The osmopressor response to water drinking
Marcus May and Jens Jordan
Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany
Submitted 19 August 2010; accepted in final form 1 November 2010
May M, Jordan J. The osmopressor response to water drinking. Am J Physiol
Regul Integr Comp Physiol 300: R40–R46, 2011. First published November 3,
2010; doi:10.1152/ajpregu.00544.2010.—Water drinking elicits profound pressor
responses in patients with impaired baroreflex function and in sinoaortic-dener-
vated mice. Healthy subjects show more subtle changes in heart rate and blood
pressure with water drinking. The water-induced pressor response appears to be
mediated through sympathetic nervous system activation at the spinal level. Indeed,
water drinking raises resting energy expenditure in normal weight and obese
subjects. The stimulus setting off the response is hypoosmolarity rather than water
temperature or gastrointestinal stretch. Studies in mice suggest that this osmopres-
sor response may involve transient receptor potential vanniloid 4 (Trpv4) receptors.
However, the (nerve) cell population serving as peripheral osmosensors and the
exact transduction mechanisms are still unknown. The osmopressor response can be
exploited in the treatment of orthostatic and postprandial hypotension in patients
with severe autonomic failure. Furthermore, the osmopressor response acutely
improves orthostatic tolerance in healthy subjects and in patients with neurally
mediated syncope. The phenomenon should be recognized as an important con-
founder in cardiovascular and metabolic studies.
osmoreceptors; autonomic failure; syncope; blood pressure
WATER CONTENT OF THE HUMAN body decreases substantially
from birth to an old age. Yet, the water molecule remains by far
the dominating body constituent throughout lifetime. In mam-
mals the relationship between free water and solutes in extra-
and intracellular compartments, which determines osmolality,
is tightly regulated through adjustment in water ingestion and
excretion (3, 24, 69, 82). Even mild abnormalities in systemic
osmoregulation can have grave consequences (2, 38, 44, 61,
69). Water intake is affected by thirst and psychosocial factors
as water drinking is considered a healthy habit. Water excre-
tion is primarily regulated through adjustment in water perme-
ability in renal distal tubules and collecting ducts. The response
is mediated largely through a rapid decrease in vasopressin
release with subsequent aquaporin downregulation. These re-
flex mechanisms are governed by osmoreceptors detecting
small changes in extracellular fluid osmolality. Central osmo-
receptors located in the organum vasculosum of the lamina
terminalis and subfornical organ (49, 51, 79), such as brain
nuclei with no blood/brain barrier (4, 7, 25, 30), play a crucial
role in osmoregulation. These mechanisms have been exten-
sively studied and reviewed elsewhere. In addition, there is
evidence for hitherto poorly characterized peripheral osmosen-
sitive neurons (29, 52, 73). We review data suggesting that
local changes in osmolality through water drinking may elicit
a powerful pressor response and changes in energy metabolism
through sympathetic nervous system activation. This osmo-
pressor response may involve activation of transient receptor
potential vanniloid 4 (Trpv4) receptors, which may be located
on putative peripheral osmoreceptors. The osmopressor re-
sponse has to be differentiated from immediate changes in
sympathetic activity and in blood pressure elicited by stimula-
tion of the oropharyngeal region or swallowing in animals (77)
and in human subjects (11, 21).
Water-Induced Pressor Response
The fact that water drinking may elicit acute cardiovascular
effects came to our attention through patients with severe
orthostatic hypotension due to autonomic failure. Autonomic
failure ensues when the sympathetic and parasympathetic
nerves comprising the efferent baroreflex portion are inter-
rupted. Neuronal degeneration within the brain or in the pe-
riphery (9, 70), enzymatic defects in catecholamine synthesis
(45, 57), and autoimmune disorders (64, 80) can be causative.
Common to all of these syndromes is debilitating orthostatic
and postprandial hypotension. Some patients are unable to
stand for more than a few seconds before presyncopal symp-
toms occur. Some autonomic failure patients reported rapid
symptomatic improvement with water drinking. Subsequently,
we tested the response to drinking 480 ml tap water in these
patients (33, 35). In patients with central autonomic failure due
to multisystem atrophy, seated systolic blood pressure in-
creased 33 mmHg. In patients with peripheral autonomic
degeneration due to pure autonomic failure, seated systolic
blood pressure increased 37 mmHg (33). The pressor response
had an onset within 5 min after water drinking, reached a
maximum in 30–40 min, and was maintained for more than 1
h (Fig. 1). The response was reproduced by other groups
(12). In elderly healthy subjects drinking 480 ml tap water,
we observed a slight increase in systolic blood pressure of
up to 11 mmHg above baseline (33, 35). In contrast, water
Address for reprint requests and other correspondence: J. Jordan, Hannover
Medical School, Institute of Clinical Pharmacology, Carl-Neuberg-Str. 1,
30625 Hannover, Germany (e-mail: Jordan.Jens@mh-hannover.de).
Am J Physiol Regul Integr Comp Physiol 300: R40–R46, 2011.
First published November 3, 2010; doi:10.1152/ajpregu.00544.2010.
0363-6119/11 Copyright © 2011 the American Physiological Societyhttp://www.ajpregu.orgR40
drinking in healthy young subjects did not elicit a pressor
response (33, 65).
More detailed hemodynamic studies provided important
insight in potential underlying mechanisms. These studies
suggested that an increase in systemic vascular resistance
rather than cardiac output mediates the pressor response in
autonomic failure patients (12). Similarly, healthy young sub-
jects showed an increase in calf vascular resistance, while
systemic vascular resistance and blood pressure remained un-
changed (65). Volume expansion is unlikely to contribute to
the pressor response because free water is distributed through-
out the extra- and intracellular space. Furthermore, drinking
480 ml water elicited a much greater pressor response than
intravenous infusion of the same volume of 5% dextrose in
water (33). Finally, water drinking did not induce major
changes in plasma volume (33) or thoracic bioimpedance (63).
Thoracic bioimpedance is related to thoracic blood volume
(19). Together, these observations suggest that water drinking
elicits changes in vascular tone that are unmasked in individ-
uals with aging-associated changes in baroreflex regulation and
more so in patients with profound baroreflex abnormalities due
to neurodegenerative diseases. The cardiovagal portion of the
efferent baroreflex arc is severed in cardiac transplant recipi-
ents. These patients show a moderate blood pressure increase
with water drinking (60, 76). These ideas are supported by
recent experiments in anesthetized mice given 25 ?l/g body wt
water through gastric or duodenal catheters over 6 min (48).
Mice with intact baroreflexes did not respond to water. In
contrast, water elicited a substantial increase in blood pressure
after interruption of the afferent baroreflex arc through sino-
aortic denervation. Remarkably, the time course of the pressor
response to water in mice resembled the time course of the
response to water drinking in human subjects.
Evidence for Water-Induced Sympathetic Activation
When we first observed the water drinking-induced pressor
response in autonomic failure patients, we were convinced that
sympathetic activation could not be involved given the under-
lying pathology. Indeed, sympathetic responses to cold pressor
testing, handgrip testing, and other sympathetic stimuli are
commonly attenuated in autonomic failure patients. One of the
more puzzling findings in autonomic failure patients is that
even in severely affected patients, loss of efferent sympathetic
function is rarely complete. Some residual efferent nerves
appear to be disconnected from central nervous system
input, making them truly autonomic. Therefore, pharmaco-
logical blockade of autonomic ganglia with trimethaphan
reduces blood pressure in a subgroup of pure autonomic
failure patients and in virtually all patients with multiple
system atrophy (68). Conversely, the ?2-adrenoreceptor antag-
onist yohimbine engages residual sympathetic efferents, thus,
raising blood pressure in a large proportion of autonomic
failure patients (6, 32, 58). Yohimbine increases sympathetic
activity by blocking the ?2-adrenergic receptors in the central
nervous system and in presynaptic adrenergic neurons (58).
Patients with complete loss of efferent sympathetic function do
not respond to yohimbine.
To address the question of whether residual sympathetic
function is required to express the water-drinking pressor
response, we tested yohimbine and water in autonomic failure
patients. Patients with a complete loss of sympathetic efferent
function suggested by absence of a pressor response to yohim-
bine showed no changes in blood pressure after water drinking.
Patients with residual sympathetic function indicated by a large
response to yohimbine also showed a large water drinking-
induced pressor response (33). In two patients with autonomic
failure, we tested the response to water with and without
trimethaphan infusion. Trimethaphan abolished the water-in-
duced pressor response (33). In sinoaortic-denervated mice,
?1- adrenoreceptor blockade with prazosin attenuated the pres-
sor response to water (48).
The idea that sympathetic nerves releasing norepinephrine
are required to express the water-induced pressor response is
supported by observations in mice with genetic deletion of the
gene encoding dopamine-?-hydroxylase. The enzyme is re-
quired for conversion of dopamine to norepinephrine. Dopa-
mine-?-hydroxylase deficiency is a rare cause of human auto-
nomic failure (45). Plasma and urine norepinephrine and
epinephrine are hardly detectable in dopamine-?-hydroxylase-
deficient human beings and mice. Dopamine-?-hydroxylase-
deficient mice did not show a pressor response to water (48).
When we tested water drinking in a middle-aged woman with
dopamine-?-hydroxylase deficiency, she did not respond either
(Jordan J, Shannon JR, and Robertson D, unpublished obser-
While changes in blood pressure after water drinking require
impairment in baroreflex function, sympathetic activation ap-
pears to be a more universal phenomenon. Water drinking
increases muscle sympathetic activity in healthy subjects in the
absence of a pressor response (65). Moreover, venous plasma
norepinephrine concentrations increased significantly with wa-
ter drinking in younger and in older healthy subjects (23, 33,
65) as well as in autonomic failure patients (55).
The sympathetic nervous system has a central role in the
regulation of energy expenditure. Therefore, a change in sym-
pathetic activity should lead to concomitant metabolic re-
sponses. Using whole-room indirect calorimetry and microdi-
alysis we assessed the response to drinking 500 ml water on
overall energy balance, substrate oxidation rates, and lipid
mobilization in young healthy subjects (8). With water drink-
ing, resting metabolic rate increased ?30% reaching a maxi-
mum after 30–40 min (Fig. 2). The response was predomi-
nantly fueled by lipid oxidation in men and carbohydrate
Fig. 1. Changes in systolic blood pressure (SBP), diastolic blood pressure
(DBP), and heart rate (HR) in patients with pure autonomic failure after
ingestion of 480 ml tap water. Patients started drinking at 0 min. The blood
pressure increase was evident within 5 min of drinking water, reached a
maximum after ?20–30 min, and was sustained for more than 60 min. [from
Fig. 1, Jordan et al. (33)]
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oxidation in women. The additional energy expenditure asso-
ciated with drinking 500 ml water averaged 100 kJ. A moder-
ate single oral beta-blocker dose attenuated the response (8).
Other groups, measuring energy expenditure with a ventilated
hood, did not observe changes in energy expenditure with
water drinking (10). Together, all of these observations suggest
that water drinking raises sympathetic activity. The increase in
sympathetic activity drives a pressor response in the setting of
impaired baroreflex function. In addition, sympathetic activa-
tion raises energy expenditure even in healthy young subjects.
With water drinking, a similar increase in endogenous nor-
epinephrine produces a much greater blood pressure increase in
autonomic failure patients compared with healthy subjects.
Autonomic failure patients are also extremely hypersensitive to
exogenous ?-adrenergic agonists (54). Loss of baroreflex
blood pressure buffering and increased vascular sensitivity
may contribute to the pressor hypersensitivity (36, 54).
While some parts of the sympathetic nervous system (e.g.,
muscle sympathetic activity and energy expenditure) are acti-
vated by water intake, there is not necessarily a general
sympathetic activation. Multiple, interacting, but modality-
specific, hierarchical systems involving neurons in the hypo-
thalamus, midbrain, and medulla build a central autonomic
network and allow a selective regulation of the vascular resis-
tance of different vascular beds and for the expression of
patterned autonomic responses (16, 17, 31, 47, 81). The orga-
nization of neural circuits specifically reacting to water inges-
tion remains to be elucidated.
Pathways Mediating Sympathetic Activation with
Activity of postganglionic adrenergic neurons, which ulti-
mately mediates all of the hemodynamic and metabolic re-
sponses to water drinking, could be engaged through various
mechanisms. Brain stem and spinal pathways are prime can-
didates. It appears less likely that water drinking produces a
signal directly affecting postganglionic adrenergic activity in
peripheral tissues. The underlying pathology in water-respon-
sive patients and the heart rate response to water drinking
helped with localizing the neural substrate for water-induced
sympathetic activation. Water drinking raises blood pressure
both in multiple system atrophy (33) and in high spinal cord-
injured patients (76). In multiple system atrophy patients, the
lesion to the efferent part of the autonomic nervous system is
located in the brain stem (5). More distal efferent sympathetic
structures are at least, in part, intact (27, 28, 68). In high spinal
cord-injured patients, spinal sympathetic neurons are intact but
disconnected from brain stem input. Postganglionic sympa-
thetic neurons can be activated by spinal reflexes but not by
reflexes travelling through the brain stem, including barore-
flexes (46). Thus, water drinking engages a spinal reflex-like
mechanism that activates sympathetic efferent nerves. This
idea is supported by the observation that heart rate decreases
with water drinking, whereas heart rate variability increases.
The response likely results from baroreflex activation of car-
diac parasympathetic efferent nerves. Similarly, spinal sympa-
thetic activation induced by bladder distention elicits hyper-
tension and bradycardia in patients with high spinal cord
injury (15). In contrast, physiological central-mediated sym-
pathetic activation typically produces tachycardia and hy-
pertension. Notable exceptions are diving and Cushing re-
flexes. Finally, bilateral subdiaphragmatic vagotomy did not
abolish the pressor response to water drinking in sinoaortic-
denervated mice (48).
Recent studies uncovered potential stimuli activating the
spinal sympathetic response to water drinking. In autonomic
failure patients, the magnitude of the water-induced pressor
response was not related to water temperature (33). Only one
third of the increase in resting energy expenditure could be
explained by warming the water from 22°C to 37°C (8). Even
drinking water of 37°C increased the metabolic rate. Gastric
distention increases sympathetic activity in humans (59). Sym-
pathetic activation elicited by gastric distention may attenuate
postprandial hypotension (26). Yet, the maximal response to
water drinking was observed after ?40 min. At this time, only
25% of the ingested water remains in the stomach (53). In
some patients with autonomic dysfunction, small amounts of
water were sufficient to trigger significant and sustained blood
pressure increases. Moreover, intragastric and intraduodenal
water infusion induced an identical pressor response in sino-
aortic-denervated mice (48). Thus, the afferent structure re-
sponding to water is likely located distally from the stomach.
Temperature or gastric distention is not sufficient to set off the
Fig. 2. Top: relative change in energy expenditure (EE) over time in obese
subjects after drinking 50 ml water (50 H2O), 500 ml water (500 H2O), or 500
ml isoosmotic saline (500 NaCl). At 0 min, subjects started to drink the fluids
in ? 5 min. Testing was conducted in a randomized and crossover fashion on
separate days. *P ? 0.05 and **P ? 0.01 vs. 500 ml water and 500 ml saline,
respectively. #P ? 0.001 vs. 500 and 50 ml water. Bottom: individual
thermogenic responses to 50 ml water, 500 ml water, or 500 ml normal saline.
Response was calculated between 0 and 90 min after drinking. The dotted
line indicates the energy required to heat 500 ml water or saline from room
temperature to body temperature. P values are given for the analysis with
Bonferroni’s post test (ANOVA, P ?0.0001). [Fig. 1 from Boschmann et
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water response leaving local/regional hypoosmolarity as a
Drinking water is hypoosmolar compared with extracellular
fluid. When liquids with different osmolarities were infused
into the stomachs of dogs, distilled water showed a twofold
greater increase in blood pressure compared with isotonic
saline (29). In rats, infusion of hypoosmolar solutions into the
portal vein with concomitant infusion of hyperosmolar solu-
tions into the vena cava elicited robust increases in diuresis
(29). The experimental setup led to selective hypoosmolar
stimulation of the liver, whereas central osmoreceptors were
exposed to isoosmolarity. The diuretic response was attenuated
when the infusions were switched. The observation suggested
the presence of hepatic osmoreceptors. Though others did not
reproduce the findings (62), there are investigations giving
evidence for hepatic osmoreceptors (13, 37).
Infusion of water elicited a much greater pressor response
compared with isotonic saline infusions in sinoaortic-dener-
vated mice (48). Moreover, in patients with autonomic failure
due to multiple system atrophy, water given through a naso-
gastric tube increased blood pressure more than the same
volume of normal saline (41). Similarly, addition of sodium
chloride to drinking water attenuated the pressure response in
autonomic failure patients (55). Finally, in healthy subjects,
hypoosmolar fluid given through a gastric tube increased sweat
production, which could be sympathetically mediated, to a
greater extent than infusion of isoosmolar solutions (29). All of
these findings support the idea that hypoosmolarity is the
stimulus for water-induced sympathetic activation. Water in-
gestion likely results in particularly large osmolality changes in
the portal tract and in the liver. Therefore, we speculate the
osmosensitive afferent neurons may be located in this anatom-
ical area. Indeed, in mice, changes in portal vein osmolality
coincide with changes in blood pressure (48). In the same set
of experiments, systemic osmolarity remained unchanged (48).
The molecular transduction mechanisms involved in sensing
hypoosmotic signals in peripheral tissues are poorly under-
stood. The transient receptor potential (Trp) channel family
including the vanilloid subfamily Trpv is involved in recogni-
tion of noxious environmental stimuli including osmolality,
temperature, and pain. Trpv4 is a prime suspect given its
sensitivity to osmotic changes (39, 40, 56, 74, 75). Indeed,
although portal osmolality decreases after water application in
wild-type and Trpv4?/?mice (all had undergone sinoaortic
denervation), only wild-type animals showed a pressor re-
sponse (Fig. 3). Yet, wild-type and Trpv4?/?mice showed a
similar increase in blood pressure due to restraint stress
(48). This observation suggests that efferent sympathetic func-
tion was intact in both strains. Thus, the presence of Trpv4 is
required to express the osmopressor response. We speculate
that Trpv4 channels on hepatic and/or portal spinal afferent
neurons could be involved.
Therapeutic Utility of Water Drinking
Recognition of the osmopressor response has had an impor-
tant impact on the management of autonomic nervous system
disorders, particularly in patients with autonomic failure and
with neurally mediated (vasovagal syncope). Water drinking
improves standing blood pressure and orthostatic tolerance in a
large subgroup of patients with autonomic failure (66). The
maximal pressor response to water is reached when other
pressor agents are only beginning to act. Furthermore, water
drinking attenuates postprandial hypotension (66). We recom-
mend that water should be ingested before meals and when
orthostatic symptoms are worst. Water ingestion is particularly
useful in the morning before arising with or without the
addition of pressor drugs. Most patients experience particularly
severe orthostatic symptoms in the morning due to sodium loss
throughout the night. Patients with supine hypertension should
avoid water drinking at least 1 h before bedtime (68). The
effects of pressor agents, such as pseudoephedrine and phen-
ylpropanolamine, are potentiated by water drinking (34). These
drug interaction effects can be exploited in the treatment of
orthostatic hypotension. However, the interaction can also lead
to potentially dangerous blood pressure surges. Excessive wa-
ter ingestion should be avoided, particularly in patients with
multiple system atrophy because potentially life threatening
hyponatremia could ensue.
Water drinking could have a therapeutic benefit in patients
with postural tachycardia syndrome (idiopathic orthostatic in-
tolerance), a syndrome that is more common than autonomic
failure. True to its name, postural tachycardia syndrome is
associated with tachycardia while standing in the absence of
significant orthostatic hypotension (42, 72). Drinking 480 ml
water lowered upright heart rate 15 and 10 beats/min after
standing 3 and 5 min, respectively (66).
Influences of water drinking on orthostatic tolerance in
healthy subjects and in patients with neurally mediated (vaso-
vagal) syncope have been studied using head-up tilt testing
combined with lower body negative pressure according to the
Leeds protocol (20) or with regular head-up tilt testing. Studies
were conducted in a crossover fashion. In young healthy
subjects water drinking can delay or even prevent syncope
during head-up tilt testing with or without lower body negative
pressure (43, 63). Patients with neurally mediated syncope
showed similar improvements in orthostatic tolerance with
ingestion of 500 ml water (14). Water drinking decreases the
risk for blood donation-related vasovagal reactions (1, 22,
Fig. 3. Blood pressure changes (?BP) after
duodenal infusion of water (25 ?l/g body wt)
in anesthetized sinoaortic-denervated tran-
sient receptor potential vanniloid 4 (Trpv4)
knockout and wild-type mice. Absence of a
pressor response in Trpv4 knockout animals
suggests that the receptor is an essential
mediator in the osmopressor response. [Fig.
5 from McHugh et al. (48)]
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50) and may be beneficial in individuals with postexercise
On the basis of acute metabolic responses to single water
applications in the metabolic chamber, we speculated that
increasing water intake by 1.5 l/day could raise energy expen-
diture by ?200 kJ/day (8). Over 1 yr, energy consumption
would increase 73,000 kJ (17,400 kcal) corresponding to the
energy content of 2.4 kg adipose tissue. In comparison, admin-
istration of 50 mg ephedrine three times a day increased energy
expenditure about 320 kJ/day (67). Whether water drinking as
a cost-free intervention has a significance in the treatment of
excess weight and obesity has not been assessed in prospective
studies. However, in overweight and obese women, drinking
water was associated with improved weight loss even after
adjustment for nutrition and physical activity (71).
Perspectives and Significance
Drinking water elicits a sympathetically mediated pressor
response in the setting of impaired baroreflex function in both
human beings and animals. The increase in sympathetic activ-
ity is associated with significant increases in resting energy
expenditure. Studies in patients with high spinal cord injury
suggest a spinal reflex-like mechanism. The signal setting off
the pressor response seems to be hypoosmolarity. Transduction
of the hypoosmotic signal requires the presence of Trpv4. We
speculate that these osmosensors may be located in liver and
portal vasculature. However, the (nerve) cell population serv-
ing as peripheral osmosensors and the exact transduction
mechanisms are still unknown. Moreover, the physiological
role of peripheral osmosensors in human beings is not fully
understood. It is possible that liver and portal osmosensors,
which are exposed to relatively large swings in blood osmola-
lity with feeding and drinking, serve as a first line of defense
for maintenance of systemic osmolality. Conditions in which
hepatic perfusion through the portal vein or hepatic innervation
is disturbed may provide relevant models for physiological
investigations. Remarkably, hyponatremia is common in pa-
tients with end-stage liver disease. Perhaps, manipulation of
peripheral osmosensors via Trpv4 could be clinically applied in
these patients. On the other hand, sympathetic activation elic-
ited by hypoosmolarity can be therapeutically exploited. In-
deed, the osmopressor response provides an effective and
inexpensive treatment of orthostatic syndromes. The increase
in metabolic rate with water drinking could be systematically
applied in the prevention of weight gain and associated meta-
bolic and cardiovascular risk factors. In essence, water drink-
ing provides negative calories. In the event, a recent study
suggests that water drinking improves weight loss during a
hypocaloric dietary intervention (18). Finally, water drinking
should be recognized as an important confounder in cardiovas-
cular and metabolic studies. All of these findings illustrate that
even in the third millennium, careful history taking and simple
bedside tests can uncover novel physiological mechanisms.
We thank all the patients and volunteers for their willingness to participate
in clinical research projects leading to the identification of the osmopressor
No conflicts of interest, financial or otherwise, are declared by the author(s).
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