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RENIN-MINERALCORTICOIDS-ANF-ADH |
Institut National de la Santé et de la Recherche Médicale, Unité-367 (S.F., N.B.) and Unité-430 (P.B., D.H.); and Hôpital Necker-Enfants Malades (A.H., S.G.), Paris, France
Address all correspondence and requests for reprints to: Dr. Nadine Bouby, Institut National de la Santé et de la Recherche Médicale, Unité-367, 17 rue du Fer à Moulin, 75005 Paris, France. E-mail: . bouby{at}ifm.inserm.fr
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Abstract |
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-subunits of the epithelial sodium channel was significantly increased by dDAVP treatment (P < 0.05). These findings provide evidence that chronic stimulation of vasopressin V2 receptor raises basal blood pressure in rats and exacerbates the development of DOCA-salt hypertension, organ damage, and mortality. These effects could be due at least in part to the sustained stimulation of sodium reabsorption by epithelial sodium channel in the distal part of the nephron, which promotes sodium retention. |
Introduction |
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It has recently been shown that vasopressin not only has an acute impact on ENaC-dependent sodium transport (3, 4, 5, 6), but also has a long-term effect on the expression of two ENaC subunits in the kidney, by activating the V2 receptors (7, 8). This effect is accompanied by significant increases in sodium and water transport (8), suggesting associated changes in functional ENaC membrane proteins. Although this vasopressin effect on ENaC probably improves the urine concentration process under physiological conditions, it may result in less efficient sodium excretion. Indeed, antinatriuretic effects of vasopressin have been observed in normovolemic rats and humans (9, 10, 11) and in the isolated erythrocyte-perfused kidney (12). Consequently, excessive vasopressin-dependent ENaC stimulation could be an additional risk factor in the onset of salt-sensitive hypertension. The contribution of vasopressin to this form of hypertension has been related solely to its volume expansion effects through the activation of V2 tubular receptors, its pressor effects, through the activation of V1a vascular receptors (13), and its modulator effect on baroreflex sensitivity and sympathetic outflow through the activation of V1b receptors in the central nervous system (14). The importance of vasopressor as well as antidiuretic activity of vasopressin in the development of deoxycorticosterone acetate (DOCA)-salt (DS) hypertension has been well demonstrated in Brattleboro rats genetically deficient in vasopressin (15). An increase in vascular reactivity in these rats replaced with vasopressin has been observed 3 d after the start of DS treatment before a rise in arterial pressure (16). In contrast, the relevance of vasopressin in the maintenance of high blood pressure in experimental malignant phase of hypertension is controversial (17, 18, 19).
The aim of the present study was to investigate the influence of chronic V2 receptor stimulation or inhibition on salt-dependent nonmalignant hypertension in the rat. The effects of selective V2 agonist or antagonist on blood pressure and renal function were evaluated before and after DS administration. Cardiac and renal consequences of the different treatments were analyzed. Although some recent work has studied the in vivo effects of vasopressin on ion channels and transporters involved in the urine concentration process and sodium transport (7, 8, 20), none has examined the changes in the gene expression of these transporters associated with DS hypertension. We therefore also investigated the gene expression of ENaC subunits in the renal cortex and in other organs synthesizing this ion channel.
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Materials and Methods |
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240 g), urine osmolality, and systolic blood pressure (SBP; n = 7/group). Under sodium pentobarbital anesthesia (6 mg/kg, ip), the right kidney was removed through a retroperitoneal flank incision in all rats. V2 agonist or antagonist treatments were started on the day of the surgery and lasted 8 wk. The first group was treated with the V2 agonist, 1-deamino-8D-arginine vasopressin (dDAVP; Minirin, Ferring Pharmaceuticals Ltd., Malmo, Sweden), infused continuously through osmotic minipumps (models 2002 and 2004, Alzet Corp., Palo Alto, CA; 570 ng/kg·d) implanted ip (dDAVP group). The second group received the V2 antagonist, SR 121463 (Sanofi-Synth\|[eacute]\|labo, Toulouse, France), mixed with the food (3 mg/kg·d; SR group). The third group was used as the control (CONT group). CONT and SR rats were sham-operated at each change of the minipumps of the dDAVP rats. Rats were offered 25 g/d standard food (A03, UAR, Villemoisson/Orge, France) containing 0.8% NaCl and water ad libitum. Two weeks after beginning treatment, DOCA-salt (DS) hypertension was induced in the three groups by the sc implantation of one pellet of DOCA (Innovative Research of America, Toledo, OH; 11 mg/rat·wk) under xylazine-ketamine anesthesia (0.4 and 4 mg/100 g BW, ip) and feeding with 4% NaCl chow. Salt was given in the food, but not in the drinking water (as is usually done), to make it possible to regulate water and sodium balance independently. All rats were given K+ supplementation (0.4% in food). The dose of DOCA and the amount of salt were chosen after a preliminary study, which had shown that they induced moderate, nonmalignant hypertension. This was confirmed at the end of the experiment by comparing the morphological and histological lesions to those of a normotensive uninephrectomized group without DS, V2 agonist, or antagonist treatment (normotensive, n = 7).
Measurement of functional and morphological data
Animals were housed in individual metabolic cages. Body weight, water and food intakes, and urinary flow rate were measured weekly on 2 consecutive d. Blood samples were taken from the jugular vein during the second (just before implanting DOCA pellet), fifth, and eighth weeks of the experiment. The following plasma and urine parameters were measured: osmolality (freezing point osmometer, Roebling, Berlin, Germany), sodium and potassium concentrations (flame photometer, model 243, Instrumentation Laboratory, France), urea concentration (urea kit, BioMérieux, Paris, France), and creatinine concentration (automatic analyzer, Orthoclinical Diagnostics). The urinary concentration of albumin was determined by radial immunodiffusion, using an antiserum against rat albumin raised in rabbit (Nordic, Tilburg, The Netherlands). Data from the 2-d urine collections were averaged for each rat.
Cardiac structure and function were studied in anesthetized rats (xylazine-ketamine) by echocardiography during the fifth week of the experiment. A short-focus 13-Mhz linear-phased array transducer connected to a Sequoia 516 device (Acuson, Mountain Valley, CA) was used. The heart was first imaged in the two-dimensional parasternal long-axis view of the left ventricle; the M-mode cursor was then positioned perpendicular to the septal and posterior walls, just below the tip of the mitral valve leaflets. End diastolic (d) and systolic (s) left ventricular diameter (LVD) and septum and posterior wall thickness (ST and PWT) were measured by using the American Society of Echography leading edge method. All dimensions were the mean of three consecutive measurements. Left ventricular fractional shortening (percentage) was calculated as [(LVDd - LVDs) x LVDd-1] x 100 and was used as an index of global contractility. Left ventricular mass indexed to body weight (BW) was calculated as LVMi = [(STd + PWTd + LVDd)3 - (LVD)3] x BW-1.
SBP was measured in conscious rats before and during the second and seventh weeks of V2 agonist or antagonist treatment by the tail-cuff method with an electrosphyngomanometer (model P300, Narco BioSystems, Basel, Switzerland). Three consecutive measurements were averaged on each day, and the mean value for 3 consecutive days was the value reported.
At the end of experiment (wk 8), the rats were anesthetized with sodium pentobarbital (6 mg/100 g BW, ip). The kidney, left ventricle, and adrenals were removed, weighed, fixed in alcoholic Bouin’s solution, and embedded in paraffin. Any rats that presented severe signs of stroke before the end of the experiment were killed, and their organs were removed. For the kidneys, 4-µm-thick sections were stained with Masson’s Trichrome for semiquantitative assessment of renal lesions or with silver staining for morphometry. Glomerular, tubulointerstitial, and vascular lesions were graded semiquantitatively as previously described (21). The glomerular surface area was measured as previously described (22) at x25 magnification (scaling factor, 0.422 µm/pixel). For the heart, 5-µ-thick transversal sections, just below the mitral valve, were stained with hematoxylin-eosin for qualitative analysis or with Sirius red for collagen staining to perform morphometric analysis with a Nacket NS 15,000 image analysis system (Nacket microsystem, Les Ulis, France). The following cardiac parameters were measured: subendocardial interstitial collagen, scar collagen, and pericoronary collagen at high magnification (scaling factor = 0.625, 1.625, and 1.625 µm/pixel, respectively). To relate the amount of collagen around coronary arteries to the size of the artery, the pericoronary collagen area was divided by the perimeter of the arterial lumen (23). The investigators doing the echography and histological analysis were unaware of the treatment status of the rats.
Molecular study
A second series of rats was used for molecular studies (n = 8/group). They were treated with the protocol described above. In view of the high level of mortality in the dDAVP group in the first series (see Results) and assuming that changes in mRNA expression occur early after change in hormonal status, these rats were killed 2 wk after induction of DS hypertension. Total RNA was isolated from distal colon (15 mm), lung (100 mg), and superficial renal cortex (100 mg). Ten micrograms were run on 1.2% agarose-2.5% formaldehyde gel and blotted to nitrocellulose membranes (Hybond-C Extra, Amersham Pharmacia Biotech, Arlington Heights, IL), according to standard procedures. Membranes were hybridized with random-primed 32P-labeled probes for 
[nucleotides (nt) 279-2164], ß (nt 385-1440), and (nt 511-2304) subunits (24). The human probe for glyceraldehyde-3-phosphate dehydrogenase (GAPDH; 1000 nt in length) was used as a reference. We verified that this housekeeping gene was expressed to a similar level per unit total RNA in the different groups. To keep the different radioactive signals within a similar range of intensity, the GAPDH probe was labeled with a 5-fold lower specific radioactivity than other probes by diluting the labeled deoxy-CTP with unlabeled nucleotides. Radioactivity bound to transcripts (, 3.7 kb; ß, 2.2 kb; , 3.2 kb; GAPDH, 1 kb) was measured with an electronic autoradiography system (InstantImager, Packard Instruments, Meriden, CT).
Statistical analysis
Results were expressed as the mean ± SEM for n number of rats. The statistical significance of the differences observed among the CONT, SR, and dDAVP groups was assessed by one-way ANOVA, with repeated measurements for parameters measured before and after DS administration. The ANOVA tests were followed, when appropriate, by Fisher’s protected least significant difference post hoc test. StatView F-4.5 software was used for the statistical analysis. The chosen level of significance was P < 0.05.
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Results |
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). Two weeks after the beginning of the V2 agonist or antagonist treatment and before DS administration, urine osmolality was 3 times higher in the dDAVP group than in the SR group. A high sodium diet induced a 6.5-fold increase in sodium excretion in each group. This sodium load induced a large increase in water intake and urine flow rate and a decrease in urine osmolality. When DS was combined with V2 antagonist, this induced a greater fall in urine osmolality, which reached levels close to those in plasma. However, combination with the V2 agonist failed to produce any significant increase in urine concentration (Table 1). Daily food intake, and therefore the excretion of the different electrolytes and of urea, were not statistically different among the three groups (not shown).
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). dDAVP-treated rats had a slightly lower hematocrit (P = NS) and higher plasma urea (P < 0.001) than the other groups. Potassium supplementation meant that hypertensive CONT and SR rats displayed slight hypokalemia, whereas dDAVP rats did not. Plasma parameter values at the eighth week for the rats that survived until the end of the experiment were not different from those measured at the fifth week (not shown).
The change in SBP is shown in Fig. 1. SBP was not different in the various groups before treatment. Before DS administration, it was significantly higher in dDAVP group (by ANOVA, P < 0.006) than in CONT and SR groups [+11 mm Hg (P = 0.02) and +16 mm Hg (P = 0.002), respectively]. Although DS administration induced a major increase in SBP in all groups, at the fifth week of the experiment, dDAVP rats exhibited higher values than those in the other two groups [by ANOVA, P < 0.042; +17 mm Hg (P = 0.083) and +25 mm Hg (P = 0.015) compared with the CONT and SR groups, respectively]. Heart rate values, measured at the fifth week of the experiment, were 264 ± 17,270 ± 6,282 ± 31 beats/min in the CONT, SR, and dDAVP groups, respectively (P = NS).
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). Urinary albumin excretion was affected by DS, but there was a strong interaction with the pretreatment (P < 0.0001). After DS administration, the increase in albumin excretion was steeper and greater in dDAVP than in the other two groups (Fig. 2). There was no significant difference between the SR and CONT groups.
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Echocardiography and morphological results
Echocardiography performed after 3 wk of DS treatment revealed a thickening of the posterior wall in the dDAVP compared with the CONT and SR groups (PWTd, 1.73 ± 0.07, 1.37 ± 0.03, and 1.33 ± 0.03 mm, respectively; P < 0.0001), whereas LVMi was not increased (2.53 ± 0.12, 2.25 ± 0.12, and 2.39 ± 0.12 mg/g BW, respectively; P = NS). No significant difference in PWTd was detected at this time between CONT or SR rats and uninephrectomized normotensive rats (without DS; 1.26 ± 0.04 mm). No change in contractility was detected among the different groups (42 ± 3%, 42 ± 1%, and 38 ± 2% in dDAVP, CONT, and SR, respectively). At the postmortem examination, left ventricular weight was greater in the three DS groups than in the normotensive rats. However, this increase was more marked in the dDAVP (+23%; P < 0.0001) and was slightly less marked in the SR (-6%; P = NS) groups than in the CONT group (Table 2). Histological examination (Fig. 3) showed fibrosis in all of the rats in the dDAVP group, with severe scar fibrosis and, in some cases, myocyte necrosis and coronary artery fibrin necrosis. The other groups showed low levels of scar fibrosis without any myocyte or vascular necrosis. Morphometric analysis revealed higher values in dDAVP than in CONT for scarring (0.003 ± 0.002 vs. 0.001 ± 0.000 µm2), pericoronary (42.4 ± 13.0 vs. 33.9± 2.6 µm), and interstitial (0.75 ± 0.02 vs. 0.66 ± 0.03%) collagens. SR treatment did not reverse the fibrosis.
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). The DS-induced changes were amplified by dDAVP treatment and tended to be lowered by SR 121463 [+32% (P < 0.0001) and -12% (P = NS), respectively, compared with CONT]. These results are in agreement with previous findings showing that kidney weight was affected by urine concentrating activity (25). Glomerular hypertrophy was induced by DS (P < 0.05), but with no difference among the dDAVP, SR, and CONT groups (16,248 ± 474, 18,923 ± 658, 18,747 ± 865, and 18,205 ± 617 µm2 in the normotensive, dDAVP, SR, and CONT groups, respectively). Renal histological lesions were almost absent in SR rats and were mild in the CONT rats, but were severe in dDAVP rats (Fig. 4). These lesions consisted of 1) arterial wall thickening in the CONT group, with fibrinoid necrosis in the dDAVP group (score of 0.02 ± 0.01 vs. 0.84 ± 0.30; P < 0.01); 2) mild interstitial fibrosis, with some dilated tubules with casts in the CONT group and with tubular atrophy and casts in the dDAVP group (score of 0.02 ± 0.02 vs. 0.50 ± 0.13; P < 0.0001); and 3) focal glomerulosclerosis in the CONT group, with necrosis and cell hyperplasia in the dDAVP group (score of 0.01 ± 0.01 vs. 0.14 ± 0.06; P < 0.05).
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-subunit mRNA level in the kidney (0.87 ± 0.04 vs. 0.74 ± 0.03; P = NS), with no difference in mRNA level of ß- and -subunits. In contrast, DS administration markedly enhanced ß and mRNA levels in the colon [ß, 1.37 ± 0.34 vs. 0.85 ± 0.07 (P = 0.11); , 0.76 ± 0.18 vs. 0.23 ± 0.05 (P < 0.05)], in agreement with previous reports on the effect of aldosterone on ENaC subunit abundance in this organ (26, 27).
The V2 agonist, dDAVP, enhanced ß and mRNA levels in the kidney of DS rats (P < 0.03 and P < 0.04, respectively), but did not alter the level of -subunit mRNA (Fig. 5). In view of the increase in kidney mass in dDAVP rats and therefore the probable increase in the amount of total mRNAs in the cortex, ß and mRNA levels per kidney may be markedly higher in dDAVP than in other groups. The expression of the different ENaC subunits was unchanged in the lung and colon (not shown). V2 antagonist had no effect on ENaC subunit mRNAs in the three organs studied.
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Discussion |
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Vasopressin and basal blood pressure
After only 10 d of vasopressin V2 agonist treatment, basal blood pressure had been increased by 11 mm Hg. As far as we are aware, no study had previously reported this effect. The implication of vasopressin in normal blood pressure regulation had been generally considered to rely on its V1 receptor-mediated pressor effect. The present observation strengthens our previous hypothesis that the action of this hormone promotes sodium retention by activating V2 receptors, activation that regulates the mRNA level, protein abundance, and the activity of ENaC in the cortical collecting duct (7, 8). This effect of vasopressin on blood pressure was probably observed in our experiments because we studied conscious euvolemic rats, thus avoiding the natriuresis induced by hormonal changes during inappropriate volemic expansion (28). Furthermore, in the uninephrectomized rat, despite the compensatory renal hypertrophy, the pressure natriuresis curve is probably reset to excrete the sodium reabsorbed under the influence of vasopressin and to maintain a stable sodium balance, as seen in our study. The observation that the V2 antagonist did not induce a significant decrease in blood pressure is in agreement with other observations (Nicco, C., and N. Bouby, unpublished) that chronic V2 antagonist administration in healthy Sprague Dawley rats does not alter ENaC mRNA abundance. To confirm that this absence of effect was not related to the dosage of antagonist chosen, in an additional experiment we tested a higher dose of the V2 antagonist (6 mg/kg·d), which lowered urine osmolality from 1744 ± 167 to 355 ± 44 mosmol/kg H2O, and did not find any significant difference in blood pressure between control and SR121463-treated rats (133 ± 6 and 132 ± 4 mm Hg, respectively). Nevertheless, we cannot rule out the possibility that other systems counteracted a reduction in V2 effects as an increase in the V1 vasopressive action of vasopressin subsequent to the rise in endogenous secretion of the hormone that followed the exposure to V2 antagonism.
It should be noted that the effect of dDAVP on blood pressure observed in the present study appears to contradict the regional vasodilator and hypotensive effects of this agonist reported by several researchers in healthy humans and animals (29, 30, 31, 32, 33, 34). This apparent contradiction could be explained by the fact that these vasodilator and hypotensive effects were induced by the short-term infusion of dDAVP and were mediated by vascular V2 receptors. In the rat kidney, stimulation of medullary V2 receptors (related to interstitial or epithelial cells) prevented the development of hypertension induced by chronic stimulation of medullary V1 receptors (35). In our experiment, this V2 effect of vasopressin on medullary blood flow was probably masked by the effect on ENaC activity in the cortical collecting duct.
Vasopressin and DS hypertension
The DS model is characterized by a low plasma renin level, and usually by increased plasma volume and severe renal lesions. In the present study the protocol was designed to induce nonmalignant hypertension. Indeed, the CONT group displayed steady weight gain, zero mortality rate, no neurological disorder, a very slight increase in natremia, no change in hematocrit, subnormal kaliemia throughout all the experiment, and moderate renal lesions.
DS administration markedly increased the urinary flow rate and decreased urinary osmolality. This apparent dilution of the urine corresponds to an enhancement of the urine concentrating activity related to the increase in sodium load as reflected by calculations of free water reabsorption [68 ± 4 vs. 91 ± 8 ml/d (P < 0.05) in CONT before and during DS, respectively]. The V2 agonist failed to increase urine osmolality when combined with DS, probably because the urine concentrating activity was already maximal under these conditions, but it could also be due to the rise in the endogenous vasopressin level (36) and V2 receptor desensitization (37) induced by the administration of DS. However, despite the lack of any effect on urinary osmolality, net deleterious effects of dDAVP were observed on blood pressure, urinary albumin excretion, hematocrit and uremia, survival rate, and cardiac and renal hypertrophy.
These functional and morphological changes were accompanied by an increase in the abundance of ß and ENaC subunit mRNA in the renal cortex. In a previous study of healthy rats (8), we showed that the increase in net sodium transport by the cortical collecting duct is far higher than the increase in the abundance of the ENaC subunit, suggesting that vasopressin enhances the number of functional channels and also activates additional mechanisms contributing to increased transport activity. Similar phenomena probably occur in DS rats treated with dDAVP. Synergism between the actions of the V2 agonist and the mineralocorticoid analog probably amplify sodium reabsorption (38). Other effects of vasopressin besides those on ENaC activity could also be responsible for the greater increase in blood pressure observed in the dDAVP group.
The V2 antagonist reduced the urine concentrating effect in DS-treated rats, but did not induce any significant reduction in their blood pressure and did not alter natremia and hematocrit despite its significant effect on diuresis. This finding conflicts with the prevailing concept that the contribution of vasopressin in DS hypertension is directly related to its antidiuretic effect. If this is the case, an increase in diuresis would significantly reduce the volemic expansion and thus lower the blood pressure. In fact, vasopressin is likely to contribute to salt-related hypertension by stimulating sodium transport in renal distal tubule and by increasing water reabsorption. In the early stages, the effect on sodium movement probably facilitates the reabsorption of free water at the expense of some sodium retention, which is rapidly offset by a pressure increase. In the later stages, it facilitates volumic expansion. This hypothesis is supported by the absence of any effect of V2 antagonist administration during the first 2 wk of the onset of hypertension in Dahl-sensitive rats fed a high sodium diet (39) and the attenuation of the increase in blood pressure by chronic V2 antagonist treatment in the DS model with severe hypertension and volume expansion (40).
In the present study end-organ damage related to hypertension was found to be worsened by the V2 effects of vasopressin and accompanied by an increase in lethality. One month after the induction of hypertension, dDAVP treatment was found to induce a significant increase in the diastolic thickness of the posterior wall, and hypertrophy of the entire left ventricle was clearly visible in the rats 2 wk later. The possible involvement of vasopressin in cardiac remodeling, independently of its effects on water retention, has not been extensively studied. In heart failure induced by creating an aortocaval fistula in the rat, V2 antagonist treatment reduces the weight of the left ventricle (41), whereas the same treatment does not influence cardiac remodeling, cardiac function, or survival in the model of congestive heart with coronary artery ligation (42). The deleterious effect of dDAVP on cardiac hypertrophy observed in our study may have been due to a direct myocardiac effect and/or to consequences of renal actions of the molecule.
The DS model, characterized by high intraglomerular pressure, has often been used to study the progression of chronic renal failure. The lack of change in the hematocrit, uremia, creatininemia, and albuminuria in CONT rats before and after 1 month of DS administration indicates that normal renal function was maintained. However, the anemia, elevated uremia, and more marked albumin excretion observed in the DS- and dDAVP-treated rats suggest ongoing renal involvement. The hyperalbuminuria is probably mainly attributable to systemic hypertension, but an additional specific effect of vasopressin cannot be excluded, because dDAVP slightly increased albumin excretion before DS, as previously reported in healthy rats and human subjects (43, 44). The increase in uremia could also be partly due to the increase in the vasopressin-dependent reabsorption of urea in the final part of the collecting tubule, leading to a decrease in the fractional excretion of urea and an increase in its plasma concentration (45). The histological analysis of the kidneys after 2 months of DS administration confirmed the presence of kidney damage in dDAVP-treated rats and demonstrated that SR treatment protected the rats against the development of renal lesions. These findings are consistent with those of our previous studies showing that the V2 effect of vasopressin is involved in the development of chronic renal failure induced by 5/6 nephrectomy in the rat (46).
In conclusion, we showed that chronic stimulation of vasopressin V2 receptors increases blood pressure in the healthy rat and worsens DS hypertension, and heart and kidney damage and the mortality it causes. Epidemiological studies indicate that blood pressure is related to the risk of cardiovascular and cerebrovascular events. Our blood pressure data under basal conditions and after DS treatment suggest that vasopressin and high urine concentrating activity could be additional risk factors in some forms of hypertension.
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Acknowledgments |
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Footnotes |
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Abbreviations: CONT, Control group; dDAVP, 1-deamino-8D-arginine vasopressin; DOCA, deoxycorticosterone acetate; DS, deoxycorticosterone acetate-salt; ENaC, epithelial sodium channel; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LVD, left ventricular diameter; LVDd, diastolic left ventricular diameter; nt, nucleotides; PWT, posterior wall thickness; PWTd, diastolic posterior wall thickness; SBP, systolic blood pressure.
Received January 14, 2002.
Accepted for publication March 27, 2002.
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References |
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, ß, and subunits of the amiloride-sensitive Na+ channel in colon, lung and kidney. Pflugers Arch 430:299–307[CrossRef][Medline]
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), V2 antagonist-treated (SR; 
), or V2 agonist-treated (dDAVP; 
) rats. A, Before any treatment; B, after 10 d of V2 antagonist or agonist treatment; C, after 4 wk of DS administration with V2 antagonist or agonist treatment still continuing. By ANOVA followed by Fisher’s post hoc test: *, P < 0.05, dDAVP or SR vs. CONT; #, P < 0.05, dDAVP vs. SR. n = 7/group.
), V2 antagonist-treated (SR; 
), or V2 agonist-treated (dDAVP; 
