Antidiuretic Action Of Vasopressin Research Articles

Diuretic Action of Apelin-13 Mediated by Inhibiting cAMP/PKA/sPRR Pathway.

Emerging evidence is showing that apelin plays an important role in regulating salt and water balance by counteracting the antidiuretic action of vasopressin (AVP). However, the underlying mechanism remains unknown. Here, we hypothesized that (pro) renin receptor (PRR)/soluble prorenin receptor (sPRR) might mediate the diuretic action of apelin in the distal nephron. During water deprivation (WD), the urine concentrating capability was impaired by an apelin peptide, apelin-13, accompanied by the suppression of the protein expression of aquaporin 2 (AQP2), NKCC2, PRR/sPRR, renin and nuclear β-catenin levels in the kidney. The upregulated expression of AQP2 or PRR/sPRR both induced by AVP and 8-Br-cAMP was blocked by apelin-13, PKA inhibitor (H89), or β-catenin inhibitor (ICG001). Interestingly, the blockage of apelin-13 on AVP-induced AQP2 protein expression was reversed by exogenous sPRR. Together, the present study has defined the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/sPRR pathway in the CD as the molecular target of the diuretic action of apelin.

A Novel Mutation in the AVPR2 Gene in a Palestinian Family with Nephrogenic Diabetes Insipidus

AbstractNephrogenic diabetes insipidus (NDI) is a urinary concentrating defect resulting from resistance of the collecting duct to the antidiuretic action of vasopressin (AVP). The X-linked recessive form is the most frequent genetic cause of inherited NDI and can be caused by mutations in the gene encoding the V2 vasopressin receptor (AVPR2). A Palestinian male infant presented in the neonatal period with failure to thrive, vomiting, irritability, fever, and polyuria, and had biochemical findings consistent with NDI. The diagnosis of NDI was established based on the clinical picture, absent response to desmopressin, and a similarly affected elder brother. Sequencing of the AVPR2 gene for the patient and his affected brother revealed a novel missense mutation with replacement of G by A in codon 82 located in exon 2 (TGC → TAC), causing a cysteine to tyrosine substitution (C82Y). Testing of the mother showed that she was the carrier of that mutation. This is the identified AVPR2 mutation in a Palestinian family. Knowledge of these mutations will allow genetic counseling and early diagnosis of affected males.

Antidiuretic Action of Collecting Duct (Pro)Renin Receptor Downstream of Vasopressin and PGE2 Receptor EP4.

Within the kidney, the (pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD), particularly in intercalated cells, and it is regulated by the PGE2 receptor EP4 Notably, EP4 also controls urinary concentration through regulation of aquaporin 2 (AQP2). Here, we tested the hypothesis that sequential activation of EP4 and PRR determines AQP2 expression in the CD, thus mediating the antidiuretic action of vasopressin (AVP). Water deprivation (WD) elevated renal PRR expression and urinary soluble PRR excretion in rats. Intrarenal infusion of a PRR decoy peptide, PRO20, or an EP4 antagonist partially prevented the decrease in urine volume and the increase in urine osmolality and AQP2 expression induced by 48-hour WD. In primary cultures of rat inner medullary CD cells, AQP2 expression induced by AVP treatment for 24 hours depended on sequential activation of the EP4 receptor and PRR. Additionally, mice lacking PRR in the CD exhibited increased urine volume and decreased urine osmolality under basal conditions and impaired urine concentrating capability accompanied by severe volume loss and a dangerous level of plasma hyperosmolality after WD. Together, these results suggest a previously undescribed linear AVP/PGE2/EP4/PRR pathway in the CD for regulation of AQP2 expression and urine concentrating capability.

Clathrin-mediated endocytosis in the mechanism of antidiuretic action of vasopressin

Regulation of water permeability of collecting duct principal cells by neurohypophysial hormone vasopressin underlies the functioning of kidneys as the main effector organs providing the maintenance of the water-electrolyte balance of the organism. Clathrin-mediated endocytosis of water channels and V2 vasopressin receptors is an important step of the antidiuretic mechanism of vasopressin. Internalization of the receptors does not only reduce the number of receptors in plasma membrane, but also activates alternative intracellular signaling pathways. This review outlines the current concept of the mechanism of clathrinmediated endocytosis of V2 receptors and AQP2 water channels, which is necessary for better understanding the molecular mechanism of vasopressin action.

Integration of thermal and osmotic regulation of water homeostasis: the role of TRPV channels.

Maintenance of body water homeostasis is critical for preventing hyperthermia, because evaporative cooling is the most efficient means of dissipating excess body heat. Water homeostasis is achieved by regulation of water intake and water loss by the kidneys. The former is achieved by sensations of thirst that motivate water acquisition, whereas the latter is regulated by the antidiuretic action of vasopressin. Vasopressin secretion and thirst are stimulated by increases in the osmolality of the extracellular fluid as well as decreases in blood pressure and/or blood volume, signals that are precipitated by water depletion associated with the excess evaporative water loss required to prevent hyperthermia. In addition, they are stimulated by increases in body temperature. The sites and molecular mechanisms involved in integrating thermal and osmotic regulation of thirst and vasopressin secretion are reviewed here with a focus on the role of the thermal and mechanosensitive transient receptor potential-vanilloid (TRPV) family of ion channels.

Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease

Tolvaptan and related V(2)-specific vasopressin receptor antagonists have been shown to delay disease progression in animal models of polycystic kidney disease. Slight elevations in serum creatinine, rapidly reversible after drug cessation, have been found in clinical trials involving tolvaptan. Here, we sought to clarify the potential renal mechanisms to see whether the antagonist effects were dependent on underlying renal function in 20 patients with autosomal dominant polycystic kidney disease (ADPKD) before and after 1 week of daily split-dose treatment. Tolvaptan induced aquaresis (excretion of solute-free water) and a significant reduction in glomerular filtration rate (GFR). The serum uric acid increased because of a decreased uric acid clearance, and the serum potassium fell, but there was no significant change in renal blood flow as measured by para-aminohippurate clearance or magnetic resonance imaging (MRI). No correlation was found between baseline GFR, measured by iothalmate clearance, and percent change in GFR induced by tolvaptan. Blinded post hoc analysis of renal MRIs showed that tolvaptan significantly reduced total kidney volume by 3.1% and individual cyst volume by 1.6%. Preliminary analysis of this small cohort suggested that these effects were more noticeable in patients with preserved renal function and with larger cysts. No correlation was found between changes of total kidney volume and body weight or estimated body water. Thus, functional and structural effects of tolvaptan on patients with ADPKD are likely due to inhibition of V(2)-driven adenosine cyclic 3',5'-monophosphate generation and its aquaretic, hemodynamic, and anti-secretory actions.

Modifications of atrial natriuretic peptide and vasopressin peptides in the rat hypothalamic supraoptic nucleus during resistance training.

Many studies have demonstrated the involvement of atrial natriuretic peptide (ANP) and vasopressin (VP) in the homeostasis of body fluids, but few studies have regarded the hypothalamic magnocellular neurosecretory system during physical exercises. The aim of the present immunohistochemical work is to study the activity of ANP and VP secreting neurons of the hypothalamic supraoptic nucleus during and after resistance training. The study was carried out in Wistar rats trained by a physical resistance-type exercise, using a rung ladder and a varying load fastened to the tail of each rat; the exercise lasted 20 min everyday for periods of 15, 30 and 45 days. Animal groups were sacrificed at the end of each training period and one group was sacrificed after 60 days from the beginning of training, i.e.15 days after completing a 45 day training. The results show that ANP and VP-immunopositivity is at first lesser in the trained rats than in the corresponding controls and then increases from the 15th to the 45th day of training; the increase of the immunopositivity in the trained rats indicates a decreased degranulation of the neurons. The comparison between VP and ANP-immunopositivity suggests that in the early phase of training VP-release in the bloodstream is higher than ANP-release, therefore the antidiuretic action of VP is expected to prevail on ANP action and an electrolyte unbalance may occur.

Physiological effects of vasopressin and atrial natriuretic peptide in the collecting duct.

Vasopressin plays a primary role in the concentration of urine to maintain body fluid homeostasis. The collecting duct as well as thick ascending limb is a major target site of vasopressin. The antidiuretic action of vasopressin is mediated by the V2 receptor in the basolateral membrane of principal cells in the collecting ducts. The binding of vasopressin to V2 receptors causes an activation of adenylate cyclase and a synthesis of cAMP. Vasopressin regulates water and ion transport through V2 receptor-mediated ion channels and transporters. In contrast, the V1a receptor mainly in the luminal membrane of distal nephron regulates basolateral V2 receptor-mediated action with regard to water and ion transport through the activation of G(q/11) and phosphoinositide turnover. Guanylate cyclase forms three types of ANP receptors, although NPR-A and B (GC-A and B) are biologically active and related to the synthesis of cGMP. Urodilatin, synthesized by the kidney, causes natriuresis by binding to GC-A in the collecting ducts. ANP causes diuresis and natriuresis, at least in part by inhibiting the V2 receptor-mediated action of AVP in the collecting ducts. The site of interaction of ANP and AVP is post cAMP synthesis, at least in the collecting ducts. The roles of AVP and ANP under pathophysiological conditions have been reported.

Antidiuretic action of vasopressin: quantitative aspects and interaction between V1a and V2 receptor-mediated effects.

(1) Vasopressin (VP), or antidiuretic hormone, is secreted in response to either increases in plasma osmolality (very sensitive stimulus) or to decreases in plasma volume (less sensitive stimulus). Its normal plasma level is very low (about 1 pg/ml, i.e. 10(-12) M), close to the detection limit of present immunoassays, and distinct antidiuretic effects are observed after infusion of small undetectable amounts of VP. (2) This antidiuretic action results from three main effects of VP on principal cells of the collecting duct (CD) mediated by occupancy of peritubular V2 receptors. (i) Increase in water permeability along the entire CD (via AQP2). (ii) Increase in urea permeability in only the terminal inner medullary CD (via UT-A1). (iii) Stimulation of sodium reabsorption, mainly in the cortical and outer medullary CD (via ENaC). VP also acts on medullary vasculature (V1a receptors) to reduce blood flow to inner medulla without affecting blood flow to outer medulla. Besides these actions, all concurring to increase urine osmolality in different and additive ways, other VP effects, probably exerted through V1a receptors located on luminal membrane, tend to limit the antidiuretic effects of the hormone. They induce the formation of prostaglandins which reduce V2-dependent cAMP accumulation in these cells and thus partially inhibit all three V2 effects. (3) Because urine is first diluted along the nephron before being concentrated in the medulla, VP is required, not only for urine concentration, but first for re-equilibration of tubular fluid osmolality with plasma osmolality, a step taking place in the renal cortex, and achieved through the reabsorption of large quantities of water (more than what is subsequently reabsorbed in the medulla to concentrate urine). Accordingly, VP effects on urine flow-rate are not linear. Small changes in plasma VP in the low range of urine osmolality will induce wide changes in urinary flow-rate, whereas in the upper range of urine osmolality larger changes in plasma VP induce much more limited further reduction in urine flow-rate. (4) Most likely, the different effects of VP require different levels of VP concentration to occur and are thus recruited successively with progressive rise in VP secretion.

Long-term regulation of urinary concentrating capacity.

Urinary concentrating capacity is regulated in part by a long-term adaptational process involving changes in the absolute abundance of the aquaporin-2 water channel in collecting duct cells. Alterations in aquaporin-2 abundance play key roles in the pathophysiology of several water balance disorders. Escape from the antidiuretic action of vasopressin, e.g. in the syndrome of inappropriate antidiuretic hormone secretion, involves a selective downregulation of aquaporin-2 expression. Excessive water retention causing hyponatremia in volume-expanded states such as congestive heart failure appears to be due in part to a failure of this escape mechanism.

Osmoregulation in clinical disorders of thirst appreciation

Thirst and drinking are essential components of normal osmoregulation in healthy man. Abnormalities of thirst appreciation, in particular hypodipsia, have profound implications for water homeostasis. The combination of cranial diabetes insipidus and hypodipsia can have particularly serious consequences, with the potential for life-threatening hyponatraemia. Although the tools for measuring thirst are subjective and lack true specificity, their use in clinical research has contributed greatly to our understanding of the physiology of thirst appreciation and the abnormal control of thirst in osmoregulatory disorders. The precise neural control of thirst appreciation remains unknown, and perhaps as a result of this, satisfactory therapies for the treatment of disorders of thirst have not yet been developed; behavioural modification and retraining of drinking habits remain the rather limited cornerstones of management.

Sex differences in the cardiovascular and renal actions of vasopressin in conscious rats.

The present study was carried out to investigate whether prostaglandins (PG) are involved in the mechanism that contributes to the sex difference in the antidiuretic and pressor actions of vasopressin. The experiments were performed in conscious male and nonestrous female rats. In hydrated rats, the graded infusion of vasopressin (10-1,000 pg.min 1.kg body wt-1) resulted in a dose-dependent antidiuresis: decreases in urine flow and free water clearance and an increase in urine osmolality. These responses were significantly greater in male than in nonestrous female rats. Pretreatment with a cyclooxygenase inhibitor, indomethacin (10 mg/kg body wt iv), significantly enhanced the antidiuretic response to vasopressin in both sexes. However, the magnitude of this enhancement was greater in female than in male rats. Thus indomethacin abolished the sex difference in the antidiuretic response to vasopressin. In a separate experiment in rats without water hydration and urine collection, infusion of pressor doses of vasopressin (1,000-6,000 pg.min-1.kg body wt-1) resulted in a greater increase in blood pressure in male than in nonestrous female rats. Treatment with indomethacin enhanced this response equivalently in both sexes and thus did not affect the sex difference in the pressor action of vasopressin. These data indicate that renal PG may mediate, at least in part, the sex difference in the antidiuretic action of vasopressin, whereas vascular PG seem not to play an important role in the sex difference in the pressor action of vasopressin.

Hereditary vasopressin resistance in man and mouse.

The DI +/+ Severe hereditary nephrogenic diabetes insipidus mouse is resistant to the antidiuretic action of vasopressin (VP) because of failure to accumulate cAMP and subsequent inability to form intramembranous particles on the apical (luminal) surface of kidney cells that normally respond to VP. The defect is primarily, if not exclusively, due to excessive activity of specific cAMP-phosphodiesterases. The abnormality can be overcome in vitro and in vivo by the phosphodiesterase inhibitor, rolipram. Most cases of hereditary NDI in man have sex-linked recessive inheritance, which appears to be due to an abnormality of the V2 receptor. The chromosomal locus of the defect is Xq28. Sporadic cases of congenital NDI have been described in females who appear to have a defect beyond the V2 receptor and the guanine nucleotide-binding stimulatory protein. There is no information on the biochemical defect in very rare cases with other types of inheritance patterns. No abnormalities of V1a and V1b receptor function have been found in patients with NDI. Mice and patients with NDI have evidence of increased AVP synthesis. AVP release in relation to plasma osmolality is increased in patients during infusion of hypertonic saline. This is the opposite of what has been described in patients with primary polydipsia (dipsogenic diabetes insipidus) who are chronically overhydrated. Together, these studies indicate that chronic dehydration and overhydration can cause up- and downregulation of the osmotic release of AVP.

Nephrogenic diabetes insipidus: clinical symptoms, pathogenesis, genetics and treatment.

This review summarizes various aspects of the inherited kidney disorder nephrogenic diabetes insipidus (NDI). The clinical manifestations of the disease are presented. The important role of the genetic localization of the NDI gene to the X-chromosome long arm, in region Xq28, for carrier detection and early (prenatal) diagnosis of the disorder is emphasized. Following an overview of the cellular physiology involved in the antidiuretic action of vasopressin, possible mechanisms in the pathogenesis of NDI are discussed. We hypothesize that NDI is most probably due to the absence or abnormality of the renal V2 receptor. This assumption is strengthened by recent findings in receptor studies, which indicate a general V2 receptor defect in NDI, and in experiments with somatic cell hybrid cell lines, which are consistent with a co-localization of the genes for NDI and for the V2 receptor in the Xq28 region. Finally, the efficacy of the combination amiloride-hydrochlorothiazide, compared with the indomethacin-hydrochlorothiazide regimen, in the treatment of NDI is presented and the advantages of the former combination are discussed.

Renal escape from vasopressin: role of pressure diuresis.

This study was designed to examine the role of increased renal artery pressure (RAP) in mediating escape from the antidiuretic action of vasopressin (AVP). In six conscious dogs in which RAP was permitted to increase, AVP infusion, at a rate (0.2 mU X kg-1 X mm-1 iv) that was acutely subpressor, gradually raised mean arterial pressure (MAP) from 97 +/- 2 to 126 +/- 4 mmHg after 5 days while decreasing urine volume and increasing urine osmolality. However, after 4-5 days of AVP infusion, urine volume and osmolality returned to control, and the hypertensive effect of AVP waned so that after 9 days of AVP, MAP averaged only 113 +/- 5 mmHg. In contrast, when RAP was prevented from increasing in seven dogs with a servo-controlled aortic occluder, AVP caused sustained decreases in urine volume and elevated urine osmolality from 609 +/- 27 to 1,160-1,711 mosmol/kg H2O throughout 8 days of infusion. The hypertensive effect of AVP did not wane when RAP was servo-controlled, and after 8 days of AVP infusion, MAP averaged 152 +/- 7 mmHg, compared with a control of 96 +/- 2 mmHg. Servo-controlling RAP also prevented the marked sodium and chloride losses seen with chronic AVP infusion in normal dogs. These findings indicate that escape from the antidiuretic action of AVP is mediated by increased RAP, which causes diuresis and natriuresis, thereby diminishing the hypertensive effect of AVP. However, when pressure diuresis and natriuresis are prevented, AVP causes severe chronic hypertensive, suggesting that AVP could be an important hypertensive mechanism when renal function is impaired.

Role of the disulfide bridge and the C-terminal tripeptide in the antidiuretic action of vasopressin in man and the rat

The antidiuretic action of a number of vasopressin analogues has been measured in the rat and man in water diuresis. These analogues had the following categories of structural alteration: a) substitution of -CH2CH2-(dicarba) and -SCH2-(6-monocarba) for the natural -SS- bridge between residues 1 and 6, b) changes in the nature of the C-terminal tripeptide produced by substitution of D-arginine and L-Nalpha-methylarginine for L-arginine in sequence position 8 and L-leucine for proline in position 7, and c) combinations of a and b. In addition, a highly active analogue which results when valine is substituted for glutamine in position 4 was tested. Trained, unanesthetized rats and normal human volunteers were complemented by a volunteer patient with posttraumatic diabetes insipidus (DI) in the total group of experimental subjects. The only change in the C-terminal tripeptide which was associated with a high antidiuretic action was D-Arg substitution. The meArg and Leu analogues showed low to very little activity and no signs of antidiuretic antagonist action. All of the carba analogues showed both high potency and prolongation of antidiuretic action in the following order (for both potency and duration): monocarba + 8-D-Arg greater than 4-Val + 8-D-Arg greater than 8-D-Arg alone, all in deamino form. None of the 8-D-Arg analogues had any side effects on the cardiovascular system, gut, uterus, bladder, etc. The prolongation was such that even with a DI patient refractory to the action of lysine-vasopressin and relatively resistant to deamino-[8-D-Arg]-vasopressin, water turnover could be reduced from untreated levels of 20 to 30 liters/day to less than 2 liters/day with only a single administration of deamino-6-carba-[8-D-Arg]-vasopressin as nose drops. The significance of these structural alterations in the vasopressin molecule for interaction with both antidiuretic and smooth muscle receptors was discussed.

Effect of hypotonicity on cyclic adenosine monophosphate formation and action in vasopressin target cells

We have shown previously that overhydration of toads renders their urinary bladders less responsive to the antidiuretic action of vasopressin (AVP). The present study investigates the relationship between osmotic swelling of vasopressin target cells and their sensitivity to AVP and dibutyryl cyclic adenosine monophosphate (db-cAMP). Conditions which engender osmotic swelling of toad bladder epithelial cells, such as immersing bladders on both surfaces in hypotonic Ringer's fluid or subjecting them to a net mucosal-to-serosal volume flux, markedly inhibited the effectiveness of db-cAMP in raising bladder permeability to water. This inhibitory phenomenon was seen both with serosal and mucosal applications of the nucleotide. Examination of isolated epithelial cells by phase contrast microscopy showed them to behave as osmometers, doubling their volume as the effective osmolality of the incubation medium was halved. AVP was found to increase the total content of cAMP about 3.5-fold both in the swollen and the normal cells, so that the actual concentration of cAMP may have diminished as the cell volume increased. Consistent with this suggestion was the observation that increasing exogenous db-cAMP abolished, in part, the inhibitory effects of hypotonicity. These observations indicate that homeostasis of body fluids in the toad depends in part upon the osmotic regulation of anti-diuretic homone action, and that intracellular cAMP may participate in coupling changes in cell volume to the altered state of responsiveness of the vasopressin target cell.

Der Einflu� eines Kaliummangels auf die renale Wirkung verschiedener Diuretica

Feeding rats a low potassium diet leads to a negative potassium balance of 1500 μeq/animal within two weeks. Glomerular filtration has been found to be slightly reduced under this condition. Na+ and urea concentration gradients between the cortex and the tip of the papilla are markedly reduced. The antidiuretic action of vasopressin is diminished. The results indicate that there is an impaired sodium transport in the ascending loop of Henle in addition to a decrease in water permeability likely to be explained by an increase in glucocorticoid secretion in potassium deficiency. The sodium diuretic effect of chlorothiazide has been found reduced under the experimental conditions described. This finding may be explained by chlorothiazide mainly acting on the loop of Henle. With reduced sodium transport in this segment in potassium deficiency, a further decrease in sodium reabsorption caused by chlorothiazide will result in a smaller amount of sodium ions excreted than with a high rate of sodium transport in normal rats. The sodium diuretic effect of furosemide has been found increased in potassium deficient rats. This result may be explained by furosemide acting on the proximal tubules and the ascending loop of Henle. Latter effect may partially prevent that there is a “corrective” reabsorption of sodium ions excluded from preceding proximal absorption under the influence of the drug. With decreased sodium transport in the loop of Henle, additional lowering of reabsorptive capacity caused by furosemide will result in a further decrease in the “correction” of the proximal effect.

THE ANTERIOR PITUITARY AND ITS RELATION TO THE ADRENAL CORTEX IN WATER DIURESIS1

IT IS WELL known, particularly from work on diabetes insipidus,that the anterior pituitary contributes to the control of water exchange by exerting a diuretic influence. This is seen most clearlywhen its action is unchecked by the antagonistic secretions of theneuro-hypophysis (reviewed by Fisher, Ingram and Ranson, 1938;and Gersh, 1939). The means by which the anterior pituitary mediatesthis effect is not fully established, but is probably multiple in nature(Richter, 1934; Schweizer, Ehrenberg and Gaunt, 1943). A somewhat different aspect of the problem can be observed when,instead of focussing attention on the daily water exchange, the disposalof measured doses of water given by stomach tube to fasted hypophysectomized animals is observed in short-term experiments. Our attention was drawn to this phase of the subject in 1939 whenwe attempted to determine whether hypophysectomized rats differedfrom normal ones in their sensitivity to the antidiuretic action of vasopressin.