Increased Urine Osmolality Research Articles

Antidiuretic effect of perorally administered DDAVP in hydrated humans.

Urine volume and osmolality were measured in volunteers hydrated with drinking water (2% of body weight). During maintained water diuresis DDAVP (1-deamino-8-D-arginine vasopressin) dissolved in water was administered per os. Within 15-30 min a dose-dependent antidiuretic response occurred with a concomitant increase in urine osmolality. Administration of DDAVP through a duodenal tube caused similar antidiuretic effects indicating that the intact peptide can be absorbed from the intestinal mucosa.

HYDROCHLOROTHIAZIDE-AMILORIDE IN NEPHROGENIC DIABETES INSIPIDUS

The effects of treatment with hydrochlorothiazide (50-75 mg/day p.o.) combined with amiloride (10-15 mg/day p.o.) were compared to hydrochlorothiazide (HCTZ) treatment alone in two brothers, aged 12 and 19 years, with nephrogenic diabetes insipidus. Whereas, both modalities of treatment resulted in reduction in voiding frequency and urine volume, decrease in daily fluid intake and increase in urine osmolality, the two-drug combination was found to be superior to HCTZ alone by preventing urinary potassium losses, hypokalemia and alkalosis. During admission of 3 weeks, it was also found that amiloride has an additive effect to the thiazide in terms of increasing initial urinary sodium excretion, reducing urine volume and free water clearance and lowering serum sodium and osmolality.

Developmental aspects of the renal responses to hemorrhage during converting-enzyme inhibition in fetal lambs.

The role of the renin-angiotensin system in modulating the renal hemodynamic and functional responses to reductions of fetoplacental blood volume (8.8-35.5%) was studied in two groups of fetal lambs (less than 120 days and greater than 130 days gestation; term 145 days) during infusion of either captopril (experimental fetuses) or dextrose 5% in water (control fetuses). At high hemorrhage levels (level III), renal blood flow decreased and renal vascular resistance increased significantly in both groups of fetuses (less than 120 days and greater than 130 days), either treated or not treated with captopril. However, at low hemorrhage levels (levels I and II), and contrary to what was observed in young fetuses (less than 120 days), near-term fetuses (greater than 130 days) receiving captopril showed neither significant decreases in renal blood flow nor increases in renal vascular resistance, whereas untreated fetuses of the same gestational ages demonstrated significant decreases in renal blood flow and increases in renal vascular resistance. It was found in both less than 120 day and greater than 130 day fetuses that hemorrhage is associated with a decrease in urinary flow rate and free water clearance accompanied by an increase in urine osmolality and sodium reabsorption. It was shown that captopril does not modify this response. The present study also demonstrated that the blood pressure response to hemorrhage was characterized by a similar decrease in less than 120 day fetuses, whether treated or untreated with captopril. On the other hand, blood pressure did not change in control fetuses greater than 130 days, but decreased slightly in captopril-treated fetuses during hemorrhage. Taken together, the present results tend to suggest that the renin-angiotensin system may be an important modulator of the renal hemodynamic response to low level hemorrhage as fetuses approach term, and may be more important in controlling blood pressure in near-term than in young fetuses.

Role of vasopressin in regulation of renal kinin excretion in Long-Evans and diabetes insipidus rats.

To study the relationship between vasopressin and the renal kallikrein-kinin system we measured the rate of excretion of kinins into the urine of anesthetized rats during conditions of increased and decreased vasopressin level. The excretion of immunoreactive kinins in Brattleboro rats with hereditary diabetes insipidus (DI) (24 +/- 3 pg min-1 kg-1) was lower than in the control Long Evans (LE) rats (182 +/- 22 pg min-1 kg-1; P less than 0.05). The DI rats also exhibited negligible urinary excretion of immunoreactive vasopressin, reduced urine osmolality, and increased urine flow and kininogenase excretion. In LE rats, volume expansion by infusion of 0.45% NaCl-2.5% dextrose to lower vasopressin secretion reduced (P less than 0.05) kinin excretion, vasopressin excretion, and urine osmolality to 41, 26, and 15% of their respective control values, while increasing (P less than 0.05) urine flow and kininogenase excretion. On the other hand, the infusion of 5% NaCl, which promotes vasopressin secretion, increased (P less than 0.05) the urinary excretion of kinins and vasopressin to 165 and 396% of control, while increasing (P less than 0.05) urine flow and kininogenase excretion. Infusion of vasopressin (1.2 mU/h, intravenous) enhanced (P less than 0.05) kinin excretion by two to threefold in DI rats and in LE rats during volume expansion with 0.45% NaCl-2.5% dextrose, while decreasing urine flow and increasing urine osmolality. This study demonstrates that the urinary excretion of immunoreactive kinins varies in relation to the urinary level of vasopressin, irrespective of urine volume and osmolality and of the urinary excretions of sodium and kininogenase. The study suggests a role for vasopressin in promoting the activity of the renal kallikrein-kinin system in the rat.

Feeding, drinking, urine osmolality in DI Brattleboro rats: Changes by morphine, naloxone, D-amino acids, prolyl-leucyl-glycinamide (PLG)

Bratteleboro rats placed in metabolism cages were injected with morphine (Mor), naloxone (Nal), D- and L-aspartic acid (D- and L-Asp), D-phenylalanine (D-Phe), D-leucine (D-Leu) and prolyl-leucyl-glycinamide (PLG), alone and in suitable combinations. Food and fluid intake, urine outflow, faeces weight, rectal temperature and urinary osmolality were determined at the end of seven hours period of time. Mor, Nal, D-Asp and PLG alone caused a significant decrease in food and fluid intake, urine volume and faeces weight and a significant increase in urinary osmolality being the osmolality of the Mor, D-Asp and PLG injected groups higher than 300 mOsmol/kg. The combination of Nal with Mor, D-Asp and PLG appeared to intensify the changes induced by Mor, D-Asp and PLG whereas L-Asp antagonized the majority of changes caused by Mor or PLG. The results were discussed in the light of the previous experimental findings.

Cardiopulmonary response to acute altitude exposure: Water loading and denitrogenation

In order to determine if a positive water balance would impair cardiovascular and ventilatory adjustment during acute altitude exposure, six healthy male subjects were exposed to 4570 m for 2 h with and without water loading. No significant differences in any of the measured variables were observed normal and overhydrated subjects. In order to determine if rapid ascent to altitude involves the formation of nitrogen bubbles which could impair gas exchange, 11 subjects were exposed to 4570 m with and without denitrogenation (by breathing 100% O 2 prior to ascent) and 6 subjects were exposed to normobaric hypoxia (14% O 2). Prior O 2 breathing reduced the hyperventilatory and alkalotic responses to altitude, tachycardia did not develop, and systemic blood pressure fell, despite the fact that arterial desaturation was similar to that during the untreated altitude exposure. Reduced urine flow and increased urine osmolality were observed in two subjects at 4570 m, but these changes were not observed in the same subjects after O 2 breathing. Breathing 14% O 2 also produced the same degree of arterial desaturation but the hyperventilatory response was significantly greater than in the prior altitude exposures. Heart rate, blood pressure, and urine flow and osmolality were not altered and symptoms of altitude illness were minimal. Thus, neither of our hypotheses proved to be correct; however, we did observed a prolonged effect of O 2 breathing on the hypoxic ventilatory response, and a potential effect of hypobaria on ventilation.

Nephrotoxicity of Fluorinated Anaesthetic Agents

SUMMARY The subject of fluorinated anaesthetic nephrotoxicity can be summarized in two figures. Figure 6 illustrates the time-course of anaesthetic defluorination following administration of methoxyflurane, enflurane and isoflurane. Figure 9 depicts changes in urinary osmolality in response to ADH administration in relationship to peak serum inorganic fluoride levels after anaesthesia. Figure 6 clearly demonstrates that the shapes of the serum inorganic fluoride curves are different after methoxyflurane, enflurane and isoflurane anaesthesia. Despite the fact that inorganic fluoride has a half-life of only 90 minutes, peak levels were maintained for three days after administration of methoxyflurane. In contrast, peak inorganic fluoride serum levels after administration of the other two agents were reached shortly after the end of anaesthesia and declined rapidly in the postanaesthetic period. To account for this prolonged elevation of fluoride levels, one has only to realize that methoxyflurane is approximately ten times more lipid soluble than either enflurane or isoflurane and that the great majority of methoxyflurane metabolism occurs in the postoperative period. Peak fluoride levels also are considerably higher after methoxyflurane anaesthesia than after administration of the other two agents. That is because methoxyflurane is biochemically more unstable than either enflurane or isoflurane and is metabolized more per unit time. Consequently, the area under the serum inorganic fluoride curve is much greater for methoxyflurane than it is for enflurane and isoflurane. Figure 9 demonstrates the strong correlation between changes in urinary osmolality after ADH administration and serum inorganic fluoride levels. Patients anaesthetized with halothane, in whom serum inorganic fluoride levels ranged from 1 to 3 /zM, showed a small increase in urinary osmolality. Volunteers anaesthetized with enflurane, in whom fluoride levels were 3 to 5 μM five days after anaesthesia, showed no change in maximum urinary osmolality, whereas an average decrease of approximately 250 mosmol/kg was seen the day after anaesthesia when the mean fluoride level was 33.6 /zM. Following high-dose methoxyflurane anaesthesia, fluoride levels ranged from 80 to 250 μM and the decrement in maximum urinary concentrating ability ranged from 400 to 600 mosmol/kg. It appears that the answers to the questions regarding inorganic fluoride nephrotoxicity are clear. Methoxyflurane is a dose-related nephrotoxin; its use should be reserved for clinical situations where it is specifically indicated, such as when a potent inhalational analgesic agent is required and when total dosage will be low (less than 2 MAC hours). Enflurane would appear to be safe in all patients, including those with mild to moderate renal impairment.

Primary Polydipsia

A patient with lifelong severe polyuria and polydipsia had normal serum antidiuretic hormone (ADH) levels and responded to water deprivation with a prompt increase in urine osmolality and maintenance of normal plasma osmolality (less than 290 mOsm/kg), despite extreme thirst. When treated with desmopressin acetate and allowed free access to water, she was able to reduce plasma osmolality below 270 mOsm/kg, and her compelling thirst disappeared. The disorder is interpreted to be the result of excessive fluid intake in response to a thirst stimulus that was not inhibited by normal plasma osmolality. This study indicates that osmoreceptor control of ADH secretion is normal. Continued administration of vasopressin has relieved the symptoms and has not resulted in water intoxication.

Stimulation of renal prostaglandins by pressor hormones in man: comparison of prostaglandin E2 and prostacyclin (6 keto prostaglandin F1 alpha).

The effect of vasoconstrictive agonists and their nonpressor analogs on renal prostaglandin production was investigated in normal subjects maintained on constant diets. Arginine vasopressin (AVP), 10 U, desamino-d arginine vasopressin (dDAVP), 4 micrograms, angiotensin II (AII), 5 ng/kg . min, des-Asp angiotensin II (AIII), 5 ng/kg . min, norepinephrine (NE), 0.1 microgram/kg . min, and NE plus phenoxybenzamine (PHB), 0.8 mg/kg, were administered on separate days. Prostaglandin E2 (PGE2) and the stable prostacyclin metabolite, 6 keto prostaglandin F1 alpha were measured in 4-h urine collections by procedures with high resolution chromatography and RIA using highly specific antisera. AVP and dDAVP similarly reduced urine volume and increased urine osmolality. AII, AIII, NE, and NE + PHB did not alter basal urine volume, osmolality, creatinine, or electrolyte excretion. Blood pressure was similarly increased by AII and NE infusions (23 +/- 3 vs. 19 +/- 2 (SE) mm Hg). AVP and AII increased only PGE2 excretion (61 +/- 8 to 151 +/- 34 ng/4 h for AVP, and 38.7 +/- 7 to 75 +/- 19 ng/4 h for AII, P less than 0.05). The nonpressor analogs, dDAVP and AIII, had no effect on urinary prostaglandin excretion. In contrast, NE increased both PGE2 (from 38.7 +/- 7 to 74.5 +/- 12 ng/4 h, P less than 0.02) and 6 keto prostaglandin F1 alpha (from 34.6 +/- 8 to 56.1 +/- 9 ng/4 h, P less than 0.02). alpha-Blockade with PHB totally abolished the NE-induced systemic pressor and prostaglandin stimulatory effect. These data suggest that renal PGE2 and prostacyclin are not altered in parallel by vasoactive stimuli. PGE2 appears to be released in response to agents that induce renal vasoconstriction and reduced renal blood flow whereas renal prostacyclin excretion is stimulated by an adrenergic agonist via alpha-receptor activation and not vasoconstriction per se.

Plasma prolactin responses to acute changes in central blood volume in man.

The present study examined the relationship between plasma prolactin (PRL) and central blood volume (CBV) in man. 6 adult males lay in a lower body pressure box at a thermoneutral ambient temperature (27 degrees C) on three occasions. On each occasion a 70-min control period was followed by a 20-min exposure to a lower body pressure of either 0 mm Hg, -20 (lower body negative pressure; LBNP), or +10 mm Hg (lower body positive pressure; LBPP), followed by a 60-min recovery period. Blood was drawn and urine collected at 30-min intervals. Blood pressure and heart rate were monitored at 30-min intervals during control and recovery periods and at 10-min intervals during lower body pressure exposure. Neither 0 mm Hg, LBNP, nor LBPP altered plasma osmolality, sodium, or potassium levels. Increasing CBV by LBPP increased systemic blood pressure (p less than 0.01) but had no effect on heart rate, plasma PRL, or urine osmolality. LBNP, in contrast, increased heart rate (p less than 0.05). Half of the subjects undergoing LBNP developed presyncopal symptoms, characteristic of a vasovagal reaction which includes precipitous hypotension. Subjects developing these symptoms tended to exhibit an increase in plasma PRL and an increase in urine osmolality. Asymptomatic subjects demonstrated no change in plasma PRL or urine osmolality. In addition, subjects exhibiting a PRL response to LBNP had a higher control period plasma PRL baseline (231%) than did asymptomatic subjects. These data suggest that while plasma PRL levels are not sensitive to nonhypotensive changes in CBV, they do respond to hypotensive decreases in CBV and/or its associated nausea.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral antidiuretic therapy: studies in the diabetes insipidus rat.

In hypothalamic diabetes insipidus, water balance is achieved primarily through the thirst mechanism. The administration of an antidiuretic agent in the drinking water should restore the antidiuretic response to volume and osmoregulatory drive. To test this hypothesis, homozygous Brattleboro strain rats were given arginine vasopressin (AVP) or 1-desamino-8-D-arginine vasopressin (dDAVP) in the drinking water in concentrations of 10-10,000 micrograms/l (AVP) and 5-10,000 micrograms/l (dDAVP). Oral AVP was found to be ineffective. Oral dDAVP resulted in 1) a progressive increase in dDAVP dose, from 2.3 to 2,559 micrograms.day-1.kg-1; 2) a dose-dependent increase in urine osmolality from 306 to 1,796 mosmol/kg; and 3) a dose-dependent decrease in urinary solute excretion. At each dDAVP dose level, stable physiological states were achieved within 24 h. Similar antidiuretic states were achieved when dDAVP was administered in increasing doses or when therapy was initiated at a high dose. These findings demonstrate that inclusion of an appropriate antidiuretic agent in the drinking water can restore the renal response to volume-osmoregulatory drive.

Single-dose aminoglycoside nephrotoxicity and lethality in rainbow trout

The nephrotoxicities of the aminoglycoside antibiotics, tobramycin (TBM) and netilmicin (NTM), were studied in rainbow trout ( Salmo gairdneri) to determine the usefulness of salmonids as a sensitive model for investigating the nephrotoxic potential of these agents. Logit analysis revealed that 8 to 12-day ip LD50s in rainbow trout for TBM and NTM were 53 ± 1 and 55 ± 1 mg/kg, respectively (95% c.i.), a nonobserved effect dose in rats. Kidney sections from treated animals showed moderate to severe dose-dependent proximal tubular necrosis in both groups, suggesting that lethality was a consequence of renal failure. NTM caused a greater incidence of glomerular lesions than did TBM. Kidney sections taken 1 month after a single injection of TBM showed active necrosis of proximal tubules suggesting a high affinity of these agents for trout renal tissue. Investigations with spinally transected, catheterized trout given single ip injections of 15 or 30 mg/kg TBM or NTM revealed that the earliest and most sensitive indicators of nephrotoxicity were decrease in clearance of [ 3H]methoxyinulin and p-[ 14C]p-aminohippuric acid. This finding was followed by decreased urine flow, increased urine osmolality, and proteinuria. Renal function indices showed the greatest difference from controls at 30 hr, while morphologic damage was greatest between Days 5 and 10. Physiological and histopathological data indicate that NTM is less toxic than TBM in rainbow trout. Results from this study suggest that the rainbow trout is a sensitive animal model in which to study the nephrotoxicity of aminoglycoside antibiotics.

Urinary concentration in the papillary collecting duct of the rat. Role of the ureter.

Urine was observed to flow intermittently in the collecting ducts of the extrarenal papilla of antidiuretic rats. The purpose of this investigation was to test Reinking and Schmidt-Nielsen's hypothesis that intermittent flow plays an important role in the production of maximally concentrated urine. Samples of collecting duct fluid were obtained from the base and tip of the papilla by micropuncture through the intact ureter. Fluid osmolality rose sharply from base, 894+/-120 mosmol/kg H(2)O(-1) (mean+/-SE), to tip, 1,667+/-114 (P<0.001), a distance of only 2 mm, and was due exclusively to reabsorption of water. After excision of the ureter, which abolished intermittent flow, osmolality fell modestly at the base to 723+/-82 mosmol/kg H(2)O(-1) (P < 0.02), but strikingly at the tip to 1,012+/-103 (P < 0.001). The pelvic ureter was paralyzed by topical verapamil and dimethylsulfoxide, which abolished intermittent flow. Osmolality of urine at the tip was not changed (1,959+/-184 mosmol/kg H(2)O(-1) before, vs. 1,957+/-126 after paralysis). The ureter was severed just beyond the papillary tip, a maneuver which preserved intermittent flow but abolished urinary reflux over the papilla. Urinary osmolality fell from 1,876+/-134 mosmol/kg H(2)O(-1) to 1,284+/-115 (P < 0.005). These findings demonstrate that when the ureter is intact, over half of the increase in urinary osmolality above isotonicity occurs in the terminal one-fourth of the medullary collecting duct and is due exclusively to water reabsorption (no net solute addition). It is the continuity of the ureter, rather than intermittent flow due to ureteral peristalsis, which is essential for the formation of a maximally concentrated urine.

Angiotensin II and renal excretion of sodium and potassium in unanaesthetized dogs

Aldosterone is a kaliuretic hormone. It is also widely believed to be instrumental for physiological renal sodium sparing. How, then, can mammals respond to incipient dehydration or low sodium intake without inappropriate potassium loss? To study this problem angiotensin II (A II) was infused intravenously in six dogs. The dose rate was 10 ng per kg per min, probably maintaining plasma A II in the upper physiological range. The A II infusions lasted 3 h, i.e. long enough for the effects of increased aldosterone release to be observable. Mean arterial blood pressure increased by 8% while effective renal plasma flow and glomerular filtration rate fell by 28% and 7%, respectively. Renal sodium excretion fell to near 8% of the preinfusion control values. Plasma aldosterone increased three-fold. Yet no kaliuresis occurred. Potassium and chloride excretion declined by 50% and 80%, respectively. In five of the six dogs urine flow decreased 50% or more with concomitant increase of urine osmolality. Our data indicate that physiological increments of A II can bring about sustained renal sodium sparing without inducing potassium wasting.

Prostaglandin E2 and F2 alpha reduces urea reabsorption from the rat collecting duct.

The present study examines the possibility that prostaglandins affect the renal tubular handling of urea. Meclofenamate (1 mg.kg-1.h-1), an inhibitor of prostaglandin synthesis, decreased fractional urea clearance from 86 to 67%, increased urine osmolality, and decreased the fractional excretion of water in rats undergoing a hypertonic sodium chloride diuresis. The percentage of [14C]urea microinjected into distal convoluted tubules that was recovered in urine fell from 75 to 64% (P less than 0.01) after meclofenamate. The fraction of injected urea excreted like inulin (direct recovery) was reduced from 20 to 8% (P less than 0.0001) by meclofenamate. Addition of PGE2 (1.2 or 89 pmol) or PGF2 alpha (1.4 pmol) to the microinjectate returned the urinary recovery of the microinjected [14C]urea to the control level, but PGA2 (3 pmol) did not. Direct urea recovery was doubled by PGE2 or PGF2 alpha. These results indicate that prostaglandin E2 and F2 alpha inhibit the reabsorption of urea in the collecting duct. Prostaglandins may participate in the renal concentrating mechanism by altering the inner medullary influx of urea.

Intranasal administration of desmopressin acetate (DDAVP) to hemophiliacs

The intravenous infusion of desmopressin acetate (DDAVP), a synthetic vasopressin analogue, has been shown to cause a sustained increase in all Factor VIII related properties (VIII-C, VIIIR-Ag, VIIIR-WF) in patients with mild to moderate hemophilia and von Willebrand's disease. This study examines the effect of high doses of intranasal DDAVP (0.4 μg/kg BiD) in four patients with hemophilia A and one patient with von Willebrand's disease. In spite of a physiologic response with a decrease in urine volume and increase in urine osmolality, there was no effect on the Factor VIII complex.

Lack of effect of chronic renal denervation on altered sodium reabsorption during increased ureteral pressure.

The role of the renal nerves in the altered sodium reabsorption which occurs during increased ureteral pressure was studied using clearance techniques in anaesthetized rats undergoing diuresis induced by isotonic saline infusion. In rats with a sham denervated kidney, an ipsilateral increase in ureteral pressure to 20 cm H2O resulted in a marked and significant decrease in sodium and water excretion, increased fractional sodium reabsorption, and increased urine osmolality with no significant change in glomerular filtration rate. A similar significant ipsilateral increase in tubular reabsorption of sodium occurred in rats with chronically denervated kidneys during increased ureteral pressure. The changes in tubular reabsorption were rapidly reversible after return of ureteral pressure to normal. These experiments indicate that enhanced tubular reabsorption of sodium during an ipsilateral increase in ureteral pressure is not mediated by increased renal nerve activity. During the antinatriuresis of increased ureteral pressure there was a decrease in the fractional reabsorption of sodium from the opposite normal kidney. The role of the renal nerves in this compensatory change in function in the opposite kidney was studied in two further groups of animals. The renal response to a contralateral increase in ureteral pressure was similar in denervated and sham-denervated kidneys. The results indicate that altered renal nerve activity, through ipsilateral or contralateral renorenal reflexes, is not responsible for the changes in tubular reabsorption of sodium which occur during increased ureteral pressure induced by partial ureteral obstruction.

The effect of carbon tetrachloride treatment on urine flow rate of the rainbow trout, Salmo gairdneri

Urine flow rate (UFR) of rainbow trout was measured as an assessment of water balance after treatment with a single ip dose of CCl 4 (2.0 ml/kg). CCl 4 produced an oliguria or anuria as early as 1 hr post-treatment and a significant reduction in the 24-hr urine output. UFR for control fish appeared to follow a diurnal pattern. Additionally, CCl 4-treated fish had a significant increase in relative wet body weight that was negatively correlated to UFR. The rainbow trout normally excretes a hypoosmotic urine; therefore, an increase in urine osmolality and a slight proteinuria further suggested that treated fish had suffered an alteration in renal homeostasis. Histological examination of kidney tissue at 24 hr post-treatment revealed early, localized pathological changes; however, extensive morphological damage was absent. The early oliguria and the lack of demonstrable renal histopathological changes in CCl 4-treated rainbow trout suggest that the reduction in UFR was not the result of a direct toxic effect on the kidney.

Effect of antidiuretic hormone to the connective tissues of rat renal papilla

We studied a strain of rats with congenital diabetes insipidus homozygote (DI). The collecting tubules could not concentrate urine. Electron microscopy shows cytoplasmic lesions, vacuoles, swelling and degenerating mitochondria in the collecting tubule cells. Heterozygous animals are similar to the normal animals and rarely show the above described lesions. The connective tissue mucopolysaccharide (MPS) in the renal papilla of normal rats stains more intensely with Alcian Blue-PAS than comparable tissue from DI rats. After vasopressin was given daily to the DI rats for a period of more than three weeks, the animals present a normal water intake, an increase in urine osmolality and an increase in MPS in the connective tissue. The cytoplasmic lesions in the collecting tubule cells also disappear. Thus, it seems reasonable to relate the morphologic changes of DI rats to a lack of appropriate ADH activity. Apparently, ADH causes alteration in the polymeric state of the MPS in connective tissue of the papilla and thereby presumably induces changes in permeability.

Central cholinergic receptors and antidiuresis due to hypertonicity in sheep.

Injection of 10 microgram of carbachol into a lateral cerebral ventricle caused a large reduction in urine flow and free water clearance and an increase in urine osmolality in water-loaded sheep. This antidiuretic effect persisted for at least 1 h, and was prevented by a prior intracerebroventricular (ICV) injection of atropine (100 microgram). ICV injections of atropine (100 microgram) given 10 min before and again midway throgh an intracarotid infusion of 2 M NaCl at 0.8 ml/min for 10 min did not alter the antidiuretic response which normally follows this hypertonic stimuli. It was concluded that in sheep, while periventricular cholinergic synapses capable of influencing antidiuretic hormone may exist, it is unlikely that ADH secretion in response to hypertonicity is mediated through such synapses. Cholinergic synapses located further from the cerebroventricular surface are not excluded from mediating the antidiuretic response to hypertonicity.