Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Other
    • ASN Publications
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • ASN Publications
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
BASIC RESEARCH
You have accessRestricted Access

Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists

Julie Perucca, Daniel G. Bichet, Pascale Bardoux, Nadine Bouby and Lise Bankir
JASN September 2008, 19 (9) 1721-1731; DOI: https://doi.org/10.1681/ASN.2008010021
Julie Perucca
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel G. Bichet
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pascale Bardoux
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nadine Bouby
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lise Bankir
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Abstract

The mechanisms by which arginine vasopressin (AVP) exerts its antidiuretic and pressor effects, via activation of V2 and V1a receptors, respectively, are relatively well understood, but the possible associated effects on sodium handling are a matter of controversy. In this study, normal conscious Wistar rats were acutely administered various doses of AVP, dDAVP (V2 agonist), furosemide, or the following selective non-peptide receptor antagonists SR121463A (V2 antagonist) or SR49059 (V1a antagonist). Urine flow and sodium excretion rates in the next 6 h were compared with basal values obtained on the previous day, after vehicle treatment, using each rat as its own control. The rate of sodium excretion decreased with V2 agonism and increased with V2 antagonism in a dose-dependent manner. However, for comparable increases in urine flow rate, the V2 antagonist induced a natriuresis 7-fold smaller than did furosemide. Vasopressin reduced sodium excretion at 1 μg/kg but increased it at doses >5 μg/kg, an effect that 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. In view of their proposed use in several human disorders, the respective influence of selective (V2) or mixed (V1a/V2) receptor antagonists on sodium handling in humans needs reevaluation.

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 (BP) 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 that 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 BP.

In an attempt to resolve these conflicting results, we undertook a series of experiments in conscious undisturbed rats to obtain precise dose-response curves to AVP and to selective agonists and antagonists of V1aR or V2R. 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 V1aR and V2R activation on urine concentration and sodium excretion and their interactions at different physiologic and supraphysiologic levels of AVP. These new results should be of special interest because nonpeptide 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

RESULTS

For most experiments, the changes induced by the various 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 various experiments are shown in Table 1.

View this table:
  • View inline
  • View popup
Table 1.

Basal values observed on day 1 in groups of rats used in the various experiments

Dose-Response Curves of the V2R Agonist and Antagonist (Experiments A and B)

The V2R agonist 1-desamino 8-d-arginine vasopressin (dDAVP) showed the expected antidiuretic action, inducing a marked decline in urine flow rate (V) and a rise in urine osmolality (Uosm). The V2R antagonist showed 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 widely known. Sodium excretion rate declined, and potassium excretion rate increased by approximately 30 to 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, whereas 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 body wt (BW) onward. Note that water excretion already rose three-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 six-fold when water excretion (i.e., V) was increased 25-fold (Figure 1). Potassium excretion rate rose with the V2R antagonist (with, however, large interindividual 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).

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Dose-dependent effects of the V2R agonist (dDAVP) and the V2R antagonist (SR121463A) on fluid and solute excretion rates (Experiments A and B, n = 4 to 6 rats per dose). Results are expressed as Exp/Basal. Thin lines illustrate the dose-dependent effects. Paired t test, experimental versus basal: *P < 0.05; **P < 0.01; ***P < 0.001.

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 approximately 35% (Figure 2). The difference for Uosm did not reach significance because of large interindividual 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, whereas urea excretion fell. The highest dose increased potassium excretion rate and TTKG by 40% (Figure 2).

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

Dose-dependent effects of AVP on fluid and solute excretion rates (Experiment C, n = 4 to 6 rats per dose). Results are expressed as Exp/Basal. Thin lines illustrate the dose-dependent effects. Paired t test, experimental versus basal: *P < 0.05; **P < 0.01; ***P < 0.001.

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, we conducted additional experiments 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 various doses (0.1, 1, and 10 mg/kg BW) were evaluated. Dose-dependent significant increases in Uosm were seen with all three doses, whereas significant decreases in V and sodium excretion occurred in some but not all rats with 10 mg/kg BW (data 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 five-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.

Figure 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3.

Effects of AVP (AVP-15,15 μg/kg BW) on urine flow rate and osmolality and on sodium excretion rate without or with the co-administration of the V1aR antagonist (Experiment D, n = 4 to 6 rats per dose). The effects of the antagonist alone and of dDAVP are also shown. Results of the experimental day are expressed as percentage of values observed during the basal day in the same rats. Paired t test, experimental versus basal: *P < 0.05; **P < 0.01; ***P < 0.001.

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-hour dehydration increased UAVP approximately 20-fold. Administration of AVP 3 μg/kg BW increased UAVP to a similar extent, whereas dDAVP did not change it (Table 2). A five-fold higher dose of 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 such that V was higher and Uosm was lower than those observed in rats receiving a smaller dose of AVP or in water-deprived rats. Several previous studies already observed this simultaneous increase in sodium excretion and urine flow rate after AVP infusions.4,6,8 In these 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 during this period. Previous studies showed 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 to 3 μg/kg BW AVP increased PAVP to levels similar to those seen after 24 h of water deprivation, whereas the dose of 15 μg/kg BW increased PAVP to higher values, reached only during exogenous vasopressin infusion.

View this table:
  • View inline
  • View popup
Table 2.

Urinary AVP and other urinary characteristics in Experiment E

Effects of the V2R Antagonist on Sodium and Water Excretion during 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 these experiments, it was interesting to determine whether this change was short-lived or sustained. Collection of urine for the 18 h after 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 V2R 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- to 24-h period despite 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.

Figure 4.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 4.

Dose-dependent effects of the V2R antagonist on urine flow rate and osmolality and on sodium excretion rate in the first 6 h after drug administration, in the subsequent 18 h (6 to 24 h), and in the whole 24 h during the experimental day (basal day not shown; Experiment B, n = 4 to 6 rats per dose). Paired t test, experimental versus basal: *P < 0.05; **P < 0.01; ***P < 0.001.

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 with 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 Exp/Basal). For both drugs, changes in sodium and in water excretion were always associated (both regression lines cross the 1 × 1 point), but the slopes of the regression lines for the sodium-to-water relationship differed markedly: 1.36 for furosemide versus 0.19 for the V2R antagonist (P < 0.001). Potassium excretion rate rose with both drugs but 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 three-fold above basal.

Figure 5.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 5.

Influence of the V2R antagonist (○ and dotted line, n = 27) or furosemide (• and solid line, n = 29) at various doses (0.1, 0.3, 1.0, 10.0, and 30.0 mg/kg BW for furosemide and 0.1, 0.3, 1.0, and 10.0 mg/kg BW for the V2R antagonist) on sodium (top) and potassium (bottom) excretion rates as a function of the simultaneous changes in fluid excretion rate (urine flow rate). Results are expressed as Exp/Basal for each rat, and regression lines are shown. For both the abscissa and the ordinate, a value of 1 means no change. The equations of the regression lines and corresponding correlation coefficients are as follows. For sodium with furosemide y = 1.360x − 0.54; r = 0.88, P < 0.001. For sodium with the V2R antagonist y = 0.189x + 0.82; r = 0.82, P < 0.001. For potassium with furosemide y = 0.099x + 0.88; r = 0.45, P < 0.05. For potassium with the V2R antagonist y = 0.058x + 0.86; r = 0.77, P < 0.001.

DISCUSSION

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 V1aR and V2R. The main findings are that V2R effects are strictly antinatriuretic, whereas V1aR effects are natriuretic above a certain threshold of hormone level. For levels of the endogenous hormone prevailing in normal life, the widely known antidiuretic effects of AVP may be associated with antinatriuretic effects of variable intensity.

One of the advantages of this study is that all experiments were conducted in conscious, unrestrained rats without any pretreatment. There was no previous oral water load or intravenous infusion of iso- or hypotonic fluid, maneuvers that induce acute perturbations of the fluid balance. Rats underwent no anesthesia and surgery that are known to stimulate potently endogenous AVP secretion. The use of highly selective nonpeptide 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 physiologic and pathophysiologic situations. Finally, each rat was its own control, a favorable situation given the large interindividual variability of urine flow rate and osmolality and of the response to AVP.17 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 This 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 loop, but previous studies suggested that the influence of AVP on sodium transport in this segment is negligible in normal conditions.21 Micropuncture 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 two-fold reduction in sodium excretion rate that was observed in healthy individuals and in individuals with nephrogenic diabetes insipidus as a result of 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 five-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, whereas 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 nonpeptide 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 previous 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 effects on 24-h sodium excretion were reported, but distinct and significant three-fold increases in sodium excretion rate are visible (although not commented on) in the first 4 or 6 h after daily dosing in figures of both articles (Figure 6 in reference25 and Figure 2 in reference26). A significant three- and five-fold increase in sodium excretion with 10 and 30 but not with 1 and 3 mg/kg BW was also reported in the previous studies of the first nonpeptide V2R antagonist, OPC-31260.27 VPA 985, another V2R antagonist, increased sodium excretion significantly in patients with hyponatremia and cirrhosis ascites28,29 but not in patients with the syndrome of inappropriate secretion of antidiuretic hormone.28 SR121463A was also shown to increase sodium excretion chronically in rats with cirrhosis.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 individuals when they were studied during high oral hydration (likely reducing their endogenous AVP level) than when they received a low fluid intake31 and that the excretion of a sodium load was two-fold faster.32

Figure 6.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 6.

Schematic representation of the dose-dependent effects of AVP on sodium excretion rate and dissociation of these effects into V2R- and V1aR-mediated responses. The abscissa represents increasing levels of plasma AVP from left (undetectable) to right. A corresponds to the lowest values of AVP which reduce urine flow rate but not sodium excretion rate. V2R antinatriuretic and V1aR natriuretic effects are depicted as sigmoid curves with different thresholds (B for V2R and C for V1aR effects). B′ and C′ correspond to the maximum effects depending on each receptor type, respectively. M corresponds to the value of plasma AVP for which the antinatriuretic and the natriuretic effects compensate each other. This value probably fluctuates according to a number of factors influencing the intensity of the responses mediated by each of the two receptor types.

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 approximately seven-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. First, the antagonist probably inhibits endogenous V2R-mediated stimulation of ENaC in the CD. Second, an increase in endogenous AVP level has been well documented in response to the rise in plasma osmolality induced by the water loss after administration of aquaretics.33,34 Thus, the increased natriuresis could also be due to enhanced V1aR effects because these effects are natriuretic, as shown in this study; however this does not seem to be the case because the co-injection 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 (data 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 widely 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 some38 but not all studies.23

V1aR Effects

In agreement with a number of previous studies of rats, dogs, sheep, and humans, we observed that AVP increased sodium excretion.2–9 The dose-response curve performed in this 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 of 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, these experiments clearly establish that the natriuresis induced by AVP is mostly due to V1aR-mediated actions.

Several possible renal and nonrenal mechanisms may account for this natriuretic effect. V1aR and V2R are expressed in multiple sites throughout the body and throughout the kidney itself. Although these experiments cannot disclose the mechanisms involved in the observed responses or 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 before and/or during AVP administration. The authors proposed that this expansion induced the release of another mediator inhibiting renal tubular sodium transport4,39; however, our 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 CD40 and to increase medullary blood flow,41,42 two effects that each will contribute in different ways to increased 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 membrane14,15; therefore, 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. They will provide different sets of water and sodium responses. The changes in sodium excretion as a result of 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 to B). Such purely antidiuretic action is visible in the study of Andersen et al.,44 who gave subpicomolar doses of AVP to individuals 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 individuals 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 reference23). 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 who received an infusion of AVP at a dose of 25 μg/min per kg BW44 or with dDAVP23 and in the isolated rat kidney perfused with a medium containing erythrocytes and dDAVP.24 This sodium-retaining effect probably explains why, in normal individuals (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 despite 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 BW (data 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 V2 effects).

The secretion of AVP is not known to depend on sodium intake. As discussed previously,20,23 the V2R-dependent stimulation of sodium reabsorption likely serves the purpose of fluid conservation rather than that of regulating sodium excretion. 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 for too intense sodium retention. An imbalance between V1aR and V2R 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 BP. Actually, it has long been known that highly selective peptide and nonpeptide inhibitors of V1aR block exogenous AVP's pressor action but that they have little effect on the basal levels of arterial BP.46 Thus, under normal conditions of cardiovascular homeostasis and appropriate extracellular fluid volume, AVP and its V1aR seem to play only a minor role in maintaining normal cardiovascular function. In contrast, several observations link BP and the antidiuretic V2R-dependent actions of AVP. Long-term dDAVP infusion in normal rats has been shown to increase BP by approximately 10 mmHg.47,48 Salt-sensitive hypertension-prone Sabra rats exhibit higher AVP mRNA, higher PAVP, and twofold higher Uosm and lower V than their salt-resistant counterparts.49 In humans, significant negative correlations were observed between 24-h V and BP.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 BP. The natriuretic effects induced by the V1aR stimulation may counteract this tendency. Thus, instead of the usually assumed pressor effect, V1a activation within the physiologic range may actually reduce the risk for V2R-induced sodium retention. Moreover, the balance between V1aR- and V2R-mediated actions in cells possessing the two types of receptors (e.g., cortical CD) may be further amplified by a downregulation of the V2R induced by a V1a-mediated pathway.51

That V1aR effects counteract V2R tubular effects could explain several puzzling observations. (1) In pathologic models in which AVP levels are known to be elevated (nitric oxide–deprived hypertensive rats and diabetic rats), the long-term administration of a selective V1aR nonpeptide antagonist worsened BP and albuminuria52 and did not prevent or even aggravated diabetes-related vascular damage.53 (2) Several other studies suggested 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 increased 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 BP as a result not of a reduced vasoconstriction but of a lower extracellular fluid volume.59

In summary, these results provide a better knowledge of the respective V2R- and V1aR-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 as a result of 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 hypertension13,60; however, more precise information is required regarding V1a and V2 effects in humans to know whether selective rather than mixed antagonists are more appropriate in each of these disorders.

CONCISE METHODS

Animals and General Procedures

Adult male Wistar rats (Charles River, L'Arbresle, France) of initial body weight 230 to 240 g were housed individually in metabolic cages with free access to tap water and powdered food (A03; Safe, Villemoisson/Orge, France) at all times before and during the experiments (except for one rat group in experiment E, discussed later). They were accustomed to the cages for 5 d before the experiments. All experiments were carried out in conscious, undisturbed rats and involved no previous water load, no instrumentation, and no pretreatment. Each experiment included 24 to 36 rats studied in parallel on two successive days. On day 1 (basal), rats were administered an injection at time 0 (approximately 10 a.m.) of the vehicle(s) only, and on day 2 (experimental) with AVP and/or various drugs (see details that follow). Urine was collected for 6 h starting just after the injection(s). Urine volume was determined gravimetrically, assuming the density of urine was equal to unity. Uosm was measured with a freezing point osmometer (Roebling, Berlin, Germany) and urinary concentration of sodium and potassium by flame photometry (IL 943, Instrument Laboratory, Lexington, MA). Urine urea concentration was measured with a standard kit (Urea Kit S 1000; BioMérieux, Lyon, France).

In each experiment, on the basis of values obtained during the basal day, the rats were divided into several groups of equivalent urine volume and osmolality (n = 4 to 6 per group) to test, during the experimental day, the effects of the various doses of hormones or drugs in groups of rats with equivalent urine concentrating activity. Usually, three or four independent experiments were performed in the same series of rats at 1-wk intervals (to allow washout from the preceding experiment). All animal procedures were conducted in accordance with the European guidelines for the care and use of laboratory animals.

V2R Agonist dDAVP: Dose-Response Curve (Experiment A)

dDAVP (Minirin; Ferring Pharmaceuticals AB, Malmö, Sweden) is a selective peptidic V2R agonist.61 The dDAVP solution was emulsified in oil (1:9 vol/vol) to prolong its bioavailability, and injected subcutaneously (under the skin of the back of the neck) in seven rat groups (600 μl emulsion/kg BW) at concentrations in the aqueous phase designed to deliver 0.00 (vehicle alone), 0.02, 0.06, 0.20, 0.60, 2.00, or 6.00 μg/kg BW (corresponding approximately to 0.02, 0.06, 0.20, 0.60, 2.00, or 6.00 nmol/kg BW).

V2R Antagonist SR121463A: Dose-Response Curve (Experiment B)

SR121463A (Satavaptan; Sanofi-Aventis, Toulouse, France) is a selective nonpeptide V2R antagonist with a relatively long half-life.62,63 On the experimental day, the V2R antagonist dissolved in DMSO (10% final volume) and saline was injected intraperitoneally (1 ml/kg BW) in six equivalent rat groups at various concentrations delivering 0 (vehicle alone), 0.01, 0.03, 0.10, 1.00, or 10.00 mg/kg BW. In this experiment, urine was collected not only for the first 6 h after the drug administration but also in separate tubes for the subsequent 18 h (i.e., from 6 to 24 h after the injection) so as to evaluate the delayed effects of the drug.

Natural AVP: Dose-Response Curve (Experiment C)

Synthetic [Arg8]-vasopressin acetate salt (Sigma-Aldrich, Chemie, Steinheim, Germany; i.e. natural AVP), dissolved in saline, was emulsified in oil (1:9 vol/vol) and injected subcutaneously, as described for dDAVP (600 μl emulsion/kg BW), in five groups of rats. The concentration of AVP in the aqueous phase was designed to deliver 0.0 (vehicle alone), 0.1, 1.0, 15.0, or 50.0 μg/kg BW (corresponding approximately to 0.1, 1.0, 15.0, or 50.0 nmol/kg BW). As in previous studies,54,57 the dose range for AVP was approximately five times higher than that for dDAVP because of the faster degradation of AVP in vivo.

Natural AVP Plus V1aR Antagonist SR49059 (Experiment D)

For evaluation of the role of V1aR in the response to the natural hormone AVP, rats of this series were administered AVP (15 μg/kg BW, same procedure as in Experiment C) without or with the concomitant administration of the selective nonpeptide V1aR antagonist SR49059 (Relcovaptan; Sanofi-Aventis) at a dose of 10 mg/kg BW, shown in previous studies to block the pressor response to AVP.64 This drug was dissolved in DMSO and cremophor (each 10% of final volume) and then in saline, and was injected intraperitoneally (1 ml/kg BW). For comparison, additional rats received vehicle alone, the V1aR antagonist alone, AVP at a lower dose (3 μg/kg BW), or dDAVP (0.6 μg/kg BW).

Urinary AVP Concentration in Various Situations (Experiment E)

To evaluate the concentration of AVP prevailing in the lumen of the CD in different situations, we performed additional experiments in which urine was collected for 6 h, as in the other experiments, under various experimental conditions, including injection of isotonic saline, injection of dDAVP 0.6 μg/kg BW, injection of AVP 3 or 15 μg/kg BW, and 24-h dehydration. Urine volume and Uosm were measured, and aliquots of urine were stored at −20°C for further AVP assay. UAVP was measured as described previously.65 The antibody used does not recognize dDAVP.

Comparison of V2R Antagonist and Furosemide Effects (Experiment F)

Classical diuretics and aquaretics (V2R antagonist) increase V by different mechanisms. To compare the respective effects of the two types of drugs on water and sodium excretion, we performed an additional experiment in which different groups of rats received either furosemide (Lasix; Sanofi-Aventis) or the V2R antagonist (prepared and injected as in Experiment B) at various doses (0.0, 0.1, 0.3, 1.0, 10.0, and 30.0 mg/kg BW for furosemide and 0.0, 0.1, 0.3, 1.0, and 10.0 mg/kg BW for the V2R antagonist). Urine was collected for 6 h after the injections.

Statistical Analysis

V and the excretion rate of the different solutes were calculated according to standard formulas. The TTKG, reflecting the intensity of potassium secretion, was calculated by dividing the urine/plasma potassium concentration ratio by the urine/plasma osmolality ratio.66 Plasma osmolality was arbitrarily considered to be 300 mOsm/kg H2O and plasma potassium concentration 5 mmol/L in all rats.

Results are expressed as means ± SEM. In Experiments A through D, each rat was its own control. Thus, for each variable, the Exp/Basal provides a quantitative estimate of the changes induced by the hormone and/or drug. The statistical significance of these changes was evaluated by paired t test comparing results of the experimental day with those of the basal day in each rat. In Experiment E, comparison between the various groups was performed by one-way ANOVA followed by Fisher post hoc test. In Experiment F, linear regressions were calculated between the changes in sodium or potassium excretion and those in water excretion.

DISCLOSURES

None.

Acknowledgments

Financial support for these studies was provided by the INSERM annual budget of Unit 872 (ex Unit 652 and 367; to L.B.) and by Canada Research Chair Program (to D.G.B.). J.P. received a fellowship from the French Society of Nephrology in 2006 to 2007.

Part of this work was presented at the annual meeting of the American Society of Nephrology; October 29 through November 1, 2004; St. Louis, MO; and published in abstract form (J Am Soc Nephrol 16: 87A, 2004).

We thank Sanofi-Aventis for supplying the antagonists used in the experiments described in this article.

We thank Claudine Serradeil-Le Gal (Sanofi-Aventis, Toulouse, France) for fruitful scientific discussions, Marie-Françoise Gonzales for pilot experiments, and Marie-Françoise Arthus and Michèle Lonergan (Hôpital du Sacré-Coeur, Montréal, Québec, Canada) for AVP measurements.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • © 2008 American Society of Nephrology

REFERENCES

  1. ↵
    Schafer JA: Abnormal regulation of ENaC: Syndromes of salt retention and salt wasting by the collecting duct. Am J Physiol Renal Physiol 283 : F221 –F235, 2002
    OpenUrlCrossRefPubMed
  2. ↵
    Leaf A, Bartter FC, Santos RF, Wrong O: Evidence in man that urinary electrolyte loss induced by pitressin is a function of water retention. J Clin Invest 32 : 868 –878, 1953
    OpenUrlCrossRefPubMed
  3. Humphreys MH, Friedler RM, Earley LE: Natriuresis produced by vasopressin or hemorrhage during water diuresis in the dog. Am J Physiol 219 : 658 –665, 1970
    OpenUrlPubMed
  4. ↵
    Buckalew VM, Dimond KA: Effect of vasopressin on sodium excretion and plasma antinatriferic activity in the dog. Am J Physiol 231 : 28 –33, 1976
    OpenUrlPubMed
  5. Balment RJ, Brimble MJ, Forsling ML, Musabayane CT: Natriuretic response of the rat to plasma concentrations of arginine vasopressin within the physiological range. J Physiol 352 : 517 –526, 1984
    OpenUrlCrossRefPubMed
  6. ↵
    Park RG, Congiu M, Denton DA, McKinley MJ: Natriuresis induced by arginine vasopressin infusion in sheep. Am J Physiol 249 : F799 –F805, 1985
    OpenUrlPubMed
  7. Forsling ML, Judah JM, Windle RJ: The effect of vasopressin and oxytocin on glomerular filtration rate in the conscious rat: Contribution to the natriuretic response. J Endocrinol 141 : 59 –67, 1994
    OpenUrlAbstract/FREE Full Text
  8. ↵
    Walter SJ, Tennakoon V, McClune JA, Shirley DG: Role of volume status in vasopressin-induced natriuresis: Studies in Brattleboro rats. J Endocrinol 151 : 49 –54, 1996
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Kompanowska-Jezierska E, Emmeluth C, Grove L, Christensen P, Sadowski J, Bie P: Mechanism of vasopressin natriuresis in the dog: Role of vasopressin receptors and prostaglandins. Am J Physiol 274 : R1619 –R1625, 1998
    OpenUrlPubMed
  10. ↵
    Verbalis JG: Vasopressin V2 receptor antagonists. J Mol Endocrinol 29 : 1 –9, 2002
    OpenUrlAbstract
  11. ↵
    Lemmens-Gruber R, Kamyar M: Vasopressin antagonists. Cell Mol Life Sci 63 : 1766 –1779, 2006
    OpenUrlCrossRefPubMed
  12. ↵
    Torres VE: Vasopressin antagonists in polycystic kidney disease. Kidney Int 68 : 2405 –2418, 2005
    OpenUrlCrossRefPubMed
  13. ↵
    Bankir L, Perucca J, Weinberger MH: Ethnic differences in urine concentration: Possible relationship to blood pressure. Clin J Am Soc Nephrol 2 : 304 –312, 2007
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Ando Y, Asano Y: Functional evidence for an apical V1 receptor in rabbit cortical collecting duct. Am J Physiol 264 : F467 –F471, 1993
    OpenUrlPubMed
  15. ↵
    Ikeda M, Yoshitomi K, Imai M, Kurokawa K: Cell Ca2+ response to luminal vasopressin in cortical collecting tubule principal cells. Kidney Int 45 : 811 –816, 1994
    OpenUrlCrossRefPubMed
  16. ↵
    Robertson GL: The regulation of vasopressin function in health and disease. Recent Progr Horm Res 33 : 333 –385, 1977
    OpenUrl
  17. ↵
    Bankir L: Antidiuretic action of vasopressin: Quantitative aspects and interaction between V1a and V2 receptor-mediated effects. Cardiovasc Res 51 : 372 –390, 2001
    OpenUrlCrossRefPubMed
  18. ↵
    Serradeil-Le Gal C, Derick S, Brossard G, Manning M, Simiand J, Gaillard R, Griebel G, Guillon G: Functional and pharmacological characterization of the first specific agonist and antagonist for the V1b receptor in mammals. Stress 6 : 199 –206, 2003
    OpenUrlPubMed
  19. ↵
    Saito M, Tahara A, Sugimoto T: 1-Desamino-8-d-arginine vasopressin (DDAVP) as an agonist on V1b vasopressin receptor. Biochem Pharmacol 53 : 1711 –1717, 1997
    OpenUrlCrossRefPubMed
  20. ↵
    Nicco C, Wittner M, DiStefano A, Jounier S, Bankir L, Bouby N: Chronic exposure to vasopressin upregulates ENaC and sodium transport in the rat renal collecting duct and lung. Hypertension 38 : 1143 –1149, 2001
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Kim JK, Summer SN, Erickson AE, Schrier RW: Role of arginine vasopressin in medullary thick ascending limb on maximal urinary concentration. Am J Physiol 251 : F266 –F270, 1986
    OpenUrlPubMed
  22. ↵
    Huang DY, Pfaff I, Serradeil-Le Gal C, Vallon V: Acute renal response to the non-peptide vasopressin V2-receptor antagonist SR 121463B in anesthetized rats. Naunyn Schmiedebergs Arch Pharmacol 362 : 201 –207, 2000
    OpenUrlCrossRefPubMed
  23. ↵
    Bankir L, Fernandes S, Bardoux P, Bouby N, Bichet DG: Vasopressin-V2 receptor stimulation reduces sodium excretion in healthy humans. J Am Soc Nephrol 16 : 1920 –1928, 2005
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Lieberthal W, Vasilevsky ML, Valari R, Levinsky N: Interactions between ADH and prostaglandins in isolated erythrocyte-perfused rat kidney. Am J Physiol 252 : F331 –F337, 1987
    OpenUrlPubMed
  25. ↵
    Yamamura Y, Nakamura S, Itoh S, Hirano T, Onogawa T, Yamashita T, Yamada Y, Tsujimae K, Aoyama M, Kotosai K, Ogawa H, Yamashita H, Kondo K, Tominaga M, Tsujimoto G, Mori T: OPC-41061, a highly potent human vasopressin V2-receptor antagonist: Pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther 287 : 860 –867, 1998
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Lacour C, Galindo G, Canals F, Segondy D, Cazaubon C, Serradeil-Le Gal C, Roccon A, Nisato D: Aquaretic and hormonal effects of a vasopressin V(2) receptor antagonist after acute and long-term treatment in rats. Eur J Pharmacol 394 : 131 –138, 2000
    OpenUrlCrossRefPubMed
  27. ↵
    Yamamura Y, Ogawa H, Yamashita H, Chihara T, Miyamoto H, Nakamura S, Onogawa T, Yamashita T, Hosokawa T, Mori T, et al.: Characterization of a novel aquaretic agent, OPC-31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist. Br J Pharmacol 105 : 787 –791, 1992
    OpenUrlCrossRefPubMed
  28. ↵
    Decaux G: Difference in solute excretion during correction of hyponatremic patients with cirrhosis or syndrome of inappropriate secretion of antidiuretic hormone by oral vasopressin V2 receptor antagonist VPA-985. J Lab Clin Med 138 : 18 –21, 2001
    OpenUrlCrossRefPubMed
  29. ↵
    Guyader D, Patat A, Ellis-Grosse EJ, Orczyk GP: Pharmacodynamic effects of a nonpeptide antidiuretic hormone V2 antagonist in cirrhotic patients with ascites. Hepatology 36 : 1197 –1205, 2002
    OpenUrlCrossRefPubMed
  30. ↵
    Jimenez W, Gal CS, Ros J, Cano C, Cejudo P, Morales-Ruiz M, Arroyo V, Pascal M, Rivera F, Maffrand JP, Rodes J: Long-term aquaretic efficacy of a selective nonpeptide V(2)-vasopressin receptor antagonist, SR121463, in cirrhotic rats. J Pharmacol Exp Ther 295 : 83 –90, 2000
    OpenUrlAbstract/FREE Full Text
  31. ↵
    Anastasio P, Cirillo M, Spitali L, Frangiosa A, Pollastro RM, De Santo NG: Level of hydration and renal function in healthy humans. Kidney Int 60 : 748 –756, 2001
    OpenUrlCrossRefPubMed
  32. ↵
    Choukroun G, Schmitt F, Martinez F, Drüeke TB, Bankir L: Low urine flow reduces the capacity to excrete a sodium load in humans. Am J Physiol 273 : R1726 –R1733, 1997
    OpenUrlPubMed
  33. ↵
    Shimizu K: Aquaretic effects of the nonpeptide V2 antagonist OPC-21260 in hydropenic humans. Kidney Int 48 : 220 –226, 1995
    OpenUrlCrossRefPubMed
  34. ↵
    Tsuboi Y, Ishikawa S, Fujisawa G, Okada K, Saito T: In vivo diuretic effect of a new non-peptide arginine vasopressin antagonist, OPC-31260, in conscious rats. J Endocrinol 143 : 227 –234, 1994
    OpenUrlAbstract/FREE Full Text
  35. ↵
    Field MJ, Stanton BA, Giebisch GH: Influence of ADH on renal potassium handling: A micropuncture and microperfusion study. Kidney Int 25 : 502 –511, 1984
    OpenUrlCrossRefPubMed
  36. ↵
    Schafer JA, Troutman SL: Effect of ADH on rubidium transport in isolated perfused rat cortical collecting tubules. Am J Physiol 250 : F1063 –F1072, 1986
    OpenUrlPubMed
  37. ↵
    Malnic G, Berliner RW, Giebisch G: Flow dependence of K+ secretion in cortical distal tubules of the rat. Am J Physiol 256 : F932 –F941, 1989
    OpenUrlPubMed
  38. ↵
    Nadvornikova H, Schuck O: The influence of a single dose of vasopressin analogs on human renal potassium excretion. Int J Clin Pharmacol Ther Toxicol 20 : 155 –158, 1982
    OpenUrlPubMed
  39. ↵
    Manning PT, Schwartz D, Katsube NC, Holmberg SW, Needleman P: Vasopressin-stimulated release of atriopeptin: Endocrine antagonists in fluid homeostasis. Science 229 : 395 –397, 1985
    OpenUrlAbstract/FREE Full Text
  40. ↵
    Bonvalet JP, Pradelles P, Farman N: Segmental synthesis and actions of prostaglandins along the nephron. Am J Physiol 253 : F377 –F387, 1987
    OpenUrlPubMed
  41. ↵
    Chou SY, Porush JG, Faubert PF: Renal medullary circulation: Hormonal control. Kidney Int 37 : 1 –13, 1990
    OpenUrlCrossRefPubMed
  42. ↵
    Schlondorff D: Renal prostaglandin synthesis: Sites of production and specific actions of prostaglandins. Am J Med 81 : 1 –11, 1986
    OpenUrlPubMed
  43. ↵
    Serradeil-Le Gal C, Raufaste D, Marty E, Garcia C, Maffrand JP, Le Fur G: Autoradiographic localization of vasopressin V1a receptors in the rat kidney using [3H]-SR 49059. Kidney Int 50 : 499 –505, 1996
    OpenUrlPubMed
  44. ↵
    Andersen LJ, Andersen JL, Schütten HJ, Warberg J, Bie P: Antidiuretic effect of subnormal levels of arginine vasopressin in normal humans. Am J Physiol 259 : R53 –R60, 1990
    OpenUrlPubMed
  45. ↵
    Bankir L, Pouzet B, Choukroun G, Bouby N, Schmitt F, Mallie JP: To concentrate the urine or to excrete sodium: Two sometimes contradictory requirements [in French]. Nephrologie 19 : 203 –209, 1998
    OpenUrlPubMed
  46. ↵
    Thibonnier M, Kilani A, Rahman M, Pilumeli DiBlasi T, Warner K, Smith MC, Leenhardt AF, Brouard R: Effects of the nonpeptide V1 vasopressin receptor antagonist SR49059 in hypertensive patients. Hypertension 34 : 1293 –1300, 1999
    OpenUrlAbstract/FREE Full Text
  47. ↵
    Fernandes S, Bruneval P, Hagege A, Heudes D, Ghostine S, Bouby N: Chronic V2 vasopressin receptor stimulation increases basal blood pressure and exacerbates deoxycorticosterone acetate-salt hypertension. Endocrinol 143 : 2759 –2766, 2002
    OpenUrlCrossRefPubMed
  48. ↵
    Montani J, Wang J, Tempini A, Yang Z, Van Vliet B: Chronic V2-vasopressin receptor stimulation at both moderate and high doses induces sustained hypertension in rats [Abstract]. FASEB J 15 : A133 , 2001
    OpenUrl
  49. ↵
    Yagil C, Ben-Ishay D, Yagil Y: Disparate expression of the AVP gene in Sabra hypertension-prone and hypertension-resistant rats. Am J Physiol 271 : F806 –F813, 1996
    OpenUrlPubMed
  50. ↵
    Bankir L, Bardoux P, Mayaudon H, Dupuy O, Bauduceau B: Impaired urinary flow rate during the day: A new factor possibly involved in hypertension and in the lack of nocturnal dipping [in French]. Arch Mal Coeur Vaiss 95 : 751 –754, 2002
    OpenUrlPubMed
  51. ↵
    Izumi Y, Nakayama Y, Mori T, Miyazaki H, Inoue H, Kohda Y, Inoue T, Nonoguchi H, Tomita K: Downregulation of vasopressin V2 receptor promoter activity via V1a receptor pathway. Am J Physiol Renal Physiol 292 : F1418 –F1426, 2007
    OpenUrlCrossRefPubMed
  52. ↵
    Loichot C, Cazaubon C, Grima M, De Jong W, Nisato D, Imbs JL, Barthelmebs M: Vasopressin does not effect hypertension caused by long-term nitric oxide inhibition. Hypertension 35 : 602 –608, 2000
    OpenUrlAbstract/FREE Full Text
  53. ↵
    Mechaly I, Krosniak M, Azay J, Cassanas G, Roque C, Cahard D, Serrano JJ, Cros G: Interactive computerized microscopy as a tool for quantifying vascular remodelling effects of diabetes and V1a receptor antagonist SR 49059 on rat mesenteric arterial bed. J Pharmacol Toxicol Methods 41 : 59 –67, 1999
    OpenUrlCrossRefPubMed
  54. ↵
    Promeneur D, Bankir L, Hu MC, Trinh-Trang-Tan MM: Renal tubular and vascular urea transporters: Influence of antidiuretic hormone on mRNA expression in Brattleboro rats. J Am Soc Nephrol 9 : 1359 –1366, 1998
    OpenUrlAbstract
  55. Berl T, Raz A, Wald H, Horowitz J, Czaczkes W: Prostaglandin synthesis inhibition and the action of vasopressin: studies in man and rat. Am J Physiol 232 : F529 –F537, 1977
    OpenUrlPubMed
  56. Breyer MD, Ando Y: Hormonal signaling and regulation of salt and water transport in the collecting duct. Annu Rev Physiol 56 : 711 –739, 1994
    OpenUrlCrossRefPubMed
  57. ↵
    Bouby N, Hassler C, Bankir L: Contribution of vasopressin to progression of chronic renal failure: Study in Brattleboro rats infused with AVP or dDAVP. Life Sci 65 : 991 –1004, 1999
    OpenUrlCrossRefPubMed
  58. ↵
    Nonoguchi H, Takayama M, Owada A, Ujiie K, Yamada T, Nakashima O, Sakuma Y, Koike J, Terada Y, Marumo F, Tomita K: Role of urinary arginine vasopressin in the sodium excretion in patients with chronic renal failure. Am J Med Sci 312 : 195 –201, 1996
    OpenUrlCrossRefPubMed
  59. ↵
    Koshimizu TA, Nasa Y, Tanoue A, Oikawa R, Kawahara Y, Kiyono Y, Adachi T, Tanaka T, Kuwaki T, Mori T, Takeo S, Okamura H, Tsujimoto G: V1a vasopressin receptors maintain normal blood pressure by regulating circulating blood volume and baroreflex sensitivity. Proc Natl Acad Sci U S A 103 : 7807 –7812, 2006
    OpenUrlAbstract/FREE Full Text
  60. ↵
    Luft FC: Vasopressin, urine concentration, and hypertension: A new perspective on an old story. Clin J Am Soc Nephrol 2 : 196 –197, 2007
    OpenUrlFREE Full Text
  61. ↵
    Richardson DW, Robinson AG: Desmopressin. Ann Intern Med 103 : 228 –239, 1985
    OpenUrlPubMed
  62. ↵
    Serradeil-Le-Gal C, Lacour C, Valette G, Garcia G, Foulon L, Galindo G, Bankir L, Pouzet B, Guillon G, Barberis C, Chicot D, Jard S, Vilain P, Garcia C, Marty E, Raufaste D, Brossard G, Nisato D, Maffrand JP, Le-Fur G: Characterization of SR 121463A, a highly potent and selective orally active vasopressin V2 receptor antagonist. J Clin Invest 98 : 2729 –2738, 1996
    OpenUrlCrossRefPubMed
  63. ↵
    Serradeil-Le Gal C: An overview of SR121463, a selective non-peptide vasopressin V(2) receptor antagonist. Cardiovasc Drug Rev 19 : 201 –214, 2001
    OpenUrlPubMed
  64. ↵
    Serradeil-Le Gal C, Wagnon J, Garcia C, Lacour C, Guiraudou P, Christophe B, Villanova G, Nisato D, Maffrand JP, Le Fur G, et al.: Biochemical and pharmacological properties of SR 49059, a new, potent, nonpeptide antagonist of rat and human vasopressin V1a receptors. J Clin Invest 92 : 224 –231, 1993
    OpenUrlCrossRefPubMed
  65. ↵
    Bichet DG, Arthus MF, Barjon JN, Lonergan M, Kortas C: Human platelet fraction arginine-vasopressin: Potential physiological role. J Clin Invest 79 : 881 –887, 1987
    OpenUrlPubMed
  66. ↵
    West ML, Bendz O, Chen CB, Singer GG, Richardson RM, Sonnenberg H, Halperin ML: Development of a test to evaluate the transtubular potassium concentration gradient in the cortical collecting duct in vivo. Miner Electrolyte Metab 12 : 226 –233, 1986
    OpenUrlPubMed
PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 19 (9)
Journal of the American Society of Nephrology
Vol. 19, Issue 9
September 2008
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists
Julie Perucca, Daniel G. Bichet, Pascale Bardoux, Nadine Bouby, Lise Bankir
JASN Sep 2008, 19 (9) 1721-1731; DOI: 10.1681/ASN.2008010021

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists
Julie Perucca, Daniel G. Bichet, Pascale Bardoux, Nadine Bouby, Lise Bankir
JASN Sep 2008, 19 (9) 1721-1731; DOI: 10.1681/ASN.2008010021
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • RESULTS
    • DISCUSSION
    • CONCISE METHODS
    • DISCLOSURES
    • Acknowledgments
    • Footnotes
    • REFERENCES
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Blocking CCL8-CCR8–Mediated Early Allograft Inflammation Improves Kidney Transplant Function
  • Kidney Failure Alters Parathyroid Pin1 Phosphorylation and Parathyroid Hormone mRNA-Binding Proteins Leading to Secondary Hyperparathyroidism
  • KLC3 Regulates Ciliary Trafficking and Cyst Progression in CILK1 Deficiency–Related Polycystic Kidney Disease
Show more Basic Research

Cited By...

  • The Effect of Tolvaptan on BP in Polycystic Kidney Disease: A Post Hoc Analysis of the TEMPO 3:4 Trial
  • Glucagon-like peptide-1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP-1 receptors
  • Coordinated Control of ENaC and Na+,K+-ATPase in Renal Collecting Duct
  • SPAK Differentially Mediates Vasopressin Effects on Sodium Cotransporters
  • Antinatriuretic Effect of Vasopressin in Humans Is Amiloride Sensitive, Thus ENaC Dependent
  • Aldosterone Requires Vasopressin V1a Receptors on Intercalated Cells to Mediate Acid-Base Homeostasis
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals
  • Wolters Kluwer Partnership

© 2022 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire