Am J Physiol Renal Physiol 299: F917–F928, 2010.
First published September 8, 2010; doi:10.1152/ajprenal.00413.2010.
Review
Vasopressin V2 receptors, ENaC, and sodium reabsorption: a risk factor
for hypertension?
Lise Bankir,1,2,3 Daniel G. Bichet,4 and Nadine Bouby1,2,3
1
Institut National de la Santé et de la Recherche Médicale, UMRS 872, Paris, France; 2Université Pierre et Marie Curie,
Université Paris Descartes, Paris, France; and 4Service de Néphrologie, Hôpital du Sacré-Coeur, Université de Montréal,
Montréal, Quebec, Canada
3
Submitted 16 July 2010; accepted in final form 7 September 2010
water conservation; antidiuresis; sodium excretion; collecting duct
VASOPRESSIN WAS FIRST IDENTIFIED as a pressor hormone and later
recognized to be also a potent antidiuretic hormone. Today,
these early historical discoveries have been explained by the
identification of different receptor types. V1a receptors (V1aR),
abundantly expressed in vascular smooth muscle cells, and
signaling through calcium and phosphatidylinositol transducer
pathways, are responsible for the pressor effects. V2 receptors
(V2R), expressed mainly in principal cells of the renal collecting duct (CD), and signaling through cAMP, mediate the
antidiuretic actions of the hormone (113).
Vasopressin is elevated in some forms of human hypertension (26, 92, 111) and in animal models of hypertension (see
reviews in Refs. 91 and 108). This hormone has long been
suspected to play a role in blood pressure control because of its
vasoconstrictive effects, well demonstrated in vitro. However,
the studies trying to evaluate the contribution of V1aR-dependent effects in hypertension are inconclusive [either in favor of
(27, 35, 70) or against (59, 98)].
Excessive sodium reabsorption by the kidney is known to
participate in the pathogenesis of some forms of hypertension.
Address for reprint requests and other correspondence: N. Bouby, INSERM
U872, Equipe 2, Centre de Recherches des Cordeliers, 15 rue de l’Ecole de
Médecine, 75006 Paris, France (e-mail: [email protected]).
http://www.ajprenal.org
Among the genes responsible for monogenic forms of blood
pressure disorders identified to date, the majority either mediate renal sodium transport in the distal part of the nephron or
are involved in its regulation. Loss of function of the corresponding proteins leads to salt-wasting states with hypotension
(48), and gain of function to salt-retaining syndromes and
hypertension. Liddle’s syndrome, a severe and hereditary form
of early onset hypertension, is due to gain-of-function mutations in the genes coding for either the ␤- or ␥-subunits of the
epithelial sodium channel, ENaC (41, 93). Patients exhibiting
this syndrome have strongly increased ENaC activity (53, 82).
If a permanent activation of ENaC is sufficient to induce severe
hypertension, more subtle stimulation of ENaC by hormones or
mediators could participate in essential hypertension (77).
ENaC is expressed in several excretory organs including the
salivary glands, colon, and kidney. In the salivary glands and
colon, aldosterone is the main hormone regulating ENaC
abundance and activity. However, in the principal cells of the
CD, vasopressin regulates ENaC activity, in addition to aldosterone. Vasopressin and V2R agonists thus not only increase
water permeability of the CD but also stimulate sodium reabsorption (88, 90, 99). Accordingly, excessive vasopressindependent ENaC stimulation could potentially be a risk factor
for sodium retention and an increase in blood pressure. This
0363-6127/10 Copyright © 2010 the American Physiological Society
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Bankir L, Bichet DG, Bouby N. Vasopressin V2 receptors, ENaC, and sodium
reabsorption: a risk factor for hypertension? Am J Physiol Renal Physiol 299: F917–
F928, 2010. First published September 8, 2010; doi:10.1152/ajprenal.00413.2010.—
Excessive sodium reabsorption by the kidney has long been known to participate in
the pathogenesis of some forms of hypertension. In the kidney, the final control of
NaCl reabsorption takes place in the distal nephron through the amiloride-sensitive
epithelial sodium channel (ENaC). Liddle’s syndrome, an inherited form of hypertension due to gain-of-function mutations in the genes coding for ENaC subunits,
has demonstrated the key role of this channel in the sodium balance. Although
aldosterone is classically thought to be the main hormone regulating ENaC activity,
several studies in animal models and in humans highlight the important effect of
vasopressin on ENaC regulation and sodium transport. This review summarizes the
effect of vasopressin V2 receptor stimulation on ENaC activity and sodium
excretion in vivo. Moreover, we report the experimental and clinical data demonstrating the role of renal ENaC in water conservation at the expense of a reduced
ability to excrete sodium. Acute administration of the selective V2 receptor agonist
dDAVP not only increases urine osmolality and reduces urine flow rate but also
reduces sodium excretion in rats and humans. Chronic V2 receptor stimulation
increases blood pressure in rats, and a significant correlation was found between
blood pressure and urine concentration in healthy humans. This led us to discuss
how excessive vasopressin-dependent ENaC stimulation could be a risk factor for
sodium retention and resulting increase in blood pressure.
Review
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VASOPRESSIN, ENAC, AND BLOOD PRESSURE
Vasopressin, ENaC, and Urinary Sodium Excretion
In the rodent and human kidney, ENaC is most abundantly
expressed in the luminal membrane of connecting tubule cells
and in principal cells of the CD, mainly in its cortical and outer
medullary parts. The activity of this channel is considered to be
the limiting step for sodium reabsorption in these segments. In
the rodent and human kidney, the same cells express the V2R
on their basolateral membrane, and aquaporin-2 (AQP2), the
vasopressin-regulated aquaporin, on their luminal membrane
(Fig. 1A). This coexpression of V2R, AQP2, and ENaC is also
observed in the amphibian urinary bladder, often used as a
model of the mammalian CD. A number of other mediators
possess specific receptors and have been shown to act specifically on the same cells, including prostaglandins, dopamine,
bradykinin, endothelin, and ␣2-adrenergic agonists.
Different time course and mechanism of vasopressin and
aldosterone effects on ENaC. The major action of hormones
involved in ENaC regulation is an alteration in channel density
at the apical membrane (20). Most of the effect of aldosterone
on sodium membrane transporters occurs over hours and involves the synthesis of specific proteins. Acute aldosteronemediated ENaC activation by rapid, nongenomic mechanisms
has been observed in isolated rabbit principal duct cells (112)
and cortical CD cell lines (see review in Ref. 43), but the
relevance of these effects in vivo are unknown. On the contrary, the rapid effects (minutes) of vasopressin on its target
tissues are well established and can be reversed quickly because of the short biological half-life of the hormone. Sustained high vasopressin levels (for days) may also induce a
long-term regulation of ENaC as explained below.
In several cell and tissue models, the addition of vasopressin
or cAMP agonists induces a rapid increase in ENaC activity.
Fig. 1. Diagrams depicting the influence of AVP on ENaC in the collecting duct (CD) and the resulting potential consequence on urinary sodium excretion.
A: vasopressin, binding to basolateral V2 receptors (V2R), not only increases water permeability through aquaporin-2 (AQP2) but also stimulates sodium
reabsorption through the epithelial sodium channel (ENaC). Several other mediators, binding to their own receptors, induce a negative regulation of
V2R-mediated effects by accelerating the degradation of cAMP by phosphodiesterases. The effect of AVP on water permeability seems to be more intense and/or
to require a lower level of AVP than the effect on sodium transport (see text and Figs. 5 and 6). B: the amount of sodium reabsorbed under the influence of
vasopressin in the CD is quantitatively small compared with that reabsorbed in other parts of the nephron. However, it may result in a very significant change
in sodium excretion. If vasopressin stimulates sodium reabsorption by only one-tenth of its basal value (from 5.0 to 5.5%), this will reduce sodium excretion
by half (from 1.0 to 0.5%). Thus even a modest stimulation of ENaC activity by vasopressin could have a large impact on sodium excretion in vivo. C, cortex,
OS, outer stripe; IS, inner stripe; IM, inner medulla; PCT and DCT, proximal and distal convoluted tubule, respectively.
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sodium-retaining effect of vasopressin may probably be additive to that occurring upstream, on the Na-K-Cl cotransporter
(NKCC) in the thick ascending limb and on the Na-Cl cotransporter (NCC) in the distal convoluted tubule (31, 64, 65, 74).
The hormone levels required for these actions in the different
parts of the distal nephron may differ and may exhibit significant species differences (5, 55). Moreover, even if vasopressin
also influences NKCC and NCC activity, ENaC in the CD is
the last transporter where a final regulation of sodium excretion
can occur.
Vasopressin and aldosterone are released in response to
different stimuli and act in different ways. The action of
aldosterone is obviously linked to the need to conserve sodium.
The renin-angiotensin-aldosterone system (RAAS) is stimulated by a low-sodium diet, and aldosterone increases sodium
reabsorption in the distal nephron, as it does in the gut. In
contrast, vasopressin is not known to be secreted in response to
low sodium intake. It is secreted in response to increases in
plasma osmolality, and mostly to hypernatremia, usually indicating a water deficit. Thus, why is renal ENaC regulated and
activated by vasopressin? This review presents experimental
and clinical data demonstrating the role of renal ENaC in water
conservation at the expense of a reduced ability to excrete
sodium and explains how this vasopressin-dependent function
might contribute to salt-sensitive hypertension.
Review
VASOPRESSIN, ENAC, AND BLOOD PRESSURE
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Fig. 2. Long-term abundance of ENaC in the kidney depends primarily on the
vasopressin/fluid status rather than on the aldosterone/sodium intake.
A: chronic infusion of the V2 agonist dDAVP increased the abundance of mRNA
of the ␤- and ␥-subunits of ENaC in the kidney cortex (and outer medulla, not
shown) of Brattleboro rats with diabetes insipidus (DI) but had no effect in the
colon. No significant change in plasma aldosterone was observed in response
to the dDAVP infusion. Adapted from Ref. 68. **P ⬍ 0.001, ***P ⬍ 0.0005
vs. control. B: chronic dDAVP infusion in Brattleboro DI rats more than
doubled the abundance of the ␤- and ␥-protein subunits of ENaC in whole
kidney homogenates. Adapted from Ref. 30. *P ⬍ 0.05 vs. vehicle. C: in
salt-sensitive hypertensive Sabra (SBH) rats, chronic high salt intake (High
Na) induced no change in the abundance of any of the ENaC subunits in the
kidney cortex. Addition of extra water to their food (High Na ⫹ High Water)
significantly reduced the abundance of the ␤- and ␥-subunits of ENaC mRNA,
in the absence of a significant change in plasma aldosterone. Adapted from
Ref. 67. *P ⬍ 0.003.
sodium transport (19, 22, 44, 78, 102). As illustrated in Fig. 3,
B and C, the acute effect of vasopressin on sodium reabsorption in cortical CD from rats or mice is markedly potentiated by
chronic stimulation of mineralocorticoid receptors (19, 90).
The different mechanisms of action described above could
account for at least some of the synergism between aldosterone
and vasopressin. Moreover, it was shown in vitro that phosphorylation of Nedd4 –2 by SGK1 or PKA, triggered by
aldosterone or vasopressin, respectively, is a central point of
convergence for ENaC regulation by the two hormones (94,
95). In this review, we purposely focused mainly on the
influence of vasopressin on ENaC. However, because of the
synergism observed in vitro, vasopressin may have only a
modest effect on ENaC activity in vivo in situations in which
aldosterone levels are very low.
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The increase in sodium transport occurs mainly by increasing
channel density at the apical membrane through targeting and
fusion of ENaC-containing vesicles (21). The translocation of
ENaC to the apical membrane is facilitated by a vasopressininduced increase in expression of an ubiquitin-specific protease
(Usp10) that stabilizes sorting nexin 3 (18). On removal of a
V2R agonist, ENaC is endocytosed from the membrane surface
and reorganized into recycling vesicles, with a mechanism
similar to that described for AQP2 regulation (21). Aldosterone
also increases the abundance of ENaC at the apical membrane,
mainly by decreasing ENaC internalization through the synthesis of SGK1, a kinase that negatively modulates the action
of Nedd4 –2 (28, 36, 96). Recent data suggest that the regulation of sodium transport is probably not only accounted for by
changes in apical channel density but also by proteolytic
maturation of its subunits and changes in open probability of
the channel (19, 50, 83). The present models of proteolytic
regulation of ENaC comprise intracellular action of furin and
furin-like convertases at the Golgi and final activation by
membrane-bound proteases or soluble proteases present in the
extracellular milieu (49, 83). Furin and prostasin have been
identified as activators of ENaC by releasing inhibitory peptides from the ␣- and ␥-subunits that increase the channel open
probability. Additional proteases can process the ␥-subunit
(CAP2, kallikrein, elastase . . .). However, the identification of
tissue-specific proteases and the mechanisms of regulation
of these proteases remain to be elucidated (50). It has been
shown that aldosterone reciprocally regulates the expression of
prostasin and protease nexin-1, an endogenous prostasin inhibitor (66). Our recent findings suggested that prostasin could be
involved in the effect of vasopressin on ENaC (87), favoring
the increase in channel open probability observed by Bugaj et
al. (19) in the isolated murine CD.
In addition to the differing kinetics of the action of aldosterone and vasopressin, these two hormones also differ by their
long-term effects on the abundance of ENaC subunits. In most
aldosterone-sensitive tissues, aldosterone regulates the abundance of ENaC subunits at both the mRNA and the protein
level (4, 32, 79). Surprisingly, however,, in the kidney aldosterone does not increase the abundance of ␤- and ␥-subunits
(the 2 subunits in which gain-of-function mutations induce
Liddle’s syndrome) and has only a very modest effect on the
␣-subunit (4, 32, 58, 106). In contrast, administration of
vasopressin or the V2R agonist dDAVP in rats has been shown
to increase significantly the abundance of the mRNA coding
for these two subunits and of the corresponding proteins (Fig. 2,
A and B) (30, 34, 68, 87). Salt-sensitive Sabra (SBH) rats,
known to have higher vasopressin secretion and higher urine
osmolality than their salt-resistant counterparts (108, 109), also
have a higher abundance of ␤- and ␥-subunits in kidney cortex
(67). Moreover, changes in dietary salt intake in SBH rats did
not modify ENaC subunit abundance, while an increase in
water intake significantly lowered ENaC expression (67) (Fig.
2C) without affecting serum aldosterone level (67, 87). As
shown in Sprague-Dawley rats, the vasopressin-induced increase in ENaC subunit abundance allows more intense sodium
reabsorption in the CD upon acute stimulation by dDAVP (68)
(Fig. 3A).
Studies of in vitro perfused cortical CD or of cell lines
derived from amphibian bladder have shown that vasopressin
and aldosterone exert synergistic actions on ENaC-mediated
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F920
VASOPRESSIN, ENAC, AND BLOOD PRESSURE
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Fig. 3. Acute and chronic effects of vasopressin on ENaC activity and sodium
transport in the CD. Interaction with aldosterone. A: in cortical CDs isolated from
Brattleboro DI rats chronically infused with dDAVP, the transepithelial potential
difference (Vte), a direct measure of the net sodium flux across the tubule
epithelium, was 70% higher than in untreated DI rats. Acute addition of dDAVP
to the bath of the tubules increased Vte 1.5-fold in untreated rats and 2-fold in rats
pretreated with dDAVP. These acute effects were largely blunted by amiloride.
Adapted from Ref. 68. *P ⬍ 0.001 vs. no in vivo pretreatment. #P ⬍ 0.001 vs. no
acute treatment. B: aldosterone and AVP exert synergistic actions on net sodium
flux in the isolated, perfused rat CD. No net sodium flux from lumen to bath
(corresponding to net reabsorption in vivo) was observed in basal conditions but a
significant reabsorption of 30 ⫾ 18 pmol·min⫺1·mm⫺1 was found when rats had been
pretreated for 2 days with an aldosterone agonist (DOCA). Acute addition of AVP to
the bath increased net sodium reabsorption only modestly in control tubules but
induced a dramatic increase in tubules from rats pretreated with DOCA (up to 160 ⫾
14 pmol·min⫺1·mm⫺1). Adapted from Ref. 90. C: water and sodium restriction have
additive effects on ENaC activity in principal cells of mouse CD studied by the
patch-clamp technique. Mice were submitted for 1 wk to a sodium-free diet (⬍0.01%)
or a moderately high-sodium diet (2% Na). Some of the mice were water-restricted
(WR) for 18–24 h before CD isolation. Stressing animals with either water or salt
restriction (leading to increase in aldosterone or vasopressin level, respectively) increased ENaC activity. Moreover, water and sodium restriction had additive effects on
ENaC activity. Adapted from Ref. 19. #Significant increase compared with free access
to water. **Significant increase compared with high-sodium diet.
Effects of ENaC stimulation by vasopressin on renal sodium
excretion in vivo. Could the V2R-mediated effects on ENaC
and sodium reabsorption demonstrated in vitro contribute to
sodium retention in vivo? A theoretical calculation suggests
that it should, as explained in Fig. 1B. Recent observations in
vivo confirm that vasopressin significantly reduces sodium
excretion. The acute administration of the potent and selective
V2R agonist dDAVP not only increased urine osmolality and
reduced urine flow rate but also reduced sodium excretion in
rats (75) and humans (10) (Fig. 4). In patients with nephrogenic
diabetes insipidus (DI) due to loss-of-function mutations of
either AQP2 or V2R, dDAVP was unable to increase urine
osmolality. However, it reduced sodium excretion in those with
AQP2 mutations but not in those with nonfunctional V2Rs (10)
(Fig. 4). In the isolated erythrocyte-perfused rat kidney (allowing good oxygenation of the medulla and thus operation of the
concentrating mechanism), addition of dDAVP to the perfusate
increased urine osmolality and decreased both urine output and
fractional sodium excretion (52). This suggests that the effect
observed in vivo is due to an intrarenal mechanism. The effect
of dDAVP on sodium excretion is probably due, in large part,
to a V2R-dependent ENaC-mediated increase in sodium reabsorption in the CD because prior administration of amiloride
prevented the antinatriuretic but not the antidiuretic effect of
dDAVP in water diuretic healthy subjects (16).
Besides these recent demonstrations of a direct negative
V2R influence on natriuresis, several previous studies in normal rats and healthy humans showed that sodium was excreted
faster or with a higher fractional excretion rate when hydration
and thus urine flow were increased above normal, suggesting
that a low urine flow impaired sodium excretion to some extent
(2, 3, 12, 17, 23, 51, 63) (Table 1).
The effect of vasopressin on sodium reabsorption probably
requires a higher hormone concentration than the effect on
water reabsorption and is detectable only when urine osmolality reaches a certain threshold, as observed in vitro and in vivo
in rats and humans. In the isolated, perfused rat cortical CD, a
relatively high vasopressin concentration in the bath was
needed to significantly stimulate sodium flux while water flux
responded to much lower concentrations (Fig. 5A) (5, 90). In
normal rats, acute V2R antagonist administration increased
urine flow rate and sodium excretion dose dependently, but the
effect on sodium was of much lesser magnitude than that on
water and required a higher drug concentration (Fig. 5B) (75).
In healthy humans undergoing water diuresis, a very low
infusion rate of vasopressin reduced only the urine flow rate
whereas a larger infusion rate (still within physiological limits)
reduced both urine flow rate and sodium excretion (3).
In normal life (without any intervention), a fall in sodium
excretion or fractional excretion is observed only when urine
osmolality rises above a certain threshold (⬃500 – 600
mosmol/kgH2O) (Fig. 6) (12, 63), suggesting that in humans
also, a higher level of vasopressin is required to influence
sodium reabsorption than water reabsorption. Moreover, these
data reveal that a reduction in the efficiency of sodium excretion with increasing urine concentration occurs in about onethird of the urine samples obtained from healthy individuals in
their usual lives.
When vasopressin levels reach pharmacological levels or are
inappropriately high, a natriuretic action progressively compensates and even largely overcomes the antinatriuretic V2R-
Review
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VASOPRESSIN, ENAC, AND BLOOD PRESSURE
mediated effect. This vasopressin-induced natriuresis is mostly
due to V1aR-mediated actions (5, 47, 75). This explains why
vasopressin has often been described to be natriuretic. However, the level of vasopressin required to induce this V1aRdependent natriuretic effect is probably not often reached in
normal conditions (75).
It is important to stress that the intensity of the urine
concentration process resulting from vasopressin action on the
CD does not depend solely on the plasma level of vasopressin.
Several hormones and mediators are known to interfere with
the cellular effects of vasopressin by acting on phosphodiesterases that promote the degradation of cAMP in CD cells (Fig.
1A) (5). Thus, for a given vasopressin level, the intensity of
vasopressin’s effects on water and sodium reabsorption will
depend on the level of all other mediators acting simulta-
neously on the same cells. For example, it is well established
that prostaglandins counteract the antidiuretic action of vasopressin, whereas nonsteroidal anti-inflammatory drugs (NSAID)
potentiate it. Although less often mentioned, these mediators
also influence its antinatriuretic action in the same way. This
may, at least in part, explain the well-known sodium retention induced by NSAID in vivo (42) as also observed in the
isolated kidney in vitro (52). Activation of V1aR in the
apical membrane of CD principal cells and in interstitial
medullary cells is known to stimulate prostaglandin production and may thus attenuate V2R-mediated effects (5, 75).
Bradykinin has also been shown, both in isolated, perfused
rat CD and in transgenic mice, to attenuate vasopressin
action on water and sodium transport (99) and urine concentration (1).
Table 1. Influence of urine concentration on sodium absolute or fractional excretion in 1 rat study and 5 different
human studies
Reference
Species
17
2 Groups of rats
3
9 Healthy volunteers
2
12 Healthy volunteers
23
8 Healthy volunteers
12
12 Normal subjects
during normal life
63
66 Normal subjects
with free food and
fluid intake
Conditions
Measurement
Increase in water intake or infusion of dDAVP
for 5–7 days. Urine collected for 2 ⫻ 24-h
periods.
Acute water diuresis followed by infusion of
25 pg 䡠 min⫺1 䡠 kg⫺1 AVP for 2 h.
Same subjects submitted to high or low oral
hydration for 3 h on 2 different days, 3 wk
apart.
Acute hypertonic iv sodium load in the same
subjects submitted to either a high or a low
oral hydration, on 2 different days, 2 wk
apart.
Urine collected in 7–8 successive micturitions
per subject over a 24-h period. Comparison
of urine samples produced with the 20 %
highest and 20 % lowest urine flow rate.
Individual spot urine samples. Subjects were
divided a posteriori into 2 groups according
to their urine concentration (urinary-toplasma creatinine concentration ratio below
or above 140).
Low Urine
Concentration
1.19 ⫾ 0.12
0.73 ⫾ 0.03
61 ⫾ 9
26 ⫾ 3
2.14 ⫾ 0.28
1.42 ⫾ 0.16
Increase in Na excretion rate
after the NaCl load,
mmol/ h
10.9 ⫾ 2.6
5.8 ⫾ 2.7
Na excretion rate, mmol/h
10.1 ⫾ 1.1
3.2 ⫾ 0.4
FE Na, %
Na excretion rate/GFR,
␮mol/100 ml
FE Na, %
FE Na, %
0.9 ⫾ 0.3 (SD)
Values are means ⫾ SE, except where stated otherwise. FE Na, fractional sodium excretion; GFR, glomerular filtration rate.
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High Urine
Concentration
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Fig. 4. Vasopressin V2R agonism reduces sodium excretion in healthy humans as well as in
subjects with DI, provided they have functional V2R. Healthy subjects and patients with
diabetes insipidus (DI) received an acute
dDAVP administration (0.3 ␮g/kg body wt iv,
20-min infusion, grey rectangle) without any
pretreatment (no water load). In healthy subjects and in subjects with central DI, dDAVP
induced a marked fall in urine flow rate and in
sodium excretion rate with also a decrease in
urea excretion rate (not shown) and only modest
changes in potassium and creatinine excretion
rates. In subjects with nephrogenic DI due to
mutations in the AQP2 gene, urine flow rate fell
only modestly but sodium excretion rate fell
largely, to less than half of basal value. In
subjects with nephrogenic DI due to mutations
in the vasopressin V2R gene, dDAVP was
without effect on either urine flow rate or
sodium excretion rate. Adapted from Ref. 10.
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VASOPRESSIN, ENAC, AND BLOOD PRESSURE
Fig. 5. Vasopressin or V2R activation affects sodium excretion to a much
lesser extent than water excretion. A: dose-dependent influence of vasopressin
(AVP) on water permeability and net sodium flux of isolated, perfused rat
cortical CDs. The water permeability response was more sensitive to low
vasopressin levels than the sodium transport response. The maximum effect on
water permeability was reached for vasopressin concentrations that elicited
only a fraction of the maximum effect on sodium transport. Adapted from Ref.
44, and reproduced from Ref. 5. B: dose-dependent influence of dDAVP on
water and sodium excretion rates in conscious rats. On day 1 (basal), all rats
were injected intraperitoneally (ip) with vehicle only. On day 2 (experimental),
rats received an ip injection of dDAVP at one of the doses indicated in the
abscissa. BW, body wt. Urine was collected for the next 6 h. The V2R agonist
induced a marked decline in urine flow (top) and rise in urine osmolality (not
shown) already close to maximum with the smallest dose used. In contrast, the
reduction in sodium excretion rate was much more progressive (thin line) and
reached its maximum at 2 mg/kg. Adapted from Ref. 75. Paired t-test,
experimental vs. basal: *P ⬍ 0.05, **P ⬍ 0.01, ***P ⬍ 0.001.
Water Conservation at the Expense of Less Efficient
Salt Excretion
Sodium and water conservation or excretion are often associated. A highly effective control mechanism keeps sodium
concentration in plasma and extracellular fluids within narrow
limits. Vasopressin is a critical hormone in this homeostatic
regulation because the osmoreceptor neurons that influence
vasopressin release are most sensitive to extracellular sodium
concentration. An increase in plasma sodium concentration
will stimulate vasopressin release, which will in turn promote
water reabsorption, but also impair to some extent the ability of
the kidney to excrete sodium because of vasopressin’s effect on
ENaC. This regulatory pathway is counterbalanced by the
pressure-natriuresis mechanism. An increase in extracellular
fluid volume due to water and sodium retention induces an
increase in blood pressure, which, in turn, reduces isosmotic
sodium and water reabsorption in the kidney and allows readjustment of the extracellular fluid volume. Note that during
AJP-Renal Physiol • VOL
Fig. 6. Relationship between urine concentration and sodium excretion in
healthy subjects. A: 12 healthy volunteers collected their urine in multiple
fractions throughout a 24-h period (6 –9 samples/subject) during their usual
activities and while maintaining their usual fluid and food intake. The resulting
92 urine samples were divided into quintiles (Q) according to decreasing
hourly urine flow rates. In the first three quintiles, urine flow rate (V) declined
sharply without affecting sodium excretion rate (Na), suggesting an ability of
the kidney to regulate independently water and sodium excretion. For urine
flow rates below 80 ml/h and urine osmolality (Uosm) above 600 mosmol/
kgH2O (Q4 and Q5), sodium excretion rate declined in parallel with urine flow
rate (and sodium concentration in the urine remained unchanged, not shown).
Adapted from Ref. 12. *P ⬍ 0.05, **P ⬍ 0.01. B: fractional excretion of
sodium (FE Na) in spot urine samples obtained in 66 normal subjects. The
urine to plasma ratio of creatinine concentration (U/P creat) is taken as an
index of urine concentration. FE Na drops sharply with increasing urine
concentration only when the U/P creat ratio rises above ⬃140 (which corresponds
to ⬃600 mosmol/kgH2O; slope traced freehand). Adapted from Ref. 63.
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pressure-natriuresis, sodium and water excretions are increased
simultaneously and to the same extent (83). This pathway
brings sodium balance back to normal, at the expense of an
increase in blood pressure (40). All individuals are not equally
sensitive to salt excess. “Salt-sensitive” subjects exhibit larger
changes in blood pressure than “salt-resistant” subjects when
submitted to abrupt changes in salt intake (62, 105). Presumably, the osmoreceptor-vasopressin-thirst system may play a
role in the magnitude of salt-dependent changes in blood
pressure. The influence of aldosterone on ENaC activity in
both the colon and kidney suggests a role for this channel in
sodium conservation. However, the fact that, in the kidney,
ENaC is also regulated by vasopressin suggests that ENaC
may, in addition, play a role in water conservation.
As explained above, low levels of vasopressin probably act
only, or mostly, on water permeability, whereas with higher
levels of vasopressin, sodium reabsorption is also stimulated
and promotes additional water reabsorption. These differences
in vasopressin’s influence on water and sodium handling may
be due to the different distribution of AQP2 and ENaC along
Review
VASOPRESSIN, ENAC, AND BLOOD PRESSURE
accumulation in the medullary interstitium and favors overall
urine concentration (33), but results in less efficient excretion
of urea (like for sodium with the effect on ENaC), as illustrated
by the fall in fractional excretion of urea with declining urine
flow rate (8). Thus vasopressin’s actions on ENaC in the cortex
and outer medulla, on the one hand, and on UT-A1 in the inner
medulla, on the other, can be viewed as two independent and
additive means to improve water conservation (Fig. 7). The
less efficient urea excretion due to vasopressin action is compensated for by an increase in plasma urea level that allows
more urea to be filtered (8, 17). The less efficient sodium
excretion may secondarily induce pressure-natriuresis. This
concept is also supported by the finding of reduced blood
pressure dipping at night (hence a relative nocturnal hypertension) in subjects in whom sodium and water excretion during
the daytime is an abnormally low fraction of the total 24-h
excretion (6, 7, 37). When subjects are in a steady state, the
influence of urine flow rate on diuresis/natriuresis is not discernable in 24-h urine because the nighttime period compensates for changes occurring during the daytime period (or vice
versa in rats which are active mostly during the nighttime).
Water Conservation and Blood Pressure:
Pathophysiological Observations
The data reported above demonstrate that vasopressin’s
effects on ENaC result in better water conservation but less
efficient sodium excretion. This effect of vasopressin on so-
Fig. 7. Coordinated actions of vasopressin on AQP2, ENaC, and urea transporters collectively contribute to water conservation. A: in addition to increasing water
permeability of the whole CD (through AQP2), vasopressin exerts 2 additional effects along discrete portions of the CD. 1) In the cortex and upper outer medulla,
vasopressin stimulates ENaC-mediated sodium reabsorption. This allows an associated isosmotic reabsorption of water that will improve the ability to concentrate
urine in 2 ways: by increasing the concentration of all solutes (except sodium) in the CD lumen and by reducing the fluid flow rate entering deeper parts of the
medulla, thus reducing the washout of solutes. 2) In the deepest portion of the inner medullary CD, vasopressin increases the permeability to urea by acting on
the facilitated urea transporters UT-A1 and UT-A3 (33). This allows more urea to diffuse into the interstitium of the deep inner medulla and favors the
maintenance of a high concentration of urea in this region that helps extracting water from the water-permeable CDs in the whole inner and outer medulla. C,
cortex; OS, outer stripe; IS, inner stripe; IM, inner medulla. B: functional significance of vasopressin and aldosterone actions on ENaC in the kidney. Both
aldosterone and vasopressin influence ENaC and stimulate salt reabsorption in the CD, but the stimuli that induce the secretion of these two hormones are different
and the functional meaning of this effect and its consequences for the body’s homeostasis are different. The salt retention induced by vasopressin is not related
to the body’s need to conserve salt but to the need to conserve water, and is one of several actions of vasopressin contributing to improve urine concentration.
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the CD. Even modest increases in water permeability will favor
water reabsorption along the entire CD, including its medullary
portion lying in a hyperosmotic environment. However, in the
cortex, osmotic equilibration with the surrounding interstitium
likely occurs relatively early along the collecting system (connecting tubule and initial cortical CD). Thus, in later sections
of this collecting system within the cortex and outer medulla,
more water can be reabsorbed only if solutes are reabsorbed
(89). ENaC-mediated sodium reabsorption creates an osmotic
driving force that allows an additional (isosmotic) reabsorption
of water (89). Such isosmotic water and sodium reabsorption in
the cortex leaves sodium concentration in the lumen unchanged
(68) but concentrates all other solutes in the tubular fluid and
thus favors final urine concentration. As recalled earlier, vasopressin is not secreted in response to a sodium deficit. Thus its
ability to regulate ENaC activity and abundance is not likely
related to the need to conserve sodium. Rather, based on the
observations listed above, we propose that the action of vasopressin on ENaC is intended to conserve water by allowing
more water to be reabsorbed from the CD, thus enhancing the
concentration of other solutes and reducing the amount of
water required for their excretion. Water conservation is favored at the expense of less efficient sodium excretion.
Interestingly, a similar improvement in water conservation
occurs with urea (Fig. 7). Although the kidney needs to excrete
a relatively large daily load of urea (on a normal protein
intake), the vasopressin-dependent urea transporter UT-A1,
located in the terminal inner medullary CD (54), allows significant amounts of urea to be reabsorbed. This improves urea
F923
Review
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VASOPRESSIN, ENAC, AND BLOOD PRESSURE
observed in the syndrome of inappropriate secretion of antidiuretic hormone (80). Moreover, complex specific tissue interactions were shown between V2 and V1a effects, at the
epithelial and vascular levels (25). Acute regional vasodilator
and hypotensive effects of dDAVP mediated by endothelial
V2R and NO production have been reported in healthy humans
and animals (15, 45, 97, 101, 103).
In summary, several local or peripheral compensatory mechanisms may offset the vasopressin/ENaC-mediated effect on
blood pressure. The resulting increase in blood pressure is
likely small and does not reach pathological values. However,
in the presence of other aggravating factors, vasopressin could
contribute to sodium retention and become one of the multideterminants of salt-dependent hypertension.
Vasopressin and blood pressure: effects of gender, ethnic
background, and geographic location in humans. Men are
known to be more susceptible to hypertension than women.
Studies have shown that men have higher vasopressin levels
than women and that the antidiuretic effect of a given dose of
vasopressin is stronger in men than in women (76). This could
contribute to their greater susceptibility to hypertension.
It is conceivable that a higher urine concentration, especially
during the daytime, may induce a temporary sodium and water
retention that favors a rise in blood pressure. In young normotensive Americans (age range 18 – 40 yr), a significant positive
correlation was observed between systolic or pulse pressure
and mean 24-h urine concentration in men but not in women
(11) (Fig. 8). Over the whole range of urine concentration,
systolic and pulse pressure were significantly higher in African
Americans (AA) than in European Americans (EA) (Fig. 8).
Now, AAs show a greater susceptibility to develop hypertension than EAs. Some studies suggest that they have higher
vasopressin levels and/or higher urine osmolality (11, 24) and
are less able to dilute urine after a water load (104). AAs also
have a less active RAAS. This has been proposed to be part of
corrective mechanisms involved in maintaining sodium balance in response to sodium retention (85). As proposed earlier,
there may be a balance between the RAAS and the osmore-
Table 2. Influence of chronic dDAVP infusion on blood pressure in conscious rats
Wistar Rats with 2 Kidneys (13)
Systolic blood pressure measured by tail-cuff method, mmHg
Rats with no pretreatment
Rats with ACEI pretreatment
Basal
132 ⫾ 3
106 ⫾ 2
dDAVP (1 wk)
132 ⫾ 4
112 ⫾ 2*
Recovery
124 ⫾ 3†
106 ⫾ 2†
Basal
dDAVP (2 wk)
125 ⫾ 3
125 ⫾ 3
131 ⫾ 7
142 ⫾ 4*
dDAVP (4 wk)
⫹DOCA-salt
189 ⫾ 8
207 ⫾ 3*
dDAVP (2 wks)
117 ⫾ 2
Recovery
108 ⫾ 3
Uninephrectomized Sprague-Dawley Rats (34)
Systolic blood pressure measured by tail-cuff method, mmHg
Control rats (no dDAVP)
Experimental rats (dDAVP)
Uninephrectomized Sprague-Dawley Rats with Continuous iv Infusion of Isotonic saline (10 ␮l/min) (60)
Mean arterial pressure measured continuously over 24-h by intra-arterial catheter, mmHg
Basal
107 ⫾ 2
Values are means ⫾ SE In all 3 studies, dDAVP was infused continuously at the following doses: top and middle, 0.6 ␮g 䡠 day⫺1 䡠 kg body wt⫺1 ip; bottom,
2 ng 䡠 min⫺1 䡠 kg body wt⫺1 iv. Top: the ACE inhibitor was perindopril (10 mg 䡠 kg⫺1 䡠 day⫺1) mixed with powdered food and started 10 days before the experiment.
experiment. Middle: dDAVP was given only in rats in the experimental group, but both groups were subjected to the DOCA-salt treatment. Comparison with
the previous period: *P ⬍ 0.05, †P ⬍ 0.01.
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dium reabsorption could influence blood pressure in the long
term, as described below.
Effects of V2 agonist or antagonist on blood pressure.
Several observations in rats suggest that long-term V2R agonist stimulation in vivo induces a rise in blood pressure. In
Brattleboro rats with central diabetes insipidus, DOCA-salt
administration induces an increase in blood pressure only if
AVP or the selective V2 agonist dDAVP is infused, and the
degree of hypertension is proportional to the dose of dDAVP
(14, 86). In Brattleboro rats, blood pressure rises less after
induction of “one kidney-one clip” hypertension than in control
Long-Evans rats, a difference abolished by chronic dDAVP
infusion (107). In normal Sprague-Dawley rats, long-term
infusion of dDAVP has been shown to raise blood pressure by
⬃10 mmHg without significant change in volemia (34, 60, 61)
and to aggravate DOCA-salt hypertension (34) (Table 2). This
blood pressure effect is favored by unilateral nephrectomy or
saline infusion and is potentiated by inhibition of the reninangiotensin system (13) (Table 2). In rats with adriamycininduced nephropathy, with DOCA-salt hypertension, or a combination of both, treatment with a selective, nonpeptide V2R
antagonist for 10 wk significantly reduced or entirely prevented
the rise in blood pressure usually seen in these models (70 –72).
Complexity of vasopressin action on blood pressure. The
effects of V1a on vascular smooth muscle are thought to raise
blood pressure. However, in the hypertensive rat model induced by nitric oxide (NO) inhibition, in which vasopressin
levels are known to be elevated, chronic treatment with a
selective V1aR antagonist unexpectedly increased blood pressure further (56). This antagonist probably inhibited the natriuretic V1aR-mediated effect and unmasked the antinatriuretic
V2R-mediated effect (75). This study suggests that, when
endogenous vasopressin secretion is elevated in some pathological situations, V1aR-mediated effects may counteract the
V2R hypertensive effects. Other mechanisms favoring natriuresis could also counterbalance the antinatriuretic V2 effects,
including suppression of plasma renin activity or aldosterone
secretion and increase in plasma atrial natriuretic peptide, as
Review
VASOPRESSIN, ENAC, AND BLOOD PRESSURE
ceptor-vasopressin-thirst system, with a stronger influence of
the latter in AAs than in EAs (11, 57).
In a large worldwide association study, significant associations were found between blood pressure and ecological variables such as latitude, temperature, and rainfall, explaining
worldwide variation in heat adaptation, as defined by functional alleles in five genes involved in blood pressure regulation (one of the alleles coding for ␤-ENaC) (110). This suggests an association during evolution between better water
conservation (an essential function in heat adaptation) and
higher blood pressure. Nephrolithiasis has been repeatedly
found to be associated with high blood pressure (69), suggesting that a common factor such as high urine concentration
favors the simultaneous occurrence of the two diseases. Smoking is known to be an aggravating risk factor for high blood
pressure and cardiovascular events. A rise in vasopressin levels
may be partially responsible for some of these adverse effects
because nicotine is a potent stimulator of vasopressin release
(46, 84).
Taken together, these observations regarding gender and
ethnic differences, and associations of high blood pressure with
AJP-Renal Physiol • VOL
climate, urolithiasis, or smoking, support the notion that hypertension is favored by high urine concentration and hence by
the balance between the antidiuretic/antinatriuretic action of
vasopressin and the counteracting effects of other humoral
factors acting on the CD.
Water conservation and blood pressure: evolutionary
aspects. In ancestral times, salt intake was low and it was
appropriate to conserve simultaneously salt and water. Reabsorbing sodium to conserve water had no adverse consequences. The present Western-type diet provides significantly
more sodium and less potassium than prehistoric food. The
typical balance between the RAAS and the thirst-vasopressin
system is still the same although water conservation is no
longer crucial. To date, conserving water and sodium simultaneously is less necessary, at least in Western countries. Moreover, natural selection during human evolution may have
favored the survival and expansion of subjects with a good
ability to conserve water, even if the price to pay was a poor,
or rather a delayed capacity to excrete sodium. Poor water
conservation increases the risk of dehydration and death within
a few days, whereas a poor sodium excretory capacity has only
long-term adverse effects by raising blood pressure and favoring cardiovascular diseases later in life, usually after the age of
reproduction, thus without influence on natural selection.
Moreover, changes in diet from the hunter-gatherer civilization to present living conditions probably makes aldosterone
and the renin-angiotensin system less important than it was in
primitive humans. In this context, and without enough time for
significant evolutionary changes, we hypothesize that the osmoreceptor-vasopressin-thirst axis has reached a greater influence in the overall regulation of water and salt homeostasis.
Conclusion
In conclusion, the studies reviewed above suggest that the
effects of vasopressin on renal ENaC abundance and activity
are part of a mechanism that contributes to water conservation
at the expense of less efficient sodium excretion. Vasopressin,
which is elevated in some forms of hypertension, could contribute to a rise in blood pressure, not by its V1aR-mediated
effects (that actually facilitate sodium excretion) but by its
V2R-mediated effects. High salt intake would probably not
affect blood pressure in salt-sensitive individuals did the kidney dispose of larger amounts of water to excrete the salt. In
Western countries, with a long life expectancy, relatively high
levels of salt intake and less risks of dehydration, it might be
appropriate to reduce, even if only modestly, the spontaneous
tendency to conserve water (i.e., to concentrate urine) that
occurs at certain times of the day, to accelerate sodium excretion after each intake. It is, however, difficult to increase fluid
intake deliberately above what natural thirst commands. Even
subjects with recurrent, painful nephrolithiasis often do not
succeed in raising their urine output above the recommended
amount of 2 liters/day (9, 73). In this context, it will be
interesting to see whether newly designed “aquaretics” (selective vasopressin V2R antagonists) (29, 38) are able to reduce
salt-sensitive hypertension with fewer side effects than classic
diuretics. Interestingly, V2R antagonists have been shown to
increase sodium excretion in cirrhotic patients (39). It is
conceivable that hyponatremic heart failure or cirrhotic patients, resistant to classic diuretics, may increase their sodium
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Fig. 8. Blood pressure and urine concentration in humans. Relationship
between pulse pressure (PP) and urine flow rate or urine concentration in
young (age range 18 – 40 yr) normotensive male European Americans (EA;
open circles) and African Americans (AA; closed circles). Similar results were
observed for systolic blood pressure, but not for diastolic blood pressure (not
shown). Separate regression lines are shown for AA (thick line) and EA (dotted
line), but the correlation coefficient (r) and statistical significance concern all
men together (n ⫽ 86). The slope of the relationship is similar in AA and EA,
but AA exhibit a 5 mmHg higher PP than EA (P ⬍ 0.002). This relationship
remained significant after adjustment for age, body mass index (BMI), and
24-h sodium and potassium excretion. In women (n ⫽ 50), who concentrate
urine less than men (76), there was no significant relationship between blood
pressure and urine volume or concentration (not shown). eUosm: estimated
urine osmolality. Adapted from Ref. 11.
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F926
VASOPRESSIN, ENAC, AND BLOOD PRESSURE
excretion if the diuretic is associated with a small dose of a
vasopressin receptor antagonist, promoting a moderate increase in urine flow rate. Finally, it will be interesting to see
whether tolvaptan treatment in patients with polycystic kidney
disease (100) will prevent or retard the development of hypertension, in addition to reducing cyst expansion.
ACKNOWLEDGMENTS
The authors thank Tilman B. Drueke (INSERM ERI-12, Amiens, France)
and Dominique Guerrot (INSERM U702, Paris, France) for valuable discussions and editing of the manuscript.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
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