All gave
written informed consent to participate in the study,
which had local Ethics Committee approval and was
conducted in accordance with the Declaration of Helsinki
(1989) of the World Medical Association. Each had a long
history ( 5 years) of chronic orthostatic hypotension
(a fall in SBP of 30 mmHg or more when changing from a
supine to an upstanding position) and documentation of
severe sympathetic denervation. A series of physiological
tests of autonomic function [4] confirmed a fall in BP of
30 mmHg in response to head-up tilt, abnormal BP
and heart rate (HR) responses to the Valsalva manoeuvre,
and a lack of a rise in BP following various pressor
tests (mental arithmetic, cutaneous cold and isometric
exercise ; Table 1). All had low levels of plasma
noradrenaline at rest ; levels were 148p30 pg\ml (meanp
S.E.M.), compared with values of 392p39 pg\ml in 59
age-matched normal controls ; there were minimal or no
changes on head-up tilt (161p29 pg\ml). No subjects
had additional neurological features (to favour multiplesystem atrophy or other Parkinsonian syndromes) or
other medical conditions, such as diabetes [5].
All medications (including fludrocortisone and the
sympathomimetic drugs ephedrine and midodrine) were
withdrawn on the day before the study. The subjects
abstained from food or fluids (including water) from
09.00 hours on the morning of the study. All subjects
emptied their bladder before starting the study.
The investigation was performed at 12.00 hours. This
maximized the effect of withdrawal of medication (over
five half-lives) and in part prevented dehydration, which
may be substantial (because of nocturnal polyuria) [6] if
water abstinence overnight was enforced. Subjects were
made to sit in a chair in a relaxed position, and
were supervised continuously to avoid any actions or
manoeuvres, such as crossing of the legs or calf con# 2001 The Biochemical Society and the Medical Research Society
Table 1 Responses to autonomic testing in 14 subjects with
pure AF and in 59 age-matched normal subjects studied in an
identical manner
Values are meanspS.E.M. ∆ denotes the difference from the resting supine
level. The results indicate sympathetic vasoconstriction failure in pure AF.
Parameter
Supine
SBP (mmHg)
DBP (mmHg)
HR (beats/min)
Pure AF
174p8
92p3
72p3
Normal subjects
124p6
77p2
71p3
Standing
∆SBP (mmHg)
∆DBP (mmHg)
∆HR (beats/min)
k93p13
k36p5
8p3
2p3
5p3
8p2
Head-up tilt (2 min)
∆SBP (mmHg)
∆DBP (mmHg)
∆HR (beats/min)
k70p10
k28p6
5p2
k8p2
3p1
2p2
Cutaneous cold
∆SBP (mmHg)
∆DBP (mmHg)
∆HR (beats/min)
k2p3
k7p2
2p1
15p2
10p2
1p1
Mental arithmetic
∆SBP (mmHg)
∆DBP (mmHg)
∆HR (beats/min)
2p2
k1p1
0p2
13p3
9p2
8p2
Handgrip
∆SBP (mmHg)
∆DBP (mmHg)
∆HR (beats/min)
1p3
k5p3
2p1
17p3
11p2
4p1
Response to Valsalva
0.98p0.04
1.62p0.06
traction, that may modify BP levels [7]. Continuous BP
was recorded with the Portapres II2 (TNO-TPD Biomedical Instruments2), with the sensor on the middle
finger of the left hand. In addition, an automated
sphygmomanometer (Dinamap2 ; Critikon2) intermittently measured brachial SBP, diastolic blood pressure
(DBP) and HR from the contralateral arm at 5 min
intervals.
A baseline recording over at least 30 min was obtained
after the subjects had been familiarized with the machines
and felt comfortable. They then drank 500 ml of distilled
water at room temperature (23–24 mC) within 3–4 min.
Recordings were continued for 1 h following water
ingestion. Calculations of SBP, DBP, HR, total peripheral resistance (TPR), stroke volume (SV), ejection
fraction (EF) and cardiac output (CO) were made using
a pressure wave analysis method, Modelflow2. There is
one report [8] suggesting that this technique might not be
accurate in estimating CO during exercise. In that report
CO did not correlate with the corroboratory method,
Haemodynamics of oral water in autonomic failure
but this occurred during exercise, and does not apply to
our present study. This non-invasive technique has been
validated in the resting state with stimulation (but nonexercising) by several groups [9–16], in terms of both
correlation with brachial blood pressure and reliability of
calculation of haemodynamic parameters, especially CO
in comparison with the thermodilution method [13]. The
Modelflow2 method calculates the haemodynamic
parameters using a non-linear, time-varying threeelement Windkessel model. The model elements include
aortic characteristic impedance, arterial compliance and
systemic vascular resistance. The aortic characteristic
impedance and arterial compliance depend on the aortic
cross-sectional area ; this is estimated by taking
into account the subject’s parameters, including mean
arterial pressure, age, gender, height and body weight
[10,15,16].
One-way repeated-measures ANOVA, followed by
post-hoc comparisons (Bonferroni’s t-test against baseline), were used for statistical analysis of the responses. A
more sensitive approach, based on the cumulative sum
(CUSUM) derivative of the peri-stimulus time histogram
[17,18], was employed to determine the onset of
increases\decreases in BP or other haemodynamic
parameters. All results are expressed as meanspS.E.M.
Figure 2 Continuous finger BP recording in a subject with
pure AF before and after water ingestion
RESULTS
BP responses
Pre-ingestion basal BP levels were 115p8 mmHg for
SBP and 64p4 mmHg for DBP (Figure 1). Following
water ingestion, both SBP and DBP rose after a few
minutes. Values remained elevated between 10 and
Figure 1 Mean values of SBP and DBP before and after
ingestion of 500 ml of distilled water in 14 subjects with pure
AF
The observed increases were significant (P 0.001), as assessed by repeatedmeasures ANOVA. The first value that is significantly different from that at time 0
is denoted by *.
Figure 3 Mean values of brachial SBP and DBP before and
after ingestion of 500 ml of distilled water
35 min post-ingestion [SBP, 133p8 mmHg (j15.6 %),
P 0.001 ; DBP, 73p4 mmHg (j14 %), P 0.001],
with a peak value at 14 min, and had returned to basal
levels at 50 min after ingestion (SBP, 117p8 mmHg ;
DBP 65p4 mmHg ; Figure 2). The first value that was
significantly higher than baseline levels was recorded
after 2 min. The greatest increases above baseline were
64 mmHg for SBP and 37 mmHg for DBP ; the smallest
were 7 mmHg and 5 mmHg respectively.
Similar values and trends were obtained with automated intermittent brachial BP recordings (Figure 3) :
SBP rose from 114p9 to 132p8 mmHg by 15 min after
water ingestion, and had returned to the basal level
(112p8 mmHg) at 45 min ; DBP rose from 71p5 to
80p4 mmHg at 15 min (P 0.001), and had returned
to basal (72p5 mmHg) at 45 min.
HR
Pre-ingestion HR was 71p2.5 beats\min ; this fell to
67p2 beats\min (k5.6 % ; P 0.001) between 10 and
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P. Cariga and C. J. Mathias
CO
Pre-ingestion CO was 4.3p0.5 litres\min ; mean values
were 4.2p0.5 litres\min (k2.3 %) between 10 and
35 min after water ingestion, and 4.4p0.5 litres\min
at 50 min after ingestion. These changes were not significant (P 0.05).
EF
Pre-ingestion EF (ratio) was 0.318p0.009 ; levels were
0.331p0.01 (j4 %) between 10 and 35 min after water
ingestion, and had returned to baseline at 50 min
after ingestion. These changes were not significant
(P 0.05).
Figure 4 Mean HR before and after ingestion of 500 ml of
distilled water in 14 subjects with pure AF
The observed increases were significant (P 0.001), as assessed by repeatedmeasures ANOVA. The first value that is significantly different from that at time 0
is denoted by *.
TPR
Pre-ingestion TPR (Figure 5) was 1.31p0.19 m-units.
Levels rose to 1.61p0.24 m-units (j22.9 % ; P 0.001)
between 10 and 35 min after water ingestion, and had
returned to 1.31p0.19 m-units at 50 min. The first value
that was significantly higher than baseline was recorded
after 3 min, and the time course of the increase was
delayed compared with the rise in BP.
DISCUSSION
Figure 5 Mean TPR before and after ingestion of 500 ml of
distilled water in 14 subjects with pure AF
TPR is given in m-units. The observed increases were significant (P 0.001), as
assessed by repeated-measures ANOVA. The first value that is significantly different
from that at time 0 is denoted by *.
35 min after water ingestion, before returning to 69p2
beats\min at 50 min (Figure 4). The first value that was
significantly higher than baseline levels was recorded
after 3 min. Similar values were obtained with the
automated brachial measurements : 70p3 beats\min at
time 0, 66p2 beats\min at time 15 min (P 0.001) and
69p2 beats\min at 50 min after water ingestion.
SV
Pre-ingestion SV was 62.7p8.4 ml ; mean values were
64p8.4 ml (j2.1 %) between 10 and 35 min after water
ingestion, and 62p8.5 ml at 50 min after ingestion. The
changes were not significant (P 0.05).
# 2001 The Biochemical Society and the Medical Research Society
These data unequivocally confirm the results of Jordan et
al. [1] with regard to the pressor effect of the oral
ingestion of water in subjects with severe sympathetic
denervation due to pure AF. Our observations were
made in carefully selected subjects, in whom a series of
physiological tests excluded their ability to raise BP in
response to a variety of stimuli designed to reflexly
activate sympathetic nerves. Their basal supine plasma
noradrenaline levels were below normal, and did not rise
with head-up postural change ; this is consistent with
observations in this group of subjects, where sympathetic
denervation is post-ganglionic [19]. This contrasts with
the situation in another group of patients with chronic
primary AF, multiple-system atrophy (MSA ; synonymous with the Shy–Drager syndrome), where the lesion
is pre-ganglionic, predominantly central and often
associated with a basal level of plasma noradrenaline
within the normal range [20].
Previous studies have suggested that the electrolytic
and mineral composition of water may influence BP. This
was raised originally in relation to hypertension in both
children and adults, although it was thought to be
unlikely, even in areas where a higher sodium content of
drinking water was observed [21–23]. Subjects with AF
can be extremely sensitive to the effects of pressor
substances or electrolytes, which was the basis of the
successful use of sea water (albeit with a considerably
higher sodium content) to reduce orthostatic hypotension in one such subject [24]. In our present study
Haemodynamics of oral water in autonomic failure
distilled water was used, and a definite pressor response
was observed, thus excluding a contribution of either
electrolytes or pressor substances to this response.
After oral water ingestion, there was a rise in both SBP
and DBP, which began after a few minutes, peaked
around 10 min and plateaued for about 30 min with
further waning, so that by 50 min the levels had returned
to baseline. In the previous study by Jordan et al. [2],
the pressor response in four AF subjects was not
temperature-dependent, as a similar rise in BP occurred
with identical volumes of water at 9 mC and 24 mC ; we
used water at room temperature (23–24 mC). In their
study, the volume ingested did, however, influence the
pressor response : in four AF subjects, ingestion of 240 ml
of water raised SBP (as derived from their figure) by
approx. 33 mmHg, while after a volume of 480 ml the
SBP rose by 47 mmHg. It was suggested [2] that gastric
distension may have been responsible for the rise in BP,
with a reflex mediated via the sympathetic nerves.
However, the time course of the pressor response after
water was over minutes rather than seconds, and thus not
as rapid as would be expected if it was reflexly induced, as
in an analogous situation during reflex sympathetic
activation in tetraplegics [25]. Furthermore, in our study
there was a pressor response to water in subjects in whom
a variety of stimuli were unable to elicit a pressor response
dependent on reflex sympathetic activation. It may be
argued that, in the face of a muted or absent sympathetic
reflex response, there was a secondary release of pressor
substances, possibly from the gut or elsewhere, which
caused a late elevation in BP. In AF subjects, as in normal
subjects, various vasoactive peptides are released in
response to food ingestion, except that these are likely to
result in vasodilation, thus accounting for post-prandial
hypotension in AF [26]. These observations were mainly
in response to liquid or solid meals of varying compositions ; water ingestion, however, is reported in
normal subjects to cause secretion of the vasodilator
vasoactive intestinal peptide [27], which would be
expected to lower BP. Therefore both the temporal
sequence and the previous observations in subjects with
AF of the responses to food ingestion militate against
either a sympathetic reflex or neurohormones from the
gastrointestinal tract accounting for the pressor responses
to oral water ingestion.
The possibility that other humoral substances and
neurohormones may contribute to the pressor response
was evaluated by Jordan et al. [2] who, on the basis of
their data, excluded a humoral explanation. Previous
observations in subjects with AF indicate low levels of
renin and aldosterone, possibly due to sympathetic
denervation of the kidney. Plasma levels of renin activity
did not change in their study, and nor did vasopressin
levels [2]. In pure AF (but not in MSA with central
lesions), vasopressin release in response to osmotic
stimuli is preserved [28,29], but water ingestion would be
expected to decrease rather than increase vasopressin
levels. Whether the release of other vasopressor substances, including endothelial-derived factors such as
endothelin (not studied by either group), may have
contributed to the pressor response and to the rise in TPR
is not known, and warrants further study.
The pressor response to oral water was not associated
with a rise in SV, CO or EF. In tetraplegics with
physiologically complete spinal cord transection,
increased isolated spinal cord reflex sympathetic activity
(as part of autonomic dysreflexia) can be induced by
visceral stimulation [25]. This results in rapid rises in BP,
SV and CO, accompanied by a transient rise in HR
followed later by bradycardia, because the baroreceptor
afferents and vagus nerves are intact and respond to the
rise in BP [30]. Continuous recordings in our subjects did
not indicate an initial transient tachycardia. There was a
small fall in HR corresponding to the rise in BP,
suggesting minimal baroreflex activation in response to
the latter ; the changes, however, were small in relation to
the rise in pressure, as expected in subjects with AF.
There was a significant rise in calculated TPR, with a
temporal profile similar to that of the pressor response,
and a time curve which followed the rise in BP. It may be
that a transient elevation of noradrenaline levels, in the
presence of α-adrenoceptor pressor supersensitivity or
even adrenaline release due to splanchnic activation,
raised BP. However, the time course of the pressor
response argues against the former. Furthermore, subjects with pure AF are unlikely to release adrenaline from
the adrenal medulla, as demonstrated with considerably
stronger stimuli such as hypoglycaemia [31].
Jordan et al. [2], on the basis of their pharmacological
evidence, favoured a sympathetic reflex as being the cause
of the pressor rise ; they reported that ganglionic blockade
lowered pre-ingestion BP in two subjects with AF and in
seven younger normal subjects, following which there
was no pressor response to oral water. Their two AF
subjects had MSA, a disorder in which post-ganglionic
sympathetic pathways are known to be preserved ;
therefore they were dissimilar to our subjects with pure
AF, who had severe peripheral sympathetic denervation.
Furthermore, during ganglionic blockade a different
protocol to the other studies was used [2], with baseline
values measured in the supine (and not the seated)
position, followed by raising the head of the bed to allow
for water drinking. Whether this itself lowered BP in the
two MSA subjects with known orthostatic hypotension
remains a possibility. Importantly, in their study Jordan
et al. [2] clearly stated that younger normal subjects do
not have a pressor response to oral water ; thus the
conclusion that ganglionic blockade abolished the pressor
response does not apply to them.
A feature of subjects with AF is their exquisite
sensitivity to changes in fluid balance ; volume depletion
can lower BP rapidly, while infusion of small volumes of
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saline can raise BP markedly [30]. In AF, despite
orthostatic hypotension, supine hypertension often can
be induced if subjects lie in a horizontal position. This
recumbency-induced reversal of hypotension is postulated to be due in part to the movement of fluid (initially
pooled in the periphery) into the central compartment,
especially in the presence of baroreceptor denervation.
During recumbency, substantial diuresis (as observed
overnight) often occurs, presumably because of better
renal perfusion, resulting in weight loss and more severe
orthostatic symptoms in the morning. The lack of
sympathetic innervation of the renal tubules may enhance
the tendency to sodium loss and contribute further to
water depletion [32]. These possible mechanisms are the
basis for the use of nocturnal head-up tilt and desmopressin to reverse nocturnal polyuria and improve morning hypotension [6,33]. A speculative explanation for the
pressor response to oral water over the time scale
observed may be an attempt to replete a negative fluid
balance and elevation or restoration of intra- and extravascular fluid volume. Jordan et al. [2] measured plasma
volume by an indirect method based on the haematocrit,
which may have caused a reduction in sensitivity,
especially in non-arterialized venous blood samples.
After oral water, repletion may have been mainly in the
central fluid vasculature, thus reducing precision in the
derivation of plasma volume in peripheral samples.
Furthermore, their derivations of plasma volume were
carried out 30 and 60 min after water ingestion, when the
pressor response had peaked and begun to wane, and
when redistribution into the extravascular spaces may
have occurred.
In conclusion, our studies in subjects with severe
sympathetic denervation due to pure AF confirm the
pressor response to oral water ingestion ; this begins after
a few minutes and lasts for approx. 30 min. The response
occurred with distilled water, thus excluding a role for
electrolytes or chemicals. Continuous recording of
haemodynamic responses excluded a rise in SV or CO.
The responses observed in our lesion deficit human
model of sympathetic denervation do not favour reflexly
mediated sympathetic activation. Previous studies [2]
exclude the likelihood of the changes being hormonally
mediated. The possibility that the observed pressor
response is due to factors that include repletion of
intra- and extra-vascular fluid compartments warrants
consideration.
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ACKNOWLEDGMENTS
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We thank Ms Katharine Bleasdale-Barr and Ms Lydia
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Received 19 September 2000/9 April 2001; accepted 25 May 2001
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