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1.2. Article publié n°1

Cet article sera publié prochainement dans JASN. Il est actuellement sous presse.

Vasopressin and sodium excretion :
responses to selective non-peptide V2 and
a receptor antagonists

Julie PERUCCA (1, 2), Daniel G. BICHET (3), Pascale BARDOUX (1),
Nadine BOUBY (1, 2), and Lise BANKIR (1, 2)

(1) INSERM, Unité 872

Centre de Recherche des Cordeliers

15 rue de l'Ecole de Médecine

Paris F-75006, France
(2) UMRS 872, Université Paris Descartes

Centre de Recherche des Cordeliers

15 rue de l'Ecole de Médecine

Paris F-75006, France
(3) Service de Néphrologie, Hôpital du Sacré-Coeur

Département de Médecine, Université de Montréal

Montréal H4J 1C5, Québec, Canada

Short title : AVP receptors and Na excretion

Word Count (abstract) : 254 words

Word Count (text) : 4592 words

Corresponding author :


Tel : 33 (1) 47 35 34 15


Fax : 33 (1) 44 07 90 40

Centre de Recherche des Cordeliers

15 rue de l’Ecole de Médecine

75006 PARIS, France

E-mail :


The present study was designed to dissociate the respective roles of vasopressin V1a and V2 receptors on sodium excretion, using selective non-peptide receptor antagonists. Experiments were performed in conscious Wistar rats without any pretreatment. Urine was collected in metabolic cages for 6h after the injections in 4-6 rats/group, on two consecutive days: basal = vehicle(s) alone, and experimental = various doses of the following drugs: dDAVP (selective V2 agonist) (0.02-6 µg/kg); SR121463A (V2 antagonist) (0.01-10 mg/kg); AVP (0.1-50 µg/kg); AVP 15 µg/kg + SR49059 (V1a antagonist) 10 mg/kg; furosemide (0.1-30 mg/kg). Urine flow and sodium excretion rates of experimental day were compared to basal day in the same rats. V2 agonism decreased and V2 antagonism increased sodium excretion rate dose-dependently. However, for comparable increases in urine flow rate, the V2 antagonist induced a natriuresis 7-fold smaller than did furosemide. Vasopressin was antinatriuretic at 1 µg/kg. Above 5 µg/kg, vasopressin was natriuretic and this effect was abolished by the V1a antagonist. Combined V2 and V1a effects of endogenous vasopressin can be predicted to vary largely according to the respective levels of vasopressin in plasma, renal medulla (acting on interstitial cells) and urine (acting on V1a luminal receptors). In the usual range of regulation, antidiuretic effects of vasopressin may be associated with variable sodium retention. Although V2 antagonists are predominantly aquaretic, their possible effects on sodium excretion should not be neglected. These results are potentially important in view of the proposed use of selective or mixed vasopressin antagonists in several human disorders.


Collecting duct, urine flow rate, urine osmolality, potassium excretion, furosemide


The mechanisms by which arginine vasopressin (AVP) exerts its antidiuretic and its pressor effects are relatively well understood. On the one hand, AVP improves water conservation by increasing the permeability to water of the renal collecting duct (CD), an effect mediated by the V2 receptors (V2R) and permitted by the insertion in the luminal membrane of principal cells of preformed aquaporin 2 (AQP2) molecules. This allows more water to be reabsorbed when these ducts traverse the hyperosmotic medulla. On the other hand, AVP increases blood pressure by inducing a vasoconstriction through its binding to V1a receptors (V1aR) expressed in vascular smooth muscle cells. For these two different effects, in vivo studies are in good agreement with the expectations based on results obtained in vitro.
In contrast, the experiments intended to study the effects of AVP on sodium handling in vitro or in vivo provide results that are difficult to reconcile. In the isolated microperfused CD, V2R activation increases sodium transport [1], an effect which should reduce sodium excretion in vivo. However, in a number of studies, AVP infusion in animals and humans has been shown to induce an increase in sodium excretion [2-9]. It is usually assumed that AVP might contribute to some forms of hypertension by its vasoconstrictive effects, but an increase in sodium excretion, if it occurred in normal life, should more likely contribute to lower blood pressure.

In an attempt to resolve these conflicting results, we undertook a series of experiments in conscious undisturbed rats in order to obtain precise dose-response curves to AVP and to selective agonists and antagonists of V1a or V2 receptors. Each rat served as its own control, receiving on separate days either the vehicle or the drug(s), and the urine produced in the next 6 h was analyzed. This allowed us to evaluate separately the respective influence of V1a and V2 receptor activation on urine concentration and sodium excretion, and their interactions at different physiological and supraphysiological levels of AVP. These new results should be of special interest because non-peptide vasopressin receptor antagonists are now proposed in hyponatremia with heart failure and cirrhosis, two conditions with severe water and sodium retention [10, 11], in polycystic kidney disease [12], and possibly in some forms of salt-sensitive hypertension [13].


For most experiments, the changes induced by the different treatments are presented as experimental day/basal day ratios (Exp/Basal). One rat group always received the vehicle(s) alone on both day 1 and day 2 as an additional control for assessing possible day-to-day variations. Absolute values obtained for the basal day in the different experiments are shown in Table 1.
Dose-response curves of the V2R agonist and antagonist (Experiments A and B).

The V2R agonist dDAVP (1-desamino 8-D-arginine vasopressin) showed the expected antidiuretic action, inducing a marked decline in urine flow rate (V) and a rise in urine osmolality (Uosm), and the V2R antagonist the expected aquaretic action (Figure 1). In addition, both drugs also influenced solute excretion rates. Urea excretion rate fell with increasing V2 agonism, as already well-known. Sodium excretion rate declined and potassium excretion rate increased by about 30-50 % with the last four doses of dDAVP. Of note, the effects of dDAVP on V and Uosm reached a maximum for the lowest dose used here while the effects on solute excretion rate showed a progressive dose-dependent increase. In response to V2R blockade, sodium excretion rate rose dose-dependently from 0.1 mg/kg BW on. Note that water excretion already rose 3-fold with the previous dose (0.03 mg/kg BW), although not yet significant. With the largest dose of antagonist, sodium excretion rate was increased 6-fold when water excretion (i.e., V) was increased 25-fold (Figure 1). Potassium excretion rate rose with the V2R antagonist (with however large inter-individual variation preventing changes to reach statistical significance in most of the dose groups). However, the transtubular potassium gradient (TTKG), an index of the active secretion of potassium in the distal nephron, rose only with dDAVP (Figure 1).
Dose-response curve of AVP and effects of the V1aR antagonist on the response to AVP (Experiments C and D).

When given at a dose of 1 µg/kg, the natural hormone AVP increased Uosm and reduced V by about 35 % (Figure 2). The difference for Uosm did not reach significance because of large inter-individual variation in the response. A tendency for a dose-dependence of the antidiuretic response is visible when considering the control and the two lowest doses (thin line), but this effect disappears with higher doses (Figure 2). Sodium excretion rate was modestly reduced along with the antidiuretic effect at 1 µg/kg, but rose markedly with higher doses of AVP while urea excretion fell. The highest dose increased potassium excretion rate and TTKG by 40 % (Figure 2).
In order to evaluate whether the loss of the antidiuretic effect of AVP and the appearance of a natriuretic effect at higher doses are due to V1aR stimulation, additional experiments were carried out with co-administration of AVP 15 µg/kg BW and a selective V1aR antagonist. In preliminary experiments, the effects of the V1aR antagonist given alone at different doses (0.1, 1, and 10 mg/kg BW) were evaluated. Dose-dependent significant increases in Uosm were seen with all three doses, while significant decreases in V and sodium excretion occurred in some but not all rats with 10 mg/kg BW (results not shown). These changes suggest that the V1aR antagonism suppressed a modest diuretic and natriuretic influence of endogenous AVP. In Experiment D, two doses of AVP were tested. AVP at 3 µg/kg was antidiuretic, lowering V by 27 % (p < 0.01) and increasing Uosm by 33 % (p < 0.001), and induced no change in sodium excretion rate. With a 5-fold higher dose (15 µg/kg), the antidiuretic effect was completely lost and a marked natriuretic effect was observed, as depicted in Figure 3. The co-administration of the V1aR antagonist at 10 mg/kg BW with AVP 15 µg/kg BW largely abolished the natriuretic effect and restored an antidiuretic effect close to that observed with dDAVP (Figure 3) and with AVP 3 µg/kg.
Urinary AVP concentration in different experimental conditions (Experiment E)

Luminal effects of AVP in the renal CD have been described [14, 15]. This prompted us to evaluate urinary AVP concentration (UAVP) that should, at least approximately, vary in proportion to its concentration in the lumen of the CD. Twenty-four h dehydration increased UAVP about 20-fold. Administration of AVP 3 µg/kg BW increased UAVP to a similar extent, while dDAVP did not change it (Table 2). A 5-fold higher dose of AVP (AVP 15 µg/kg BW) increased UAVP close to five times more. This high luminal AVP concentration was associated with an increase in diuresis and natriuresis (as in Experiment D) and a decline in Uosm so that V was higher and Uosm lower than those observed in rats receiving a smaller dose of AVP or in water-deprived rats. Several previous studies have already observed this simultaneous increase in sodium excretion and urine flow rate after AVP infusions [4, 6, 8]. In the present experiments, it would have been difficult to evaluate the mean plasma AVP (PAVP) level reached during 6 h (duration of the urine collection). Measurements of the AVP excretion rate provide more integrated information over this period of time. Previous studies have shown that urinary AVP excretion rate is roughly proportional to the plasma level when osmolar excretion remains stable [16]. Thus, given the results presented in Table 2, it may be assumed that administration of 1-3 µg/kg BW AVP increased PAVP to levels similar to those seen after 24 h water deprivation, whereas the dose of 15 µg/kg BW increased PAVP to higher values, reached only during exogenous vasopressin infusion.
Effects of the V2R antagonist on sodium and water excretion over the whole 24 h (Experiment B)

Selective V2R antagonists are usually reported to increase markedly urine output without affecting solute excretion. Because a significant increase in sodium excretion rate was observed in the present experiments, it was interesting to determine if this change was short-lived or sustained. Collection of urine for the 18 h following the initial 6 h collection, and calculation of the antagonist's effects during these two aggregated periods showed that the aquaretic but not the natriuretic effect remained detectable over 24 h (Figure 4). Most probably, thirst and thus fluid intake increased during the whole duration of V2 receptor blockade and resulting aquaresis. After the initial loss of sodium, compensatory sodium retention occurred in the subsequent hours, bringing back sodium balance to zero. A similar compensation also occurred for potassium and urea. Note that, with the highest dose of the antagonist, sodium retention occurred during the 6-24 h period in spite of a persisting increase in aquaresis (Figure 4). It is conceivable that the natriuretic effect induced by the V2 antagonist could be sustained over the whole 24 h, along with the aquaresis, if the rats could compensate the initial salt loss (that probably stimulates their salt appetite) by having access to a source of salt independent of the food, as they do for water.
Comparison of V2R antagonist and furosemide (Experiment F)

Because the V2R antagonist induced an increase not only of water but also of sodium excretion, we performed an additional experiment designed to compare these effects to those of a classical diuretic in the same experimental setting. Figure 5 shows the results obtained in 56 rats studied in parallel and receiving various doses of either furosemide or V2R antagonist (results of 14 time-control rats receiving only the vehicles are not included). The changes in sodium or potassium excretion are plotted as a function of the simultaneous changes in water excretion (both changes expressed as experimental day/basal day). For both drugs, changes in sodium and in water excretion were always associated (both regression lines cross the 1 x 1 point), but the slopes of the regression lines for the sodium to water relationship differed markedly: 1.36 for furosemide vs. 0.19 for the V2R antagonist (p < 0.001). Potassium excretion rate rose with both drugs, however less intensely with the V2R antagonist (slope = 0.058) than with furosemide (slope = 0.099) although the difference did not reach significance (p = 0.097). Note that the potassium excretion rate decreased (Exp/Basal < 1) when the aquaretic effect was less than 3-fold above basal.


AVP is mostly known for its effect on water conservation. Its possible effects on sodium excretion in usual life are rarely addressed. This study evaluated the dose-dependent influence of AVP on sodium excretion in vivo in conditions as close as possible to normal life, and dissociated the respective roles of V1a and V2 receptors. The main findings are that V2R effects are strictly antinatriuretic while V1aR effects are natriuretic above a certain threshold of hormone level. For levels of the endogenous hormone prevailing in normal life, the well-known antidiuretic effects of AVP may be associated with antinatriuretic effects of variable intensity.
One of the originality of this study is that all experiments were conducted in conscious unrestrained rats without any pretreatment. There was no prior oral water load or intravenous infusion of iso- or hypotonic fluid, maneuvers that induce acute perturbations of the fluid balance. They underwent no anesthesia and surgery that are known to potently stimulate endogenous AVP secretion. The use of highly selective non-peptide V1aR or V2R antagonists with relatively long half-life and the building of dose-response curves allowed a better evaluation of AVP effects within the range occurring in usual physiological and pathophysiological situations. Finally, each rat was its own control, a favorable situation given the large inter-individual variability of urine flow rate and osmolality, and of the response to AVP [17]. The fact that food and fluid intakes were not measured represents a limitation in interpreting some of the results. dDAVP is known to have some affinity for V1b receptors, but this affinity is much lower in rats than in humans [18, 19]. The present experimental design was not intended to address the possible V1b receptor-mediated effects.

V2R effects

Experiments performed with the V2R agonist and antagonist confirm that V2R-mediated effects are not only antidiuretic but also antinatriuretic. This is consistent with observations made in isolated CD or in various mammalian or amphibian cell culture models. In these tissues, AVP, applied to the basolateral side, increases amiloride-sensitive sodium transport, an effect mediated by the epithelial sodium channel ENaC [1, 20]. V2R are also expressed in the thick ascending limb of Henle's loops, but previous studies suggest that the influence of AVP on sodium transport in this segment is negligible in normal conditions [21]. Micropucture experiments in rats receiving SR121463A confirmed that the aquaretic effect was located downstream of the early distal tubule and thus did not involve the thick ascending limb [22]. In humans, acute dDAVP administration also induced a 2-fold reduction in sodium excretion rate that was observed in healthy subjects and in subjects with nephrogenic diabetes insipidus due to mutations of AQP2, but not in those with mutations of the V2R [23]. In the isolated, erythrocyte-perfused kidney (a model in which a good oxygenation allows an efficient urine concentration) dDAVP induced a 5-fold decrease in the fractional excretion of sodium [24].
Noteworthy, in the present experiments, the antidiuretic effects of dDAVP reached their maximum for low doses while the effects on solute excretion rate rose progressively with increasing doses (Figure 1). This suggests a very sensitive influence of V2R activation on AQP2 and resulting water permeability in the CD, and a less sensitive action on ENaC and on the urea transporter UT-A1, in agreement with in vitro findings [23].

Most studies describing the effects of selective non-peptide V2R antagonists in experimental animals or humans concluded that these drugs behave as pure "aquaretics" with no effect on electrolyte excretion [10]. Why was the natriuretic effect of aquaretics not disclosed in earlier studies? As shown in Figure 4, the natriuretic effects observed here were not apparent in 24 h urine because compensatory sodium retention occurred after the initial loss. In two previous studies in conscious rats receiving daily injections of a V2R antagonist, no effect on 24 h sodium excretion were reported, but distinct and significant 3-fold increases in sodium excretion rate are visible (although not commented) in the first 4 or 6 h after daily dosing in figures of both papers (Figure 6 in [25] and Figure 2 in [26]). A significant 3 and 5-fold increase in sodium excretion with 10 and 30 but not with 1 and 3 mg/kg BW was also reported in the early studies of the first non-peptide V2R antagonist, OPC-31260 [27]. VPA 985, another V2R antagonist increased sodium excretion significantly in hyponatremic cirrhotic patients with ascitis [28, 29] but not in patients with the syndrome of inappropriate secretion of antidiuretic hormone [28]. SR121463A was also shown to increase sodium excretion chronically in cirrhotic rats [30]. In agreement with the natriuretic effect of V2R antagonists, it is interesting to note that the fractional excretion of sodium was 50 % higher in healthy subjects when they were studied during high oral hydration (likely reducing their endogenous AVP level) than when they received a low fluid intake [31], and that the excretion of a sodium load was 2-fold faster [32]. Even if aquaretics increase sodium excretion to some extent, it should be kept in mind that their natriuretic effect remains far smaller than their aquaretic effect, at variance with the action of classical diuretics, as shown here in Figure 5. For comparable increases in V, the V2R antagonist induced a natriuresis about 7-fold smaller than did furosemide. Thus, even if their effects on electrolyte excretion should not be neglected, V2R antagonists remain predominantly aquaretic.
Several mechanisms may contribute to the natriuretic effect of the V2R antagonist. The antagonist probably inhibits endogenous V2R-mediated stimulation of ENaC in the CD. An increase in endogenous AVP level has been well documented in response to the rise in plasma osmolality induced by the water loss following administration of aquaretics [33, 34]. Thus, the increased natriuresis could also be due to enhanced V1aR effects since these effects are natriuretic, as shown in the present study. However this does not seem to be the case because the coinjection of 10 mg/kg V1a antagonist with 10 mg/kg V2 antagonist resulted in changes in V, osmolality and sodium excretion very similar to those observed with the V2 antagonist alone (results not shown).
The effects of the V2R agonist and antagonist on potassium handling deserve some comments. Although both drugs have opposite effects on all other variables, they both increased potassium excretion rate. These puzzling results are easily explained by two well-known previous observations. First, stimulation of V2R is known to increase potassium secretion by the CD [35, 36]. This is confirmed here by the dose-dependent increase in TTKG seen in rats receiving dDAVP (Figure 1, bottom left). Second, large increases in V are known to increase potassium excretion by a flow-dependent mechanism [37]. As seen in Figure 1 (bottom right), this physical effect is not due to an increase in potassium secretion because there is no significant increase in TTKG. Of note, the influence of dDAVP on potassium secretion was also seen in healthy humans in some [38] but not all studies [23].

V1aR effects

In agreement with a number of previous studies in rats, dogs, sheep and humans, we observed that AVP increased sodium excretion [2-9]. The dose-response curve performed in the present study shows that this effect occurred only for high doses (15 and 50 µg/kg BW) that probably increased PAVP levels distinctly above those involved in water conservation, even after 24 h water deprivation, as judged here by the urinary AVP data (Table 2). With lower doses (0.1 and 1 µg/kg BW), likely corresponding to the range of usual osmotic stimuli, the antidiuretic effects of AVP were accompanied by a small but significant reduction in sodium excretion, as with dDAVP. Because the natriuretic effect of AVP 15 µg/kg BW was largely abolished by the co-administration of the selective V1aR antagonist, the present experiments clearly establish that the natriuresis induced by AVP is mostly due to V1aR-mediated actions.
Several possible renal and non-renal mechanisms may account for this natriuretic effect. V1a and V2 receptors are expressed in multiple sites throughout the body and throughout the kidney itself. Although the present experiments cannot disclose the mechanisms involved in the observed responses neither the organs/tissues/cell types contributing to these changes, we can briefly mention some possible pathways. (1) In several previous studies, the AVP-induced natriuresis was assumed to result from the volume expansion induced by fluid loads given orally and/or intravenously prior to and/or during AVP administration. The authors proposed that this expansion induced the release of another mediator inhibiting renal tubular sodium transport [4, 39]. However, the present experiments show that AVP increased sodium excretion even in the absence of any fluid load. (2) Prostaglandins are known to reduce sodium transport in the CD [40] and to increase medullary blood flow [41, 42], two effects which will each contribute in different ways to increase sodium excretion. Actually, prostaglandins have been shown to contribute to the AVP-induced natriuresis [9]. AVP stimulates prostaglandin production in interstitial medullary cells [40], which express V1aR [43] and in the cortical CD [40]. V1aR in the CD are mostly located in the luminal membrane [14, 15] and thus, urinary, rather than peripheral AVP could be involved here. Of note, AVP concentration is known to be higher in the CD lumen and in the medullary interstitium than in peripheral blood [17]. (3) Finally, the natriuretic effects of AVP could be due to pressure-natriuresis resulting from the vasopressor effects of the hormone, either within the whole circulation or selectively within the kidney vasculature.

Integration of V2R and V1aR effects

This functional in vivo dissection of the respective influence of V1aR and V2R on sodium handling by the kidney provides for the first time several clues for a better understanding of the integrated actions of AVP in vivo. Combined effects mediated by V2R and V1aR can be predicted to vary greatly according to the levels of plasma and urinary AVP reached. They will provide different sets of water and sodium responses. The changes in sodium excretion due to the algebraic sum of V2 and V1a effects over progressively increasing plasma levels of AVP are represented schematically in Figure 6. V2R antinatriuretic and V1aR natriuretic effects are depicted as sigmoid curves with different thresholds (B for V2R and C for V1aR effects), and different AVP levels inducing the maximum effects for each receptor type (B' and C', respectively).
In the range of very low plasma levels of AVP, only the V2 effects on water permeability of the CD are apparent and AVP will reduce V without any effect on sodium excretion rate (Figure 6, range A-B). Such purely antidiuretic action is visible in the study of Andersen et al [44] who gave subpicomolar doses of AVP to subjects undergoing water diuresis. Although these doses did not increase PAVP above the detection limit of the assay, V fell and Uosm rose significantly without any change in sodium excretion rate. Another example is found in subjects with central diabetes insipidus in whom dDAVP induced a marked decline in V independent of any change in sodium excretion rate (see Figure 4 in [23]). This action of AVP in the low range of plasma concentrations can induce the reabsorption of very large amounts of solute-free water [17].
When PAVP rises a little more (beyond B in Figure 6), V2R effects stimulate sodium reabsorption and should thus reduce sodium excretion rate in addition to reducing V, as seen in healthy humans infused with AVP at a dose of 25 µg/min/kg BW [44] or with dDAVP [23] and in the isolated rat kidney perfused with a medium containing erythrocytes and dDAVP [24]. This sodium retaining effect probably explains why, in normal subjects (with normal fluid and food intake) who provided multiple urine samples, sodium excretion rate declined in parallel with V in the samples in which Uosm exceeded 600 mosm/kg H2O, but was not altered in those under this limit in spite of wide differences in V (from 60 to 300 ml/h) [45]. This is in agreement with in vitro data showing that the effect of AVP of sodium transport in isolated perfused rat CD requires higher levels of peritubular AVP than the effect on water permeability [17].
With further increases in PAVP, V1aR-dependent natriuretic effects appear and increase progressively, but the net effect of AVP is still antinatriuretic (PAVP between C and M in Figure 6). Finally, with much higher levels of AVP, such as those induced by exogenous AVP infusion at a rate higher than 5 µg/kg, the V1a natriuretic effects overcome the V2 effects, leading to increased natriuresis (PAVP beyond point M in Figure 6). We want to underline that the dose of AVP inducing either negative or positive effects on sodium excretion was quite variable among rats and experiments between 1 and 5 µg/kg/min (results not shown). This variability may be due to different sensitivities of the two receptors and/or of subsequent signal transduction, and to differences in AVP concentrations in luminal fluid of the CD and/or in medullary tissue (determining V1a effects) with respect to peripheral AVP concentration (determining its V2 effects).
The secretion of AVP is not known to depend on sodium intake. As discussed previously, the V2R-dependent stimulation of sodium reabsorption likely serves the purpose of fluid conservation rather than that of regulating sodium excretion [20, 23]. A stronger sodium reabsorption in the AVP-sensitive distal nephron, which expresses both ENaC and AQP2, will drive more water out of the lumen and will thus increase the concentration of all other solutes but sodium. Thus, AVP will help conserve water at the expense of a less efficient sodium excretion. V1aR-dependent effects that increase sodium excretion may be viewed as a safeguard mechanism limiting the risk of too intense sodium retention. An imbalance between V1a and V2 receptor sensitivity or signal transduction may thus influence the ability of the kidney to excrete sodium and may, indirectly, be responsible for inappropriate sodium retention and resulting increase in blood pressure. Actually, it has long been known that highly selective peptide and non-peptide inhibitors of V1aR block exogenous AVP's pressor action, but that they have little effect on the basal levels of arterial blood pressure [46]. Thus, under normal conditions of cardiovascular homeostasis and appropriate extracellullar fluid volume, AVP and its V1aR appear to play only a minor role in maintaining normal cardiovascular function. In contrast, several observations link blood pressure and the antidiuretic V2R-dependent actions of AVP. Chronic dDAVP infusion in normal rats has been shown to increase blood pressure by about 10 mm Hg [47, 48]. Salt-sensitive hypertension-prone Sabra rats exhibit higher AVP mRNA, higher PAVP and 2-fold higher Uosm and lower V than their salt-resistant counterparts [49]. In humans, significant negative correlations were observed between 24 h V and blood pressure [13, 50].
In the usual range of PAVP the antidiuretic effect of AVP is possibly associated with an antinatriuretic effect of variable intensity depending on the level of urine concentration. This will delay the excretion of sodium and could thus result in some degree of sodium and volume retention, which could favor an increase in blood pressure. The natriuretic effects induced by the V1aR stimulation may counteract this tendency. Thus, instead of the usually assumed pressor effect, V1a activation within the physiological range may actually reduce the risk of V2R-induced sodium retention. Moreover, the balance between V1a and V2 receptor-mediated actions in cells possessing the two types of receptors (like the cortical CD) may be further amplified by a down-regulation of the V2R induced by a V1a mediated pathway [51].
That V1aR effects counteract V2R tubular effects could explain several puzzling observations. (1) In pathological models in which AVP levels are known to be elevated (NO-deprived hypertensive rats and diabetic rats), the chronic administration of a selective V1aR non-peptide antagonist worsened blood pressure and albuminuria [52] and did not prevent or even aggravated diabetes-related vascular damage [53]. (2) Several other studies suggest that V1a effects attenuate or counteract several direct and indirect V2R-dependent effects in normal rats and in rats with renal failure [54-57]. (3) In patients with chronic renal failure, the increasing urinary excretion of AVP per remaining nephron correlated positively and more significantly than for any other hormone with the fractional excretion of sodium, suggesting that luminal AVP contributed to ensure an appropriate natriuresis through V1aR-mediated luminal effects [58]. (4) Interestingly, mice with deletion of the V1aR exhibit a lower blood pressure due, not to a reduced vasoconstriction but to a lower extracellular fluid volume [59].
In summary, the present results provide a better knowledge of the respective V2 and V1a receptor-dependent effects of AVP on sodium excretion in rats. Whether a similar balance between V1aR and V2R-dependent effects occurs in humans remains to be determined. These results are potentially important in view of the proposed use of AVP antagonists in several human disorders [10-12]. In patients with hypervolemic hyponatremia due to heart failure or cirrhosis, the additional effect of V2 antagonism on sodium excretion may be beneficial and may decrease diuretic use. V2R antagonists may also be beneficial in some forms of salt-sensitive hypertension [13, 60]. However, more precise information is required regarding V1a and V2 effects in humans, in order to know if selective rather than mixed antagonists are more appropriate in each of these disorders.

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