Role of V1- and V2-receptors in mechanism of physiological paradox--an increase of reabsorption of the solute free water and simultaneous rise of diuresis

In experiments on non-anesthetized rats with administration into stomach of water (5 ml/100 g body mass) direct correlation has been found between an increase of diuresis and excretion of solute free water (r = 0.98, p < 0.01), while after injection to these animals of 5 x 10(-11) M arginine-vasotocin - between an increase of diuresis and simultaneous rise reabsorption of solute free water (r = 0.8, p < 0.01). The rise of diuresis after the vasotocin injection is due to inhibition of sodium re- absorption, with the solute excretion fraction increasing from 2.6 +/- 0.2 % to 11.9 +/- 1.2, p < 0.001. A similar physiological paradox - an increase of diuresis with the simultaneous increase of reabsorption of solute free water - has been revealed at night hours in children with tendency for nocturnal enuresis (r = 0.64, p < 0.01). Mechanism responsible for this phenomenon consists in a rise of diuresis due to a decrease of sodium ion reabsorption in the ascending Henle loop limb. A problem is discussed of the homeostatic significance of a decrease of sodium reabsorption combined with an increase of solute-free water reabsorption; it is suggested that this phenomenon is based on a redistribution of reabsorption inside the nephron - a decrease of ion and water reabsorption in the initial parts of the nephron distal segment and an increase of solute free water reabsorption with the antidiuretic hormone-stimulated high osmotic permeability of terminal parts of renal tubules. An intraperitoneal injection of V1-anatagonist (OPC-21268) decreased the natriuretic component of response to arginine-vasotocin, while injection of V2-antagonist (OPC-31260) eliminated the antidiuretic component.     

Evolutionary Advantages of Participation of Vasopressin instead of Vasotocin in Regulation of Water–Salt Balance in Mammals

In experiments on non-anesthetized Wistar white rats there was studied reaction of kidney to an intramuscular injection of arginine vasotocin or arginine vasopressin at doses from 0.001 to 0.05 µg/100 g body mass on the background of a water load. Water (5 ml/100 g body mass) was administered through a catheter into stomach to suppress secretion of endogenous antidiuretic hormone (ADH). In experiments with water administration, diuresis increased due to a decrease of osmotic permeability of renal tubules and to excretion of osmotically free water, with the constant clearance of sodium ions. Injection of 0.05 µg arginine vasopressin led to a marked decrease of diuresis due to a rise of reabsorption of osmotically free water without elevation of excretion of osmotically active substances. Injection of the same dose of arginine vasotocin resulted in no increase of diuresis; however, reabsorption of osmotically free water and excretion of osmotically active substances including sodium ions were more pronounced. Hence, both vasotocin and vasopressin increased osmotic permeability of the tubular epithelium, but vasotocin, unlike vasopressin, promoted reduction of reabsorption of sodium ions and their loss with urine. A suggestion is made that one of the reasons for replacement in mammals of the molecular ADH forms (vasotocin by vasopressin) was the absence of the pronounced natriuretic effect in arginine vasopressin. This was of crucial significance to preserve sodium ions in the organism, to maintain water–salt balance in animals adapted to the terrestrial life, and to provide not only osmo-, but also volumoregulation.     

Mechanism of the central action of insulin on kidney function

Injection of insulin to the CSF in the presence of spontaneous diuresis and hydration gives rise to the growth of reabsorption of osmotically free water accompanied by high tubular transport, as well as to the development of antinatriuresis and inhibition of diuresis. Experiments with a preliminary blockade of beta-adrenoreceptors with propranolol or administration of a beta-blocker following insulin injection demonstrated beta-adrenoreactive brain structures to be involved in the mechanism of action of insulin. Secondary activation of vasopressin secretion and release in the blood may be mediated via these structures, as a result of which reabsorption of osmotically free water in renal tubules gets increased. Thus, CSF insulin effects its influence on renal function via the central neurohumoral mechanisms which work due to beta-adrenergic brain receptors.     

Release of antidiuretic hormone (ADH) under the influence of gastric distention in the rabbit. Demonstration by radioimmunoassay]

In this investigation, are studied in rabbits, the effects of gastric distention upon plasma concentration of vasopressin; the arginine-vasopressine is determined by a very sensitive radio-immunologic method. Increases of intragastric ballonet pressure up to 10-20 cmH2O induce significant rise in plasma vasopressin concentrations averaging 21 +/- 3,7 muU/ml (base line 6,25 +/- 2,3 muU/ml). Increase of vasopressin is associated with significantly lowered diuresis. Intravenous injections of nicotine induce similar decrease in urine flow and increase of plasma AVP concentrations up to 12,01 +/- 1,7 muU/ml.     

Renal effects of cyclic AMP in normal and congenital diabetes insipidus rats

The administration of dibutyryl cyclic AMP to normal rats undergoing water diuresis and to rats with congenital diabetes insipidus resulted in a rise in the excretion of Na⁺ and K⁺. A reduction in free water clearance was also observed in the normal rat, but this could not be entirely attributed to the effect of the nucleotide alone. Infusion of cyclic AMP to Brattleboro rats led to a modest rise in urine osmolality and a fall in urine flow, free water clearance and solute excretion, all of which could be explained on the basis of a fall in GFR. From the present experiments, it may be concluded that at the doses used neither cyclic AMP nor its dibutyryl derivative mimic the effects of ADH on water reabsorption by the kidney in vivo.     

Effects of atrial natriuretic factor on renal handling of water and electrolytes in rats

The intravenous injection of an extract of atrial myocardium into anesthetized rats during a hypotonic diuresis resulted in an increase in the renal excretion of water, sodium, potassium, calcium, magnesium, and phosphate. There was an increase in urine concentration which was probably a result of the secretion of vasopressin since it did not occur in Brattleboro (di/di) rats. A transient increase in glomerular filtration rate and renal plasma flow occurred during the first five minutes with a more sustained rise in filtration fraction. Injection of atrial extract also caused a partial inhibition of solute-free water formation in Brattleboro rats subjected to water diuresis and a partial inhibition of solute-free water reabsorption in rats subjected to maximal antidiuresis by infusing vasopressin. In neither case was the degree of inhibition as profound as that observed after injecting furosemide in a dose which caused a comparable natriuretic response. A large dose of furosemide blocked the natriuretic response to atrial extracts whereas, when a comparable level of sodium and water output was produced by massive infusions of saline, the natriuretic response to atrial extract was increased. It is suggested that atrial natriuretic factor might inhibit sodium transport in nephron segments beyond the medullary thick ascending limb. Furosemide might also act at the same tubular site or inhibit tubular secretion of the atrial natriuretic factor.     

Antidiuretic reaction of the human and rat kidney to peroral administration of arginine-vasopressin and desmopressin

Water in amount of 5 ml/100 g body weight was administered through a gastric probe into the stomach in alert rats; subjects-volunteers drank 20 ml of water per 1 kg of body weight. This resulted in diuresis at the peak of which the excreted water fraction reached 23% in rats and 12.4% in human subjects, whereas excretion of the osmotically free water amounted to 0.103 +/- 0.018 ml/min/100 g body weight and 10.0 +/- 1.8 ml/min/1.73 m2 of the body surface, respectively. These data indicate a practically complete inhibition of the arginine vasopressin secretion. On intragastric administration of 10 micrograms of arginine vasopressin or 0.2 microgram of desmopressin, with water in rats, a prolonged and quite obvious antidiuretic response occurred, with a marked increase of reabsorption of the osmotically free water in kidneys. A direct correlation has been found between the dose of the intragastrically administered vasopressin in the dose range from 0.1 to 10 micrograms/100 g body weight and a decrease of clearance of the osmotically free water. In subjects volunteers, an antidiuretic reaction to administration of 0.2 mg of desmopressin with water, was found. The data obtained provide a direct proof of intestinal absorption of nanopeptides without loss of their physiological activity. Significance of the data obtained for physiology of digestion and for clinical medicine, is discussed.     

Responses of the rat kidney to the water load test and vasopressin administered during normal feeding and fasting

Parameters of water-salt balance in Wistar rats were compared on empty stomach and at standard alimentary regimen (satiated animals). On empty stomach, the blood serum osmolatity amounted to 284 +/- 2, while in satiated rats--to 290 +/- 5 mOsm/kg H2O (p < 0.05); sodium ion concentration on empty stomach lower, whereas no difference in potassium concentration was found. After an intragastric administration of water (5 ml/100 g body mass) to unanaesthetised rats, the blood serum osmolality decreased, while diuresis increased to an equal extent in both groups of rats. For 120 min after the water administration the rats on an empty stomach excreted 92.9% of the administrated fluid, whereas the satiated animals--80.7%. The urine composition differed qualitatively: in fasting rats the increment of diuresis was due to a rise of osmotic free water excretion, whereas in satiated rats--to an increase of excretion of osmotic active substances (including Na and K ions) with water and a simultaneous increase of the osmotic free water reabsorption in the kidney. After the water load and injection of 0.005 nmole/100 g body mass of arginine-vasopressin for 2 hr of the study, diuresis in both groups of animals decreased to an equal extent, but in fasting animals this was due mostly to an increase of the osmotic free water. The data obtained indicate that, under conditions of usual alimentary regimen, the response of kidney to the water load had a character of a volume-regulating response, whereas in fasting rats--of the specific osmorequlating one. A problem is discussed of the concept of norm under usual conditions and at certain clinically accepted restrictions, for instance, on empty stomach.     

Evidence against bicarbonate reabsorption in the ascending limb, particularly as disclosed by free-water clearance studies.

Bicarbonate reabsorption in the thick ascending limb of Henle's loop was examined by studies of free-water clearance (CH2O) and free-water reabsorption (TcH2O). During maximal water diuresis in the dog, CH2O/GFR was taken as an indes of sodium reabsorption in, and urine flow (V/GFR) as an index of delivery of filtrate to, this scarbonate, infusion of a nonreabsorbable solute (hypotonic mannitol) and administration of an inhibitor of bicarbonate reabsorption (acetaent, but less than that achieved with hypotonic saline infusion. This suggests that sodium that sodium bicarbonate is not reabsorbed in the ascending limb. Rather, it is the sodium chloride, swept out of the proximal tubule by osmotic diuresis due to nonreabsorbed mannitol or sodium bicarbonate, that is reabsorbed in the ascending limb thereby increasing CH2O, whereas the nonreabsorption of mannitol and sodium bicarbonate results in a depressed CH20 per unit V when compared with hypotonic saline. V/GFR is not a satisfactory index of delivery to the ascending limb during osmotic diuresis, since it includes water obligated by nonreabsorbable solutes. When a better index of delivery, the sum of the clearances of chloride (CC1) and free-water (CH2O) is used, hypotonic bicarbonate infusion, hypotonic mannitol infusion and acetazolamide administration increase CH2O/GFR per unit delivery to the same extent as odes hypotonic saline infusion. Studies in dogs and rats on TcH2O also indicate that sodium bicarbonate is an impermeant solute in the ascending limb. Osmotic diuresis due to sodium bicarbonate diuresis, produced either by inhibition of sodium bicarbonate reabsorption (acetazolamide, L-lysine mono-hydrochloride) or infusion of sodium bicarbonate, or mannitol diuresis both produced marked chloruresis and increased TcH2O to the same extent as did hypertonic saline infusion. If chloride excretion was almost eliminated by hemodialysis against a chloride-free dialysate (dogs) or prolonged feeding of a salt-free diet (rats), TcH2O formation was unimpaired if hypertonic saline was infused but virtually obliterated during mannitol or sodium bicarbonate diuresis. Sodium reabsorption in the ascending limb, therefore, appears to be dependent upon chloride as the accompanying anion. At any given rate of bicarbonate excretion, more cloride is delivered out of the proximal tubule (as estimated from CC1 + CH2O) with hypotonic sodium bicarbonate infusion than with acetazolamide administration. This suggests that magnitude of the chlorutesis accompanying bicarbonate diuresis depends, not only on osmotic diuresis due to nonreabsorbed sodium bicarbonate, but also on the extent to which concomitant changes in effective extracellular volume influence overall sodium chloride reabsorption.     

The effect of calcitonin on the mechanisms of urine formation and sodium excretion in normotensive and spontaneously hypertensive rats]

The effects of the pig calcitonin on the kidney excretory function in normotensive (NR) and spontaneously hypertensive rats (SHR) were examined. Calcitonin injection in the dose of 0.6 U/100 g of the body mass in NR and SHR in the conditions of 6-hour spontaneous diuresis caused the increase in the urination volume due to the inhibition of the tubular water reabsorption and growth of the glomerular filtration rate. The important role in the mechanism of the decrease in the water reabsorption in SHR plays the decrease in the content of vasopressin in the blood and urea in the kidney interstitium while in NR a more marked inhibition of the water reabsorption is caused by the decrease in the concentration of both urea and sodium in the kidney layers. The natriuretic effect of calcitonin was noticed only in NR.     

The effect of intravenous hypertonic saline infusion on renal function and vasopressin excretion in sheep.

Conscious Merino ewes were given an intravenous hypertonic sodium chloride load of 4 mmol.min-1 for 100 min. This resulted in increases in urine flow, sodium and potassium excretion and plasma sodium concentration and osmolality. Urinary vasopressin output and solute-free water reabsorption increased and plasma renin activity declined. Renal plasma flow and glomerular filtration rate (GFR) rose, as did the solute clearance. The change in urinary osmolality was related to the initial urine osmolality such that when the initial urine osmolality was high the urine became more dilute, and vice versa. Tubular sodium reabsorption increased but the fractional reabsorption rate fell. It is suggested that the increase in GFR was at least partly due to the increase in AVP and that the electrolyte loss can be accounted for by the increase in GFR without necessarily involving AVP or other hormonal effects at the tubular level.     

Inhibition by angiotensin II of some vasopressin effects on renal function in sheep.

The effects of intravenous infusions of arginine vasopressin (AVP) alone and with angiotensin II (AII) on renal function were studied in conscious Merino ewes. AVP at 11.5 pmol.min-1 caused an increase in water and electrolyte output which was associated with a rise in glomerular filtration rate (GFR), solute clearance, solute-free water reabsorption and tubular sodium reabsorption. Addition of AII of 100 ng.min-1 generally reversed all of these effects. The filtration fraction, which rose during AVP infusion, increased further when AII was added due to a greater fall in renal plasma flow than in GFR. The diuretic and electrolyte-excreting effects of infused AVP appeared to be brought about by an increase in GFR. It is suggested that this inappropriate effect of AVP, which is secreted in response to water deprivation, could be countered by the simultaneous production of AII.     

The effects of two analogues of arginine-vasopressin (ornithine-vasopressin and desamino-D-arginine-vasopressin) on kidney function in sheep.

The effects of intravenous infusion of ornithine-vasopressin (OVP) and desamino-D-arginine-vasopressin (dDAVP) were studied in normal and hydrated Merino sheep. In normal sheep, OVP resulted in a diuresis, increased urinary sodium and potassium excretion, and a fall in the plasma potassium concentration. Renal plasma flow remained constant but glomerular filtration rate and filtration fraction rose markedly. dDAVP in normal sheep was antidiuretic, but its only significant effect was a small decrease in plasma osmolality. In the hydrated sheep OVP was antidiuretic and resulted in increased urinary excretion of sodium and potassium, and a fall in the plasma potassium level. Renal plasma flow fell, but glomerular filtration and filtration fraction tended to rise. dDAVP in the hydrated sheep was also antidiuretic but urinary sodium and potassium excretion was reduced. Renal plasma flow and glomerular filtration fell, with a small decrease in filtration fraction. These results suggest that the diuretic effect in normal sheep and the electrolyte-excreting effects in both normal and hydrated sheep of OVP are related to the increase in glomerular filtration, which in turn is dependent on the vasopressor activity of the hormone. The increase in glomerular filtration caused by OVP is due to an increase in the filtration fraction of an unchanged renal plasma flow, which could be brought about by an increase in renal efferent arteriolar tone. The effects of hydration of the sheep were the conventional increased urine flow, decreased urine osmolality and decreased solute-free water reabsorption. Sodium and potassium excretion rose slightly and plasma osmolality fell. Renal plasma flow and glomerular filtration both increased with little change in filtration fraction. These effects could be brought about by suppression of endogenous vasopressin and a decrease in both afferent and efferent renal arteriolar tone.     

The effect of vasopressin on renal function in young rats a clearance and micropuncture study.

Using micropuncture techniques, the author studied the effect of vasopressin on renal function in young rats at three stages of development -- in the middle of the weaning period (22 days), after weaning was over (30 days) and at the beginning of the sexual maturation period (42 days). In the presence of a hypotonic load, a small dose of vasopressin (12 muU/100 g b.w., i.v.) was most effective in the youngest age group, where it reduced the urine flow by 82% both by increasing water reabsorption and by reducing the GFR. In this group, vasopressin lowered the TF/P Na+ ratio and raised the TF/P K+ ratio in the initial part of the distal tubules of the superficial nephrons, but raised water absorption only beyond the initial part of the distal tubules. Vasopressin reduced the urine flow by 72% in 30-day-old rats by raising water reabsorption beyond the initial part of the distal tubules. The only ion to be affected was K+, whose concentration rose in the final urine. In 42-day-old rats the effect of vasopressin was manifested in only mild depression of the GFR. In this age group, as distinct from younger animals, anaesthesia and surgery evidently led to endogenous vasopressin release, so that the small dose of exogenous vasopressin did not significantly influence the test parameters. This is also underlined by the significant difference between the control urine flow of the 42-day-old and the younger rats.     

An increase in the excretion of total protein and albumin by the human kidney during water diuresis

The rate of excretion of the total protein and albumin during an increase in diuresis after water loading was studied in healthy volunteers. In the control period, the excretion of protein (7.3–11.1 mg/2 h) and albumin (0.29–0.42 mg/2 h) was within of the physiological norm range. Water loading (20 ml/kg) caused water diuresis, urine formation rate increased by a factor of 15, and the reabsorption of solute-free water changed into its excretion. The increase in diuresis was accompanied by a statistically significant increase in the urinary protein and albumin excretion, as well as by an increase in the protein-to-creatinine ratio. After water loading, the excretion of total protein, as compared to the initial period, increased by a factor of 8.4, and of the albumin excretion, by a factor of 2.8, exceeding the generally accepted limits of the norm. The role of intraglomerule hemodynamics in the development of physiological proteinuria related to water diuresis is discussed.     

Diuretic effect of intraventricular and intravenous infusions of noradrenaline in conscious sheep

Infusion of noradrenaline at rates between 32-160 nmol.min-1 for 30 min into one lateral cerebral ventricle of conscious sheep caused a diuresis which was accompanied by negative solute-free water reabsorption and which lasted for 90-120 min. The range of noradrenaline infusion rates used reflects differences between individual animals in the rate of infusion necessry to cause diuresis. Intracerebroventricular (ICV) infusion of noradrenaline at half the diuretic rate caused no significant changes in urine flow. The diuresis induced by ICV noradrenaline infusion was prevented by concurrent ICV administration of the alpha-adrenergic antagonist, phentolamine, but was not prevented by concurrent ICV administration of the beta antagonist, propranolol, or by concurrent intravenous infusion of phentolamine. Intravenous infusion of noradrenaline at rates that were diuretic by ICV infusion caused a diuresis of approximately 30 min duration which coincided with the period of intravenous noradrenaline infusion. This diuresis was prevented by concurrent intravenous infusion of phentolamine. These results were interpreted as indicating that the higher rates of ICV infusion of noradrenaline caused the prolonged water diuresis by acting at a site in the brain and, thereby, inhibiting the release of endogenous vasopressin. ICV infusion of noradrenaline at all rates was followed by a reduction in mean arterial blood pressure and pulse pressure with variable changes in heart rate and by depression of the rates of renal clearance of PAH, potassium and total solute.     

Neural lobe function in aged Wistar/Tw strain rats showing polydipsia and polyuria

Neural lobe function in male rats of the Wistar/Tw strain was studied at 3, 7 and 16-18 months of age. A significant rise in the serum arginine vasopressin (AVP) level was noted in 16-18-month-old rats showing polydipsia and polyuria. The content and concentration of AVP in the neural lobe of aged rats were significantly less than those of younger animals (3 and 7 months). These results point out an enhancement of AVP release from the neural lobe of aged rats. The reduction in urinary volume in aged rats subjected to 24 hours of water deprivation was less than those in younger animals. No increase in urinary sodium, potassium and chloride concentrations was observed in aged rats, and the decrease in electrolyte excretion from urine during the dehydration period was less in aged rats than younger ones. These results suggest that the antidiuretic response to osmotic stimuli was reduced in aged rats. The administration of AVP to aged rats resulted in a significant decrease in water intake and urinary volume, but AVP administration did not induce any change in the electrolyte balance. Therefore, it is concluded that the main cause of the development of polydipsia and polyuria is the decline in renal function but not in neurosecretory activity, although exogenous AVP can effectively reduce water intake and urinary output in aged rats.     

Effects of continuous infusion of vasopressin on circadian rhythms of food and water intake, urine output and electrolyte excretion in Brattleboro rats

Food intake (FI), water intake (WI), urine output (UO), Na+ and K+ excretions were investigated for 2 days at 4-h intervals during continuous infusion of saline or vasopressin (VP) 1.0 UI/day, in male Brattleboro vasopressin-deficient rats. Continuous VP infusion reduced significantly 24-h amounts of WI and UO, and increased Na+ excretion. A significant (3.5 h) phase advance of the circadian rhythm of WI was observed, while the group circadian rhythm of Na+ excretion was eliminated due to irregular phase shifts in the different rats. The results suggest that VP do not play a role in the generation of the circadian rhythms of water input and output, but it may participate in their internal synchronization.     

Lithium clearance in water immersion-induced natriuresis in humans

Lithium clearance (CLi) has been advanced as a measure of sodium delivery from the proximal tubules. Because information on the intrarenal effects of water immersion is only limited, and available data are conflicting with respect to the effects on the proximal tubule, we examined the effects of 3 h of water immersion on renal functional parameters, including CLi, in eight healthy subjects. Studies were carried out during maximal water diuresis. Water immersion resulted in a significant increase in sodium excretion, from preimmersion values of 74.0 +/- 9.6 to 155.4 +/- 12.0 mumol/min at the third immersion hour (P less than 0.01). This natriuresis was accompanied by an increase in CLi from 26.3 +/- 1.9 (preimmersion) to 37.0 +/- 3.1 ml/min (P less than 0.01). Fractional lithium reabsorption (FRLi) decreased from 76.4 +/- 1.0 to 69.6 +/- 1.3% (P less than 0.01). None of these changes was found in eight healthy subjects undergoing a time-control study without water immersion. The large fall in FRLi found during immersion is compatible with a major resetting of the proximal glomerulotubular balance. In this regard the renal response to water immersion resembles saline expansion rather than mere intravascular expansion. The lithium data suggested a large rise in distal delivery accompanied by an almost as large rise in distal reabsorption. The free water clearance data were in agreement with this interpretation. However, no changes were found in fractional excretion of phosphate and uric acid. Therefore such a major resetting of proximal glomerulotubular balance can be doubted.(ABSTRACT TRUNCATED AT 250 WORDS)     

Osmoregulating reactions following serotonin metabolism inhibition or activation

Effect of p-chlorphenilalanine and 5-hydroxytriptophan on the urine flow (V), glomerular filtration rate (GFR), free water reabsorption (TCH2O), and sodium fraction excretion (ENa.F%) in Wistar rats loaded with water or 2% sodium chloride solution, was studied. It was found that treatment of rats with inhibitor of serotonin biosynthesis, p-chlorphenilalanine (300 mg/kg, 48 hrs before the experiment) had no effect on the kidney response to the water loading in the experimental rats as compared to the control ones: changes in V, GFR, TCH2O and ENa.F% were the same. Treatment of rats with precursor of serotonin, 5-hydroxytriptophan which is known to increase the serotonin level in the brain (50 mg/kg) simultaneously with the water loading prevented the development of the diuretic reaction because of the high level of TCH2O reflected in the blood vasopressin concentration. Injection of 5-hydroxytriptophan at the maximum level of water diuresis resulted in the sharp increase in TCH2O and drop of the V. 5-hydroxytriptophan had no significant effect on the kidney response to the loading with the 2% sodium chloride solution. Under these conditions, increase in V was produced by suppression of the distal tubular sodium reabsorption, the TCH2O remaining at the high level. It is suggested that the brain serotonin manifested a significant stimulating effect on the vasopressin release from the neurohypophysis, but it is not involved in the mechanisms of suppression of its release into the blood. Serotonin seems not to interact with brain mechanisms regulating natriuretic function of the kidney.