Dual actions of vasopressin and oxytocin in regulation of water permeability in terminal collecting duct

1993 ◽  
Vol 265 (1) ◽  
pp. F26-F34 ◽  
Author(s):  
J. S. Han ◽  
Y. Maeda ◽  
M. A. Knepper
Keyword(s):  
Water Permeability ◽  
Receptor Agonist ◽  
Collecting Duct ◽  
Free Calcium ◽  
Vasopressin Receptor ◽  
Osmotic Water Permeability ◽  
Camp Production ◽  
Inhibitory Effects ◽  
Osmotic Water ◽  
Collecting Ducts

We conducted studies in isolated perfused terminal inner medullary collecting ducts (IMCD) from rats to investigate the roles of oxytocin and vasopressin in the regulation of osmotic water permeability. Vasopressin and oxytocin were found to have both stimulatory effects (at 0.1 nM) and inhibitory effects (at 10 nM) on osmotic water permeability. Measurements of adenosine 3',5'-cyclic monophosphate (cAMP) production demonstrated that both vasopressin and oxytocin increase cAMP production. Both the selective oxytocin-receptor agonist [Thr4,Gly7]oxytocin (10 nM) and the selective V1b agonist [deamino1,D-3-(pyridyl)Ala2,Arg8]vasopressin (10 nM) inhibited vasopressin-stimulated osmotic water permeability. In contrast, the selective V1a vasopressin-receptor agonist [Phe2,Ile3,Orn8]vasopressin (10 nM) had no effect on vasopressin-stimulated osmotic water permeability. These effects on water permeability correlated with the ability of the agents to transiently increase intracellular free calcium. The oxytocin/vasopressin-receptor antagonist [des-glycinamide9,d(CH2)5(1),O-Me-Tyr2,Thr4,Orn8]vasot ocin, which almost completely blocks vasopressin-induced calcium mobilization, also blocked the ability of 10 nM vasopressin to inhibit osmotic water permeability relative to that found with 0.1 nM vasopressin. We conclude the following. 1) Oxytocin, like vasopressin, has dual effects on osmotic water permeability, increasing it at subnanomolar concentrations and inhibiting it at suprananomolar concentrations. 2) Oxytocin, like vasopressin, can increase cAMP production, perhaps accounting for the increase in water permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Adrenomedullin Inhibits Osmotic Water Permeability in Rat Inner Medullary Collecting Ducts

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2533
Author(s):  
Fuying Ma ◽  
Guangping Chen ◽  
Eva L. Rodriguez ◽  
Janet D. Klein ◽  
Jeff M. Sands ◽  
...  
Keyword(s):  
Water Permeability ◽  
Collecting Duct ◽  
Osmotic Water Permeability ◽  
Water Reabsorption ◽  
Kinase C ◽  
Osmotic Water ◽  
Collecting Ducts ◽  
Medullary Collecting Duct ◽  
Camp Levels ◽  
Reduced Water

Adrenomedullin (ADM) is a vasodilator that causes natriuresis and diuresis. However, the direct effect of ADM on osmotic water permeability in the rat inner medullary collecting duct (IMCD) has not been tested. We investigated whether ADM and its ADM receptor components (CRLR, RAMP2, and 3) are expressed in rat inner medulla (IM) and whether ADM regulates osmotic water permeability in isolated perfused rat IMCDs. The mRNAs of ADM, CRLR, and RAMP2 and 3 were detected in rat IM. Abundant protein of CRLR and RAMP3 were also seen but RAMP2 protein level was extremely low. Adding ADM (100 nM) to the bath significantly decreased osmotic water permeability. ADM significantly decreased aquaporin-2 (AQP2) phosphorylation at Serine 256 (pS256) and increased it at Serine 261 (pS261). ADM significantly increased cAMP levels in IM. However, inhibition of cAMP by SQ22536 further decreased ADM-attenuated osmotic water permeability. Stimulation of cAMP by roflumilast increased ADM-attenuated osmotic water permeability. Previous studies show that ADM also stimulates phospholipase C (PLC) pathways including protein kinase C (PKC) and cGMP. We tested whether PLC pathways regulate ADM-attenuated osmotic water permeability. Blockade of either PLC by U73122 or PKC by rottlerin significantly augmented the ADM-attenuated osmotic water permeability and promoted pS256-AQP2 but did change pS261-AQP2. Inhibition of cGMP by L-NAME did not change AQP2 phosphorylation. In conclusion, ADM primarily binds to the CRLR-RAMP3 receptor to initiate signaling pathways in the IM. ADM reduced water reabsorption through a PLC-pathway involving PKC. ADM-attenuated water reabsorption may be related to decreased trafficking of AQP2 to the plasma membrane. cAMP is not involved in ADM-attenuated osmotic water permeability.

Endothelin-1 inhibits AVP-stimulated osmotic water permeability in rat inner medullary collecting duct

1991 ◽  
Vol 261 (6) ◽  
pp. F951-F956 ◽  
Author(s):  
R. Oishi ◽  
H. Nonoguchi ◽  
K. Tomita ◽  
F. Marumo
Keyword(s):  
Water Permeability ◽  
Collecting Duct ◽  
Renal Plasma Flow ◽  
Inhibitory Effect ◽  
Osmotic Water Permeability ◽  
Camp Generation ◽  
Osmotic Water ◽  
Collecting Ducts ◽  
Medullary Collecting Duct

Endothelin causes diuresis despite an accompanying decrease in glomerular filtration rate and renal plasma flow. Binding sites for endothelin are located not only in glomeruli but also in the inner medulla, possibly in inner medullary collecting ducts (IMCD). To determine whether endothelin has a direct tubular effect, effects of endothelin on water and urea transport were investigated using isolated microperfusion of rat IMCD segments in vitro. Endothelin, at 10(-10) and 10(-8) M, reversibly inhibited 10(-11) M arginine vasopressin (AVP)-stimulated osmotic water permeability (Pf) by 18 and 24%, respectively. Endothelin (10(-8) M) also inhibited Pf by 23% in the presence of a much higher dose of AVP (10(-9) M), whereas endothelin had no effect on Pf in the absence of AVP. On the other hand, 10(-8) M endothelin did not inhibit Pf stimulated by 10(-3) M dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP). Endothelin had no inhibitory effect on AVP-stimulated urea permeability. These data suggest that endothelin can cause diuresis by inhibiting AVP-stimulated Pf in IMCD and that the site of action is previous to cAMP generation.

Experimental tests of three-dimensional model of urinary concentrating mechanism.

1992 ◽  
Vol 2 (12) ◽  
pp. 1677-1688
Author(s):  
J S Han ◽  
K A Thompson ◽  
C L Chou ◽  
M A Knepper
Keyword(s):  
Water Permeability ◽  
Collecting Duct ◽  
Three Dimensional ◽  
Renal Medulla ◽  
Osmotic Gradient ◽  
Osmotic Water Permeability ◽  
Dimensional Model ◽  
Three Dimensional Model ◽  
Osmotic Water ◽  
Collecting Ducts

Recently, a new model of the urinary concentrating process has been proposed that takes into account the three-dimensional architecture of the renal medulla. Under the assumptions of the model, computer simulations predicted significant axial osmolality gradients in the inner medulla without active transport by the inner medullary loop of Henle. Two of the model assumptions (which constitute hypotheses for this study) were: (1) the osmotic water permeability of the initial part of the inner medullary collecting duct (initial IMCD) is very low even in the presence of vasopressin; and (2) there is significant lateral separation of structures such that thin descending limbs are far from the collecting ducts at the same inner medullary level. The first hypothesis was addressed by perfusing rat initial IMCD segments in vitro and measuring osmotic water permeability. With the osmotic gradient oriented as predicted by the model (lumen greater than bath), vasopressin increased the osmotic water permeability from 286 to 852 microns/s. Three additional series of experiments confirmed the high water permeability in the presence of vasopressin. The second hypothesis was addressed by morphometric analysis of histologic cross-sections of the rat renal medulla. Mean distances of descending limbs to the nearest adjacent collecting duct were very small throughout the inner medulla (less than 6 microns) and substantially less than in the outer medulla (28 microns). It was concluded that the data are inconsistent with both hypotheses and therefore do not support the feasibility of the "three-dimensional" model of the renal inner medulla. The axial distributions of loops of Henle and collecting ducts in the rat renal medulla are also reported.

scholarly journals Role of PKC and AMPK in hypertonicity-stimulated water reabsorption in rat inner medullary collecting ducts

2019 ◽  
Vol 316 (2) ◽  
pp. F253-F262 ◽  
Author(s):  
Josephine K. Liwang ◽  
Joseph A. Ruiz ◽  
Lauren M. LaRocque ◽  
Fitra Rianto ◽  
Fuying Ma ◽  
...  
Keyword(s):  
Water Permeability ◽  
Collecting Duct ◽  
Adenosine Monophosphate ◽  
Osmotic Water Permeability ◽  
Water Reabsorption ◽  
Compound C ◽  
Ampk Phosphorylation ◽  
Osmotic Water ◽  
Medullary Collecting Duct

Hypertonicity increases water permeability, independently of vasopressin, in the inner medullary collecting duct (IMCD) by increasing aquaporin-2 (AQP2) membrane accumulation. We investigated whether protein kinase C (PKC) and adenosine monophosphate kinase (AMPK) are involved in hypertonicity-regulated water permeability. Increasing perfusate osmolality from 150 to 290 mosmol/kgH2O and bath osmolality from 290 to 430 mosmol/kgH2O significantly stimulated osmotic water permeability. The PKC inhibitors chelerythrine (10 µM) and rottlerin (50 µM) significantly reversed the increase in osmotic water permeability stimulated by hypertonicity in perfused rat terminal IMCDs. Chelerythrine significantly increased phosphorylation of AQP2 at S261 but not at S256. Previous studies show that AMPK is stimulated by osmotic stress. We tested AMPK phosphorylation under hypertonic conditions. Hypertonicity significantly increased AMPK phosphorylation in inner medullary tissues. Blockade of AMPK with Compound C decreased hypertonicity-stimulated water permeability but did not alter phosphorylation of AQP2 at S256 and S261. AICAR, an AMPK stimulator, caused a transient increase in osmotic water permeability and increased phosphorylation of AQP2 at S256. When inner medullary tissue was treated with the PKC activator phorbol dibutyrate (PDBu), the AMPK activator metformin, or both, AQP2 phosphorylation at S261 was decreased with PDBu or metformin alone, but there was no additive effect on phosphorylation with PDBu and metformin together. In conclusion, hypertonicity regulates water reabsorption by activating PKC. Hypertonicity-stimulated water reabsorption by PKC may be related to the decrease in endocytosis of AQP2. AMPK activation promotes water reabsorption, but the mechanism remains to be determined. PKC and AMPK do not appear to act synergistically to regulate water reabsorption.

Alpha 2-adrenergic-mediated inhibition of water and urea permeability in the rat IMCD

1996 ◽  
Vol 271 (1) ◽  
pp. F150-F157 ◽  
Author(s):  
A. J. Rouch ◽  
L. H. Kudo
Keyword(s):  
Collecting Duct ◽  
Control Period ◽  
Phosphodiesterase Inhibitor ◽  
Wistar Rat ◽  
Osmotic Water Permeability ◽  
Inhibitory Effects ◽  
Cellular Events ◽  
Urea Permeability ◽  
Osmotic Water ◽  
Medullary Collecting Duct

These studies were conducted to determine whether the alpha 2-agonists epinephrine and dexmedetomidine inhibit osmotic water permeability (Pf) and urea permeability (Pu) in the rat inner medullary collecting duct (IMCD). Wistar rat IMCD segments were perfused via standard methods, and Pf and Pu were determined in separate studies. The control period was followed by adding 220 pM arginine vasopressin (AVP) or 10(-4) M dibutyryladenosine 3',5'-cyclic monophosphate (DBcAMP) to the bath. Epinephrine or dexmedetomidine, both at 1 microM, was then added to the bath, and this period was followed by adding 1 microM atipamezole, a selective alpha 2-antagonist. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine was present in all experiments with DBcAMP. Epinephrine inhibited AVP- and DBcAMP-stimulated Pf by 90% and 80%, respectively. Dexmedetomidine inhibited AVP- and DBcAMP-stimulated Pf by 98% and 97%, respectively. Epinephrine inhibited AVP- and DBcAMP-stimulated Pu by 70% and 60%, respectively. Dexmedetomidine failed to affect Pu. Atipamezole reversed all inhibitory effects. These data confirm an alpha 2-mediated mechanism in the IMCD that modulates Pf and Pu, and they indicate that inhibition occurs via post-cAMP cellular events.

Vasopressin- and cAMP-induced changes in ultrastructure of isolated perfused inner medullary collecting ducts

1993 ◽  
Vol 265 (2) ◽  
pp. F225-F238 ◽  
Author(s):  
S. Nielsen ◽  
J. Muller ◽  
M. A. Knepper
Keyword(s):  
Water Permeability ◽  
Apical Membrane ◽  
Endocytic Pathway ◽  
Ultrastructural Changes ◽  
Osmotic Water Permeability ◽  
Intercellular Spaces ◽  
Osmotic Water ◽  
Collecting Ducts ◽  
Induced Changes ◽  
Camp Stimulation

Studies were performed to correlate arginine vasopressin (AVP)-induced changes in epithelial ultrastructure with changes in osmotic water permeability in isolated perfused rat terminal inner medullary collecting ducts (tIMCD). The tubules were perfused in three time periods, i.e., a 40-min basal period, a 40-min period with 0.1 nM AVP in the bath, and a 60-min withdrawal period. In each phase, the osmotic water permeability (Pf) was measured, and the perfused tubules were fixed for electron microscopy. AVP caused a four- to eightfold increase in Pf and induced several ultrastructural changes as follows: increased cell height of IMCD cells, expansion of the intercellular spaces, formation of large vacuoles, and increased coated pit density in the apical plasma membrane [from 0.6 +/- 0.2 (n = 6) to 2.9 +/- 0.3 (n = 7) pits/100 microns membrane length]. During AVP withdrawal, Pf decreased toward the basal value in association with partial reversal of the ultrastructural changes including a decrease in coated pit density to 1.0 +/- 0.2 (n = 4). Stimulation with 8-bromoadenosine 3',5'-cyclic monophosphate (8-bromo-cAMP) (0.1 mM) produced similar changes in Pf. Coated pit density increased to 2.1 +/- 0.4 (n = 4) after cAMP stimulation and after cAMP withdrawal decreased to 1.2 +/- 0.2 (n = 6). In contrast to stimulation with AVP, cAMP stimulation did not result in dilated intercellular spaces or formation of large vacuoles. The only ultrastructural feature that directly correlated with the water permeability was the density of coated pits in the apical membrane. Organelles involved in the endocytic pathway were studied with cationized ferritin or albumin-gold in the luminal perfusate. At the end of 40 min basal perfusion or AVP stimulation, luminal tracer was found almost exclusively in large multivesicular bodies (MVB). Tubules perfused with tracer during AVP withdrawal demonstrated rapid tracer accumulation in small vesicles and small MVB within 3-5 min, a time point corresponding to the rapid phase of Pf decrease. Later (30-60 min) the label was mainly confined to large MVB. Occasionally during AVP stimulation or withdrawal, small coated vesicles and smooth vesicles with coated extensions were noted to contain tracer. The data demonstrate AVP-mediated coated pit formation and cellular changes and show very rapid internalization of apical membrane after AVP withdrawal.

scholarly journals Aldosterone Decreases Vasopressin-Stimulated Water Reabsorption in Rat Inner Medullary Collecting Ducts

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 967 ◽  
Author(s):  
Yanhua Wang ◽  
Fuying Ma ◽  
Eva L. Rodriguez ◽  
Janet D. Klein ◽  
Jeff M. Sands
Keyword(s):  
Direct Effect ◽  
Gene Transcription ◽  
Water Permeability ◽  
Collecting Duct ◽  
Osmotic Water Permeability ◽  
Water Reabsorption ◽  
Inner Medullary Collecting Duct ◽  
Urea Permeability ◽  
Osmotic Water ◽  
Medullary Collecting Duct

Aldosterone indirectly regulates water reabsorption in the distal tubule by regulating sodium reabsorption. However, the direct effect of aldosterone on vasopressin-regulated water and urea permeability in the rat inner medullary collecting duct (IMCD) has not been tested. We investigated whether aldosterone regulates osmotic water permeability in isolated perfused rat IMCDs. Adding aldosterone (500 nM) to the bath significantly decreased osmotic water permeability in the presence of vasopressin (50 pM) in both male and female rat IMCDs. Aldosterone significantly decreased aquaporin-2 (AQP2) phosphorylation at S256 but did not change it at S261. Previous studies show that aldosterone can act both genomically and non-genomically. We tested the mechanism by which aldosterone attenuates osmotic water permeability. Blockade of gene transcription with actinomycin D did not reverse aldosterone-attenuated osmotic water permeability. In addition to AQP2, the urea transporter UT-A1 contributes to vasopressin-regulated urine concentrating ability. We tested aldosterone-regulated urea permeability in vasopressin-treated IMCDs. Blockade of gene transcription did not reverse aldosterone-attenuated urea permeability. In conclusion, aldosterone directly regulates water reabsorption through a non-genomic mechanism. Aldosterone-attenuated water reabsorption may be related to decreased trafficking of AQP2 to the plasma membrane. There may be a sex difference apparent in the inhibitory effect of aldosterone on water reabsorption in the inner medullary collecting duct. This study is the first to show a direct effect of aldosterone to inhibit vasopressin-stimulated osmotic water permeability and urea permeability in perfused rat IMCDs.

scholarly journals Metformin, an AMPK activator, stimulates the phosphorylation of aquaporin 2 and urea transporter A1 in inner medullary collecting ducts

2016 ◽  
Vol 310 (10) ◽  
pp. F1008-F1012 ◽  
Author(s):  
Janet D. Klein ◽  
Yanhua Wang ◽  
Mitsi A. Blount ◽  
Patrick A. Molina ◽  
Lauren M. LaRocque ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Water Permeability ◽  
Therapeutic Option ◽  
Apical Plasma Membrane ◽  
Osmotic Water Permeability ◽  
Urea Transporter ◽  
Aquaporin 2 ◽  
Urea Permeability ◽  
Osmotic Water ◽  
Collecting Ducts

Nephrogenic diabetes insipidus (NDI) is characterized by production of very large quantities of dilute urine due to an inability of the kidney to respond to vasopressin. Congenital NDI results from mutations in the type 2 vasopressin receptor (V2R) in ∼90% of families. These patients do not have mutations in aquaporin-2 (AQP2) or urea transporter UT-A1 (UT-A1). We tested adenosine monophosphate kinase (AMPK) since it is known to phosphorylate another vasopressin-sensitive transporter, NKCC2 (Na-K-2Cl cotransporter). We found AMPK expressed in rat inner medulla (IM). AMPK directly phosphorylated AQP2 and UT-A1 in vitro. Metformin, an AMPK activator, increased phosphorylation of both AQP2 and UT-A1 in rat inner medullary collecting ducts (IMCDs). Metformin increased the apical plasma membrane accumulation of AQP2, but not UT-A1, in rat IM. Metformin increased both osmotic water permeability and urea permeability in perfused rat terminal IMCDs. These findings suggest that metformin increases osmotic water permeability by increasing AQP2 accumulation in the apical plasma membrane but increases urea permeability by activating UT-A1 already present in the membrane. Lastly, metformin increased urine osmolality in mice lacking a V2R, a mouse model of congenital NDI. We conclude that AMPK activation by metformin mimics many of the mechanisms by which vasopressin increases urine-concentrating ability. These findings suggest that metformin may be a novel therapeutic option for congenital NDI due to V2R mutations.

Regulation of osmotic water permeability during differentiation of inner medullary collecting duct

1991 ◽  
Vol 260 (5) ◽  
pp. F710-F716 ◽  
Author(s):  
E. Siga ◽  
M. F. Horster
Keyword(s):  
Water Permeability ◽  
Epithelial Transport ◽  
Collecting Duct ◽  
Osmotic Water Permeability ◽  
Osmotic Concentration ◽  
Inner Medullary Collecting Duct ◽  
Osmotic Water ◽  
Nephron Segment ◽  
Medullary Collecting Duct

Urinary osmotic concentration capacity during renal ontogeny is subject to changes of medullary cytoarchitecture and of segmental epithelial transport characteristics. Osmotic equilibrium between interstitial and tubular fluid of the terminal nephron segment in response to vasopressin is an absolute essential of maximal urinary osmotic concentration. The regulation of osmotic water permeability (Pf) in this terminal epithelial segment during ontogenetic differentiation has not been documented. The inner medullary collecting duct (IMCD), the terminal 40% of total segmental length, was dissected at two stages of postnatal ontogenetic differentiation from immature (days 7-15) and from mature (days 33-37) rat kidneys and perfused in vitro. Pf (micron/s) was measured (bath hyperosmotic) in the absence and presence of arginine vasopressin (AVP, 230 pM). Basal Pf was 32.3 +/- 4.03 (n = 26) in the immature IMCD (IMCDi) and 111.5 +/- 20.6 (n = 15) in the mature segment (IMCDm). AVP increased Pf in IMCDi from 46.4 +/- 10.5 to 102 +/- 25.7 micron/s, whereas in IMCDm the AVP-dependent change of Pf was from 104.2 +/- 41.2 to 693 +/- 176 micron/s. AVP (2,300 pM) did not further increase Pf in IMCDi. Forskolin (50 microM) changed Pf in IMCDi from 34.9 +/- 6.3 to 104.1 +/- 16 micron/s; the corresponding change in IMCDm was from 150 +/- 32 to 985.8 +/- 133 micron/s. An analogue of adenosine 3',5'-cyclic monophosphate (cAMP; 10(-3) M) increased Pf in IMCDi from 35.5 +/- 11.4 to 138.5 +/- 32.6 and in IMCDm from 79.6 +/- 32.3 to 702.2 +/- 283 micron/s.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation of inner medullary collecting duct to dehydration involves a paracellular pathway

1995 ◽  
Vol 268 (1) ◽  
pp. F53-F63 ◽  
Author(s):  
B. Flamion ◽  
K. R. Spring ◽  
M. Abramow
Keyword(s):  
Water Permeability ◽  
Apical Membrane ◽  
Collecting Duct ◽  
Basolateral Membrane ◽  
Osmotic Water Permeability ◽  
Inner Medullary Collecting Duct ◽  
Osmotic Water ◽  
Medullary Collecting Duct ◽  
Paracellular Pathways

Prolonged fluid restriction in rats is accompanied by functional modifications of the terminal part of the inner medullary collecting duct (IMCD) revealed by a sustained increase in arginine vasopressin (AVP)-independent transepithelial osmotic water permeability (PTE) in vitro. The cellular basis of this adaptation was explored in isolated and perfused terminal IMCDs of Sprague-Dawley rats using video and fluorescence microscopy. Basolateral membrane osmotic water permeability (Posm), transcellular Posm, and PTE were measured in quick sequence in every tubule. They were expressed per unit area of basolateral membrane corrected for infoldings, based on previous stereological studies and assuming no major change in membrane surface area between hydrated and dehydrated animals. Compared with IMCDs of rats with a high water intake, IMCDs of rats deprived of fluid for 36 h displayed a significantly higher basal PTE (24.9 +/- 5.1 vs. 6.1 +/- 0.6 microns/s), a similar basolateral Posm, and a higher transcellular Posm, implying a higher permeability of the apical membrane, despite the absence of exogenous AVP. However, when IMCDs of thirsted rats were exposed to AVP in vitro, their transcellular Posm (36.0 +/- 2.4 microns/s) was significantly smaller than their PTE determined simultaneously (51.8 +/- 7.1 microns/s), suggesting that part of the water flow may follow a paracellular route. A change in paracellular pathways was supported by higher apparent permeabilities to [14C]sucrose (0.85 +/- 0.27 vs. 0.28 +/- 0.04 x 10(-5) cm/s) and to [methoxy-3H]inulin (0.25 +/- 0.04 vs. 0.14 +/- 0.03 x 10(-5) cm/s) in IMCDs of thirsted rats. The nonelectrolyte permeabilities were affected neither by AVP nor by urea-rich bathing solutions. We conclude that in vivo factors related to dehydration produce a conditioning effect on terminal IMCD, which includes stabilization of the apical membrane in a state of high Posm and opening up of paracellular pathways revealed by a higher permeability to water and nonelectrolytes. The role of these adaptive phenomena remains unclear but may pertain to the sudden transitions between antidiuresis and diuresis.

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