See

discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/23152432

Physiology and pathophysiology of the

vasopressinergic system
Article in Baillire&#x27 s Best Practice and Research in Clinical Anaesthesiology July 2008
DOI: 10.1016/j.bpa.2008.03.004 Source: PubMed

CITATIONS

READS

36

51

2 authors:
Jean-Louis Vincent

Fuhong Su

Universit Libre de Bruxelles

Universit Libre de Bruxelles

1,209 PUBLICATIONS 76,504 CITATIONS

69 PUBLICATIONS 790 CITATIONS

SEE PROFILE

All in-text references underlined in blue are linked to publications on ResearchGate,

letting you access and read them immediately.

SEE PROFILE

Available from: Fuhong Su

Retrieved on: 07 May 2016

Vincent, Jean Louis, & Su, FUHONG

Physiology and pathophysiology of the vasopressinergic system

Article. Version publie - Published version.

ELSEVIER
Citation APA:
Vincent, J. L., & Su, F. (2008, June). Physiology and pathophysiology of the vasopressinergic system. Best Practice and
Research: Clinical Anaesthesiology, 22(2), 243-252. doi:10.1016/j.bpa.2008.03.004

DOI: 10.1016/j.bpa.2008.03.004
Also available at: http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/79658
Cet article publi par ELSEVIER provient du Dpt institutionnel de lUniversit Libre de Bruxelles, DIfusion http://difusion.academiewb.be. Il nest accessible quaux membres de la communaut universitaire de
lULB sur le rseau scuris de lULB.
Tout utilisateur autoris peut lire, tlcharger ou reproduire cet article des fins d'usage priv ou des fins
non commerciales d'enseignement ou de recherche scientifique. Il ne peut tre atteint lintgrit de larticle,
et les noms des auteurs et de lditeur doivent tre conservs. Tout tlchargement systmatique des articles
publis par ELSEVIER mis disposition dans DI-fusion est interdit.
This article published by ELSEVIER comes from the Institutional repository of Universit Libre de
Bruxelles, DI-fusion http://difusion.academiewb.be. It is accessible only to the members of the university
community of ULB on the ULB secure network.
Any authorized user may read, download or reproduce this article for private usage, or for non commercial
research or educational purposes. The integrity of the article and identification of the author and copyright
owner must be preserved. Systematic downloading of articles published by ELSEVIER that are available in
DI-fusion is not permitted.

Best Practice & Research Clinical Anaesthesiology

Vol. 22, No. 2, pp. 243252, 2008
doi:10.1016/j.bpa.2008.03.004
available online at http://www.sciencedirect.com

1
Physiology and pathophysiology of the
vasopressinergic system
Prof.

Jean-Louis Vincent *

MD, PhD

Dr. Fuhong Su MD, PhD

Department of Intensive Care, Erasme Hospital, Universite libre de Bruxelles,
Route de Lennik 808, 1070 Brussels, Belgium

Arginine vasopressin, a hypothalamic peptide hormone, has multiple physiological functions,

including body water regulation, control of blood pressure and effects on body temperature,
insulin release, corticotropin release, memory and social behaviour. These functions are
achieved via at least three specific G-protein-coupled vasopressin receptors. Development of
specific vasopressin receptor antagonists in recent years is helping to elucidate the precise
actions of vasopressin at each of these receptor types. The complex signalling and messenger
processes which take place after receptor stimulation are now more clearly understood. Vasopressin dysregulation can occur in various disease processes, and a better understanding of the
mechanisms underlying physiological synthesis, release and regulation of vasopressin will help in
the development of therapies to treat these conditions.
Key words: hyponatraemia; thirst; diabetes insipidus; SIADH; water regulation.

Arginine vasopressin, also known as antidiuretic hormone, was first characterized in

1895 by Oliver and Schaefer1, who demonstrated that extracts of the pituitary gland
altered blood pressure. It was first isolated in 1952. The vasopressinergic system is
involved in multiple physiological processes, ranging from control of blood pressure2
to effects on body temperature, insulin release3, corticotropin release4, memory5
and social behaviour.6 The importance of vasopressin in survival is demonstrated by
its evolutionary persistence; oxytocin and vasopressin-like peptides have been
identified in invertebrate and vertebrate families, suggesting that the ancestral gene
encoding the precursor protein predates the divergence of vertebrates and invertebrates, making it more than circa 700 million years old!7
* Corresponding author. Tel.: 32 2 555 3380; Fax: 32 2 555 4555.
E-mail address: jlvincen@ulb.ac.be (J.-L. Vincent).
1521-6896/$ - see front matter 2008 Elsevier Ltd. All rights reserved.

244 J.-L. Vincent and F. Su

Although vasopressin has been used for many years in the treatment of variceal
haemorrhage and diabetes insipidus, it is only relatively recently that interest has
developed in the potential role of vasopressin as a therapeutic agent in patients
with shock. This chapter will discuss the regulation of vasopressin synthesis and
release, basic receptor physiology and the physiological role of vasopressin, and briefly
highlight the potential clinical impact of dysregulation of the vasopressinergic system.
REGULATION OF ENDOGENOUS VASOPRESSIN
SYNTHESIS AND RELEASE
Synthesis
Vasopressin is 9 amino acid peptide, a nonapeptide, with a disulphide bridge between
its two cysteine residues. Endogenous human vasopressin is also called arginine
vasopressin to distinguish it from other members of the vasopressin family, such as
lysine vasopressin, found in other mammalian species. It differs in structure from
oxytocin by just two amino acids, isoleucine instead of phenylalanine, and leucine
instead of arginine (Figure 1).
The gene for vasopressin is situated on chromosome 20, not far from the gene for
oxytocin. Vasopressin is synthesized as a large prohormone, preprovasopressin,
consisting of: an amino-terminal signal peptide; the vasopressin peptide; neurophysin,
a carrier protein; and a carboxyl-terminal co-peptide. This prohormone is synthesized
principally by the magnocellular neurons of the paraventricular and supraoptic nuclei in
the hypothalamus, from where it travels along the supraoptichypophyseal tract to the
magnocellular presynaptic terminals in the posterior lobe of the pituitary gland. During
transport, vasopressin separates from its prohormone peptides, and is stored in secretory granules on arrival in the posterior lobe. The carrier protein, neurophysin, is
believed to be important in sorting the prohormone into the regulated secretory pathway.8 The process of synthesis, transport and storage takes 12 h.9
Release
The most potent stimuli for vasopressin synthesis and release are hypertonic conditions, severe hypotension and hypovolaemia, although other factors, including pain,

Cys Tyr Phe Glu Asn Cys Pro - Arg - Gly - (NH2)

Vasopressin
Cys Tyr Ile Glu Asn Cys Pro - Leu - Gly - (NH2)

Oxytocin

Figure 1. Amino acid composition of vasopressin and oxytocin, showing disulphide bonds between cysteine
residues.

Physiology and pathophysiology of the vasopressinergic system 245

nausea, hypoxia, acute hypoglycaemia and even smoking, can also be associated with
increased release of vasopressin.10,11 Stimulation by whatever cause results in calcium
influx, followed by release of vasopressin from the granules after separation from
neurophysin and glycopeptide. The granules fuse with the cell membrane and extrude
their contents into the perivascular space and the posterior pituitary capillary
system.12
Osmoregulation
Osmotic regulation of vasopressin production and release is controlled by osmoreceptors located peripherally, in the hepatic portal vein region, and centrally outside the
bloodbrain barrier in the anteroventral region of the third ventricle. Central osmoreceptors detect changes in systemic osmolality, whereas peripheral osmoreceptors
enable early detection of the effects on osmolality of food and fluid ingestion. Afferent
impulses from the osmoreceptors ascend via the vagus nerve to the nucleus tractus
solitarius, the area postrema and the ventrolateral medulla before projecting to the
paraventricular nuclei.13 In addition, the magnocellular neurons of the hypothalamus
are depolarized directly by hypertonic conditions, resulting in increased release of
vasopressin, and hyperpolarized in hypotonic conditions, resulting in decreased release
of vasopressin. There is a linear relationship between increase in plasma osmolality and
plasma vasopressin concentrations. Osmoregulatory systems maintain plasma osmolality within narrow limits (284295 mOsmol/kg), and the osmotic regulation of
vasopressin is very sensitive; an increase in osmolality of just 1% will change plasma
vasopressin by an average of 1 pg/mL, which is enough to alter urine concentration
significantly.14
Baroregulation
Less important than osmoregulation in physiological conditions, baroregulation only
really comes into play with blood pressure decreases of more than 10%. Blood volume
and blood pressure act via different pathways to influence vasopressin release.
Baroreceptors in the left atrium and ventricle detect changes in blood volume, with
afferent impulses decreasing vasopressin release, whereas receptors in the aortic
arch and carotid sinus are influenced by changes in arterial blood pressure. Large
decreases in blood pressure are accompanied by exponential increases in vasopressin
release unlike the linear relationship seen with osmoregulation. Interestingly, severe
hypovolaemia alone does not influence the level of vasopressin until it is accompanied
by a fall in arterial pressure.12 Importantly, a rise in vasopressin levels in response to
hypotension or hypovolaemia does not affect osmoregulation of vasopressin release,
because hypotension alters the plasma osmolalityvasopressin relationship such that
higher plasma vasopressin levels are needed to maintain normal osmolality.15,16
Other regulatory factors
Many other factors can be implicated in vasopressin release including catecholamines,
hypoxia, hypercapnia and nitric oxide.17 Acetylcholine, histamine, prostaglandins and
catecholamines stimulate vasopressin release directly; hypercapnia stimulates carotid
body chemoreceptors, thus increasing the level of vasopressin; and opioids inhibit
vasopressin release via a2-adrenoceptors.

246 J.-L. Vincent and F. Su

Metabolism and negative feedback

Once released into the circulation, vasopressin is metabolized rapidly by vasopressinases in the liver and kidney, and has a short half-life of 1035 min. Vasopressin
synthesis and release are controlled by several negative feedback loops. Vasopressin
release reduces plasma osmolality, which reduces vasopressin synthesis. In addition,
production of adrenocorticotrophic hormone is stimulated by the interaction of
vasopressin with V3 receptors, resulting in an increased glucocorticoid concentration
which inhibits further secretion of vasopressin.18 Vasopressin itself causes desensitization of V1 and V2 receptors, which become phosphorylated and bind to beta-arrestin
scaffolding proteins, inhibiting further interaction with G-proteins. The desensitization
is accompanied by internalization of the receptors and sequestration inside the cell.19
This process occurs rapidly for V1 receptors, which recycle equally rapidly; desensitization and recycling is much slower for V2 receptors.20
RECEPTOR PHYSIOLOGY
The actions of vasopressin are dependent on interaction with receptors that form part
of the superfamily of G-protein-coupled receptors, which consist of seven hydrophobic transmembrane a-helices joined by alternating intracellular and extracellular loops,
and possessing an extracellular N-terminal domain and a cytoplasmic C-terminal
domain.21,22 The different vasopressin receptors are closely related, with overall
similarity varying from 40 to 85%, and the most conserved regions being the transmembrane a-helices and the first extracellular loop.23 Nevertheless, the small structural differences are enough to confer different functions. Three specific vasopressin
receptors have been identified: V1, V2 and V3 (Table 1, Figure 2). Various signalling
pathways, largely routed by G-proteins, are involved in the effects mediated by receptor stimulation.24 Vasopressin also acts on oxytocin and P2 purinergic receptors. In
this issue of Best Practice & Research Clinical Anaesthesiology, Maybauer et al review
the physiology and pharmacology of these five vasopressin receptors in detail. In
addition, various other vasopressin receptors have been described, including the
vasopressin-activated calcium-mobilizing receptor and the dual angiotensin II/vasopressin receptor.25 The functions of these, and potentially other, receptor subtypes
in physiological and pathophysiological processes remain to be defined more clearly.

Table 1. Vasopressin receptor types, locations and key functions.

Receptor

Key mediated function(s)

Location

Principal second
messenger system

V1

P2 purinergic

Vasoconstriction

Vascular smooth muscle,

platelets, liver, testes,
brainstem
Kidney collecting duct cells
Central nervous system
Uterine myometrium and
endometrium, vascular
endothelium
Cardiac endothelium

Phosphatidylinositol/calcium

V2
V3
Oxytocin

Vasoconstriction,
platelet aggregation,
glycogenolysis
Water retention
Corticotropin secretion
Vasodilation

Adenylate cyclase/cAMP
Phosphatidylinositol/calcium
Phosphatidylinositol/calcium

ATP

Physiology and pathophysiology of the vasopressinergic system 247

ARTERIAL
HYPOTENSION
Hormones
Catecholamines
Cytokines

Hyperosmolarity
Myocardial stretch

HYPOTHALAMUS
ACTH

POSTERIOR
PITUITARY GLAND

V3 receptors

VASOPRESSIN

V2 receptors
V1 receptors

antidiuretic effects

oxytocin receptors (OTR)

vascular smooth muscle

contraction

NO

(renal collecting duct & endothelial cells)

Figure 2. Key factors that regulate the release of vasopressin and its key functions. ACTH, adrenocorticotrophic hormone; NO, nitric oxide.

PHYSIOLOGICAL EFFECTS OF ENDOGENOUS VASOPRESSIN

The normal plasma vasopressin concentration in a healthy, normally hydrated individual is about 1 pg/mL, although there is considerable diurnal variation and values can be
up to two-fold higher during sleep.26,27 There may also be gender, genetic and racial
variations in normal plasma vasopressin levels.14 Best known for its effects on water
homeostasis, vasopressin is involved in many other physiological processes including
body temperature, insulin release3, corticotropin release4, memory5 and social
behaviour.6 However, in physiological conditions, the main role of vasopressin is the
regulation of water balance28; it does not appear to play a major role in the vascular
regulation of blood pressure in physiological conditions when other vasoregulatory
systems (the sympathetic system and the reninangiotensin system) are intact. Indeed,
the syndrome of inappropriate antidiuretic hormone secretion (SIADH), where
endogenous vasopressin levels are abnormally high, is not associated with hypertension. In healthy volunteers, exogenous vasopressin infusion of up to 300 pg/mL does
not alter blood pressure29, demonstrating the importance of the sympathetic and
reninangiotensin systems in cardiovascular regulation. The maintenance of adequate
water balance depends on regulation of water intake, which is controlled by the
availability of water, the sensation of thirst and regulation of water excretion by the
kidney, which is under vasopressin control and reliant on functioning V2 receptors
and aquaporin channels.30 Thirst is a key factor in the appropriate physiological
response to altered osmolality. In general, stimuli which cause thirst also stimulate
the release of vasopressin to concentrate the urine. In general, however, the threshold
plasma osmolality that stimulates thirst is slightly higher than that which stimulates
vasopressin release, so there is usually a basal presence of vasopressin while thirst
is perceived intermittently.31

248 J.-L. Vincent and F. Su

DISEASES ASSOCIATED WITH DYSREGULATION

OF THE VASOPRESSIN SYSTEM
Many diseases are directly associated with dysregulation of the vasopressin system, the
most common of which will be considered below.
Syndrome of inappropriate antidiuretic hormone secretion
SIADH, first described 40 years ago32, is characterized by hypotonic hyponatraemia,
increased urine osmolality compared with plasma osmolality, normal natriuresis,
euvolaemia or volume depletion, and normal renal and adrenal function. Elevated
vasopressin secretion leads to renal water retention and extracellular fluid expansion,
which is initially compensated for by increased urinary sodium excretion. This combination of water retention and sodium excretion leads to hyponatraemia. In patients
with SIADH, vasopressin secretion is regulated inadequately, but the mechanism of
dysregulation can vary; some patients have excessive and erratic vasopressin secretion
unrelated to plasma osmolality, others have a reduced trigger point for vasopressin
secretion, and others have persistent vasopressin release despite low plasma osmolality.33 SIADH is a relatively common condition and can be present in a wide variety of
clinical conditions, including tumours that produce ectopic vasopressin, human
immunodeficiency virus/acquired immunodeficiency syndrome, pulmonary disease,
endocrine disease, neurological disease or trauma, or administration of some drugs.34
Traditional management relies largely on restricting fluid intake, but V2 receptor antagonists are being developed and have demonstrated good efficacy and safety in early
clinical trials.35 Administration of urea can also increase the elimination of excessive
water by osmotic diuresis.
Congestive heart failure
Congestive heart failure is a complex syndrome in which the pathophysiology combines haemodynamic derangements and neurohormonal imbalances.36 In physiological
conditions, the sympathetic nervous system and the reninangiotensinaldosterone
system are the key to the maintenance of normal blood pressure and circulation.
Vasopressin plays a relatively small role in normal physiology. However, in congestive
heart failure, plasma levels of vasopressin are increased despite the atrial distension,
hyponatraemia and low osmolality which would normally inhibit its release.37 Hyponatraemia in patients with congestive heart failure is associated with worse
outcomes.38,39 Persistent stimulation of V1 receptors by the high level of vasopressin
causes vasoconstriction and an increase in systemic vascular resistance and afterload,
and thus has a further adverse effect on cardiac function.36 V2 receptor stimulation
increases water retention, leading to oedema, and can contribute to the hyponatraemia commonly seen in patients with congestive heart failure. The mechanism underlying the persistently high level of vasopressin in these patients is uncertain, but it is
believed to be due to abnormal feedback control, such that hypoosmolality does
not reduce the level of vasopressin, and to baroreceptor-stimulated release of
vasopressin. The low cardiac output in patients with heart failure causes reduced
arterial pressure, which unloads the carotid sinus and aortic arch baroreceptors, triggering vasopressin secretion in an effort to increase sodium and water retention.40 V2
or combined V1/V2 receptor antagonists may be beneficial in such patients40, although

Physiology and pathophysiology of the vasopressinergic system 249

a recent large randomized study reported no benefit of the V2 antagonist, tolvaptan,

on risk of death or hospitalization.41
Decompensated cirrhosis
Many patients with decompensated liver cirrhosis and ascites have impaired renal
water handling with water retention, and many of these will have associated dilutional
hyponatraemia. Patients with decompensated cirrhosis have a persistently high level of
vasopressin despite hypo-osmolality and hyponatraemia, which would normally
suppress the release of vasopressin. There are several potential mechanisms behind
the high level of vasopressin, including decreased metabolism of vasopressin due to
altered liver function, and non-osmotic release of vasopressin secondary to reduced
effective arterial filling associated with arterial vasodilation characteristic of cirrhosis.42 Interestingly, nitric oxide is believed to play a role in arterial vasodilation in
cirrhosis, and may also be able to directly stimulate vasopressin release centrally,
thus contributing indirectly and directly to the high level of vasopressin.42
Diabetes insipidus
Diabetes insipidus is characterized by excretion of large amounts of diluted urine, and
is due to a defect in vasopressin production or a reduction in the renal effects of
vasopressin. There are various forms of diabetes insipidus.30 The most common
form is central diabetes insipidus, which occurs following damage to the hypothalamus
or pituitary gland due to tumour, stroke, neurosurgery or brain death. Less common is
nephrogenic diabetes insipidus, in which the kidney fails to respond normally to vasopressin; this form can be hereditary due to mutations in V2 receptors or aquaporin-2
protein, or acquired, most commonly due to electrolyte disturbances, urinary tract
obstruction or exposure to certain drugs. Other forms of diabetes insipidus are
adipsic diabetes insipidus, which is due to a defect in the thirst mechanism located
in the hypothalamus where increased thirst suppresses vasopressin synthesis; and
gestational diabetes insipidus, which only occurs during pregnancy and is associated
with increased placental production of vasopressinases and hence increased metabolism of vasopressin. Administration of vasopressin (as desmopressin) is effective in
central but not in nephrogenic diabetes insipidus. V2 receptor antagonists may act
as pharmacological chaperones in such patients, stabilizing the mutant receptors
thus enabling them to function normally.43
Septic shock
Arterial hypotension is typically associated with an appropriately high level of vasopressin.28 The high level of vasopressin causes vasoconstriction by several mechanisms
including activation of V1 receptors, modulation of ATP-sensitive K channels, modulation of nitric oxide and potentiation of adrenergic and other vasoconstrictor agents,
including noradrenaline and angiotensin II44, helping to restore and maintain blood
pressure. However, in septic shock, the vasopressin response to hypotension seems
to be blunted.45,46 The mechanism underlying these reduced vasopressin levels is
unclear, with possible mechanisms including reduced production of vasopressin47, depletion of vasopressin stores, inhibition of vasopressin release, impaired baroreflexmediated vasopressin secretion, and increased vasopressin degradation. Restoration

250 J.-L. Vincent and F. Su

of vasopressin levels with low doses of endogenous vasopressin may be beneficial in

such patients.48 This will be discussed in other chapters in this issue.
SUMMARY
The field of neurohormonal physiology is highly complex. Since vasopressin was isolated in the early 1950s, much has been learnt about its function in health and disease,
but we are far from a complete understanding of its different and diverse functions,
and have much to discover in terms of the complex interactions between vasopressin
and other neurohormones and mediators. The development of specific agonists and
antagonists for the different vasopressin receptors in recent years has enabled
research to examine their individual and combined roles in physiological homeostasis
more precisely, and to propose therapeutic uses for these agents in various common
disease processes. Vasopressin and its analogues have also been used in the treatment
of diabetes insipidus, bleeding oesophageal varices, shock, particularly septic shock,
and cardiopulmonary resuscitation. Further research into the physiological roles of
vasopressin, the complex signalling pathways associated with receptor stimulation,
and the multiple feedback loops which regulate vasopressin secretion and release
will offer improved insight into this fascinating peptide, and provide future targets
for therapeutic investigation.

Research agenda
 many aspects of vasopressins functions remain poorly understood
 further research is needed to improve understanding of the molecular basis of
receptor function using newly developed specific vasopressin receptor
antagonists
 ongoing studies will help to elucidate the complex mechanisms regulating
vasopressin synthesis and release, and the interactions of vasopressin with
other neurohormonal and vasoregulatory pathways
 clinical studies are warranted to evaluate further the role of vasopressin
receptor antagonists in various disease processes, including congestive heart
failure and hyponatraemia

REFERENCES
1. Oliver G & Schaefer EA. On the physiological action of extract of pituitary body and certain other
glandular organs. The Journal of Physiology 1895; 18: 277279.
2. Mutlu GM & Factor P. Role of vasopressin in the management of septic shock. Intensive Care Medicine
2004; 30: 12761291.
3. Oshikawa S, Tanoue A, Koshimizu TA et al. Vasopressin stimulates insulin release from islet cells through
V1b receptors: a combined pharmacological/knockout approach. Molecular Pharmacology 2004; 65: 623
629.
4. Tanoue A, Ito S, Honda K et al. The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions. The Journal of Clinical Investigation
2004; 113: 302309.
5. Weingartner H, Gold P, Ballenger JC et al. Effects of vasopressin on human memory functions. Science
1981; 211: 601603.

Physiology and pathophysiology of the vasopressinergic system 251

6. Bielsky IF, Hu SB, Ren X et al. The V1a vasopressin receptor is necessary and sufficient for normal social
recognition: a gene replacement study. Neuron 2005; 47: 503513.
7. Acher R, Chauvet J & Chauvet MT. Man and the chimaera. Selective versus neutral oxytocin evolution.
Advances in Experimental Medicine and Biology 1995; 395: 615627.
*8. de Bree FM & Burbach JP. Structurefunction relationships of the vasopressin prohormone domains.
Cellular and Molecular Neurobiology 1998; 18: 173191.
9. Sklar AH & Schrier RW. Central nervous system mediators of vasopressin release. Physiological Reviews
1983; 63: 12431280.
10. Baylis PH. Osmoregulation and control of vasopressin secretion in healthy humans. American Journal of
Physiology 1987; 253: R671R678.
11. Feldberg W, Guertzenstein PG & Rocha e Silva Jr. M. Vasopressin release by nicotine: the site of action.
British Journal of Pharmacology 1975; 54: 463474.
12. den Ouden DT & Meinders AE. Vasopressin: physiology and clinical use in patients with vasodilatory
shock: a review. Netherlands Journal of Medicine 2005; 63: 413.
13. Kam PC, Williams S & Yoong FF. Vasopressin and terlipressin: pharmacology and its clinical relevance.
Anaesthesia 2004; 59: 9931001.
*14. Bankir L. Antidiuretic action of vasopressin: quantitative aspects and interaction between V1a and V2
receptor-mediated effects. Cardiovascular Research 2001; 51: 372390.
15. Quillen Jr. EW & Cowley Jr. AW. Influence of volume changes on osmolality-vasopressin relationships in
conscious dogs. American Journal of Physiology 1983; 244: H73H79.
16. Schrier RW, Berl T & Anderson RJ. Osmotic and nonosmotic control of vasopressin release. American
Journal of Physiology 1979; 236: F321F332.
17. Leng G, Brown CH & Russell JA. Physiological pathways regulating the activity of magnocellular
neurosecretory cells. Progress in Neurobiology 1999; 57: 625655.
18. Bahr V, Franzen N, Oelkers W et al. Effect of exogenous glucocorticoid on osmotically stimulated
antidiuretic hormone secretion and on water reabsorption in man. European Journal of Endocrinology
2006; 155: 845848.
19. Birnbaumer M. Vasopressin receptors. Trends in Endocrinology and Metabolism 2000; 11: 406410.
20. Oakley RH, Laporte SA, Holt JA et al. Association of beta-arrestin with G protein-coupled receptors
during clathrin-mediated endocytosis dictates the profile of receptor resensitization. The Journal of
Biological Chemistry 1999; 274: 3224832257.
21. Barberis C, Mouillac B & Durroux T. Structural bases of vasopressin/oxytocin receptor function. The
Journal of Endocrinology 1998; 156: 223229.
22. Birnbaumer M, Seibold A, Gilbert S et al. Molecular cloning of the receptor for human antidiuretic
hormone. Nature 1992; 357: 333335.
23. Chini B & Manning M. Agonist selectivity in the oxytocin/vasopressin receptor family: new insights and
challenges. Biochemical Society Transactions 2007; 35: 737741.
24. Neves SR, Ram PT & Iyengar R. G protein pathways. Science 2002; 296: 16361639.
*25. Holmes CL, Landry DW & Granton JT. Science review: vasopressin and the cardiovascular system
part 1 receptor physiology. Critical Care (London, England) 2003; 7: 427434.
26. George CP, Messerli FH, Genest J et al. Diurnal variation of plasma vasopressin in man. The Journal of
Clinical Endocrinology and Metabolism 1975; 41: 332338.
27. Nadal M. Secretory rhythm of vasopressin in healthy subjects with inversed sleepwake cycle: evidence
for the existence of an intrinsic regulation. European Journal of Endocrinology 1996; 134: 174176.
28. Forrest P. Vasopressin and shock. Anaesthesia and Intensive Care 2001; 29: 463472.
29. Williams TD, Da Costa D, Mathias CJ et al. Pressor effect of arginine vasopressin in progressive
autonomic failure. Clinical Science (London) 1986; 71: 173178.
30. Peters HP, Robben JH, Deen PM & Wetzels JF. Water in health and disease: new aspects of disturbances
in water metabolism. Netherlands Journal of Medicine 2007; 65: 325332.
31. Robertson GL. Abnormalities of thirst regulation. Kidney International 1984; 25: 460469.
32. Bartter FC & Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. American Journal of Medicine 1967; 42: 790806.
33. Multz AS. Vasopressin dysregulation and hyponatremia in hospitalized patients. Journal of Intensive Care
Medicine 2007; 22: 216223.

252 J.-L. Vincent and F. Su

34. Rai A, Whaley-Connell A, McFarlane S & Sowers JR. Hyponatremia, arginine vasopressin dysregulation,
and vasopressin receptor antagonism. American Journal of Nephrology 2006; 26: 579589.
*35. Soupart A, Gross P, Legros JJ et al. Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide
vasopressin V2-receptor antagonist. Clinical Journal of the American Society of Nephrology 2006; 1: 1154
1160.
36. Goldsmith SR. The role of vasopressin in congestive heart failure. Cleveland Clinic Journal of Medicine
2006; 73(Suppl 3): S19S23.
*37. Kalra PR, Anker SD & Coats AJ. Water and sodium regulation in chronic heart failure: the role of
natriuretic peptides and vasopressin. Cardiovascular Research 2001; 51: 495509.
38. Chin MH & Goldman L. Correlates of major complications or death in patients admitted to the hospital
with congestive heart failure. Archives of Internal Medicine 1996; 156: 18141820.
39. Klein L, OConnor CM, Leimberger JD et al. Lower serum sodium is associated with increased shortterm mortality in hospitalized patients with worsening heart failure: results from the Outcomes of
a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIMECHF) study. Circulation 2005; 111: 24542460.
40. Kumar S, Rubin S, Mather PJ & Whellan DJ. Hyponatremia and vasopressin antagonism in congestive
heart failure. Clinical Cardiology 2007; 30: 546551.
*41. Konstam MA, Gheorghiade M, Burnett Jr. JC et al. Effects of oral tolvaptan in patients hospitalized for
worsening heart failure: the EVEREST Outcome Trial. The Journal of the American Medical Association
2007; 297: 13191331.
42. Gines P, Berl T, Bernardi M et al. Hyponatremia in cirrhosis: from pathogenesis to treatment. Hepatology
1998; 28: 851864.
43. Morello JP, Salahpour A, Laperriere A et al. Pharmacological chaperones rescue cell-surface expression
and function of misfolded V2 vasopressin receptor mutants. The Journal of Clinical Investigation 2000;
105: 887895.
*44. Holmes CL, Landry DW & Granton JT. Science review: vasopressin and the cardiovascular system
part 2 clinical physiology. Critical Care (London, England) 2004; 8: 1523.
*45. Landry DW, Levin HR, Gallant EM et al. Vasopressin deficiency contributes to the vasodilation of septic
shock. Circulation 1997; 95: 11221125.
46. Sharshar T, Blanchard A, Paillard M et al. Circulating vasopressin levels in septic shock. Critical Care
Medicine 2003; 31: 17521758.
*47. Sharshar T, Carlier R, Blanchard A et al. Depletion of neurohypophyseal content of vasopressin in septic
shock. Critical Care Medicine 2002; 30: 497500.
*48. Vincent JL. Vasopressin in hypotensive and shock states. Critical Care Clinics 2006; 22: 187197.