Trials for simplified hypertonic saline test

Hypertonic saline test is indispensable for the evaluation of posterior pituitary function. However the test is not simple, including water loading, urine sampling and at least 45 min of hypertonic saline infusion, mostly because the test relies on urinary osmolality as an index of ADH secretion. The object of this study is try to simplify the test by directly measuring plasma ADH concentration before and after 10 min of hypertonic saline infusion. Intravenous infusion of hypertonic saline (5% NaCl, 0.24 ml/kg/min, for 10 min) was performed on normal subjects, patients with diabetes insipidus and patients with renal failure under chronic hemodialysis. Venous blood samples were obtained seriously including just before and after 10 min of the infusion. ADH was extracted from plasma using Sep-Pak C18 column and assayed by specific RIA. Minimum sensitivity of the assay was 0.25 pg/ml. The hypertonic saline infusion resulted in an increase of plasma osmolality by about 8 mOsm/kg H2O and plasma sodium concentration by 4 mEq/l. Plasma ADH increased from 0.77 +/- 0.09 to 3.42 +/- 0.73 pg/ml (m +/- SE, n = 8, p less than 0.01) in normal subjects of ad lib. water drinking and from 0.55 +/- 0.33 to 2.34 +/- 0.33 (m +/- SE, n = 4, p less than 0.05) in water loaded normal subjects (20 ml/kg of water, 60 min before hypertonic saline infusion).(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic hypernatremia derived from hypothalamic dysfunction: impaired secretion of arginine vasopressin and enhanced renal water handling.

We analyzed the disorder of water metabolism in a 32 year-old female with chronic hypernatremia. She had meningitis at 4 years, and ventriculo-peritoneal shunt operation at 13 years because of normal pressure hydrocephalus. At 14 years hypernatremia of 166 mmol/l was initially found and thereafter hypernatremia ranging from 150 to 166 mmol/l has been persisted for the last 18 years. Physical and laboratory findings did not show dehydration. Urine volume was 750-1700 ml per day and urinary osmolality (Uosm) 446-984 mmol/kg, suggesting no urinary concentrating defect. Plasma arginine vasopressin (AVP) levels ranged from 0.4 to 1.2 pmol/l despite hyperosmolality of 298 through 343 mmol/kg under ad libitum water drinking. There was no correlation between plasma osmolality (Posm) and plasma AVP levels, but Uosm had a positive correlation with Posm (r=0.545, P < 0.05). Hypertonic saline (500 NaCl) infusion after a water load increased Uosm from 377 to 679 mmol/kg, and plasma AVP from 0.2 to 1.3 pmol/l. There was a positive correlation between Posm and plasma AVP levels in the hypertonic saline test (r=0.612, P<0.05). In contrast, an acute water load (20 ml/kg BW) verified the presence of impaired water excretion, as the percent excretion of the water load was only 8.5% and the minimal Uosm was as high as 710 mmol/kg. Urinary excretion of aquaporin-2 remained low in concert with plasma AVP levels. No abnormality in pituitary-adrenocortical function was found. These results indicate that marked hypernatremia is derived from partial central diabetes insipidus and elevated threshold of thirst, and that enhanced renal water handling may contribute to maintenance of body water in the present subject.     

Posterior pituitary function in Sheehan's syndrome

OBJECTIVE: We studied posterior pituitary function in 27 patients with Sheehan's syndrome and 14 controls. DESIGN: All patients were investigated by water deprivation test and 26 of them by 5% hypertonic saline infusion test. None of the patients had symptoms of diabetes insipidus and all patients were on adequate glucocorticoid and thyroid hormone replacement therapy before testing. RESULTS: According to dehydration test, 8 (29.6%) patients had partial diabetes insipidus (PDI group) and 19 (70.3%) had normal response (non-DI group). During the 5% hypertonic saline infusion test, the maximal plasma osmolality was higher in PDI (305 +/- 4.3) and non-DI (308 +/- 1.7) groups when compared with controls (298 +/- 1.7 mOsm/kg; P < 0.005), but the maximal urine osmolality was lower in PDI group (565 +/- 37) than in non-DI (708 +/- 45) and control (683 +/- 17 mOsm/kg) groups (P < 0.05). The osmotic threshold for thirst perception was higher in PDI (296 +/- 4.3) and non-DI (298 +/- 1.4) groups when compared with control group (287 +/- 1.5 mOsm/kg) (P < 0.005). Basal plasma osmolalities were also higher in PDI (294 +/- 1.0) and non-DI (297 +/- 1.1) groups than in controls (288 +/- 1.2 mOsm/kg; P < 0.001). CONCLUSIONS: Our findings demonstrated that patients with Sheehan's syndrome have an impairment of neurohypophyseal function. The thirst center may be affected by ischemic damage and the osmotic threshold for the onset of thirst in patients with Sheehan's syndrome is increased.     

Arginine vasopressin and the renal response to water loading in congestive heart failure

Previous studies have shown on the basis of isolated comparisons that plasma arginine vasopressin (AVP) levels are inappropriately increased for a given serum osmolality in patients with CHF. To explore further the osmoregulation of AVP in this condition, the response of plasma AVP to a 15- to 20-ml/kg oral water load was compared in 26 patients with CHF and 14 normal subjects. In the normal subjects, serum osmolality decreased from 289 +/- 5.0 to 282 +/- 5.0 mOsm/kg (p less than 0.001) and AVP from 3.6 +/- 1.1 to 2.1 +/- 0.78 pg/ml (p less than 0.001). In the patients with CHF, osmolality decreased from 289 +/- 7.0 to to 281 +/- 7.0 mOsm/kg and AVP from 7.1 +/- 3.6 to 5.8 +/- 3.4 pg/ml (p less than 0.001). As a percentage of the control value, the decrease in AVP was much greater in the normal group, 41 +/- 15% vs 18 +/- 10% (p less than 0.001). Urinary osmolality levels were measured before and after water loading in 11 patients and in 7 normal subjects. Normal subjects diluted from 812 +/- 130 to 133 +/- 26 mOsm/kg (p less than 0.001) and CHF patients from 599 +/- 218 to 253 +/- 170 mOsm/kg, a statistically significant (p less than 0.01) but smaller (p less than 0.05) level of suppression. There were, however, 2 distinct groups within the CHF population: one in which urine osmolality was appropriately decreased (from 594 +/- 269 to 144 +/- 37 mOsm/kg, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pathogenesis of chronic hypernatremia with dehydrated and non-dehydrated states in hypothalamic space-occupying lesions

The present study was undertaken to determine pathophysiology of body water control in hypernatremic subjects with hypothalamic space-occupying lesions. Eight subjects with hypothalamic space-occupying lesions were divided into two groups of hypernatremia in the presence or absence of body water deficit. In 5 dehydrated hypernatremic subjects whose ages ranged from 20 to 67 years, serum sodium (Na) levels were 156.4 +/- 3.1 mmol/l; plasma osmolality (Posm), 320.6 +/- 9.8 mmol/kg; and urinary osmolality (Uosm), 246.8 +/- 46.7 mmol/kg under ad libitum water drinking. In 3 non-dehydrated hypernatremic subjects whose ages ranged from 21 to 32 years, serum Na levels were 150.3 +/- 5.4 mmol/l; Posm, 300.3 +/- 11.6 mmol/kg; and Uosm, 738.7 +/- 237.1 mmol/kg. Serum Na levels had a positive correlation with hematocrit (Ht) in 2 of 5 subjects with dehydration, but it totally disappeared in the 3 subjects without dehydration. Plasma arginine vasopressin (AVP) levels were 0.7 +/- 0.1 pmol/l, and there was no response of AVP release to intravenous administration of 5% NaCl in the subjects with dehydration. Plasma AVP was 0.7 +/- 0.1 pmol/l, and there was the reduced response of AVP release to 5% NaCl in those without dehydration. In one of 3 subjects a positive correlation between Posm and plasma AVP levels was obtained. Drinking behavior was totally abolished in the subjects with dehydration, and partly reduced in those without dehydration. The present study indicates that hypothalamic space-occupying lesions causes central diabetes insipidus and hypodipsia, and that sporadic and paradoxical release of AVP, enhanced renal concentrating ability and reduced drinking behavior may possess body water minimally in the hypernatremic subjects without water deficit.     

Evidence for normal antidiuretic responses to endogenous and exogenous arginine vasopressin in patients with guanine nucleotide-binding stimulatory protein-deficient pseudohypoparathyroidism

In six patients with pseudohypoparathyroidism (PHP) who were deficient in guanine nucleotide-binding stimulatory protein (Ns) activity, the response to endogenous arginine vasopressin (AVP) was tested during water deprivation. Hourly plasma osmolality (Posm), urinary osmolality (Uosm), and urinary AVP (UAVP) values were compared to those in normal subjects. The Uosm vs. Posm and the UAVP vs. Uosm relationships of the patients were all within the normal range. Four patients with Ns-deficient PHP were subjected to maintained water loads and infused with AVP at three different rates for 1 h each to assess their responses to exogenous AVP. Urinary volume and osmolality values from the final 30 min of each infusion rate were measured. All volume values except 1 were within 1.6 SD of normal, and all osmolality values except 1 were within 1.1 SD of normal. In conclusion, these studies indicate that these six patients with Ns-deficient PHP are not resistant to the antidiuretic (cAMP-mediated) action of endogenous or exogenous AVP, in contrast to the previously documented resistance of patients with Ns-deficient PHP to the actions of PTH, TSH, glucagon, and gonadotropins.     

Changes in plasma copeptin, the c-terminal portion of arginine vasopressin during water deprivation and excess in healthy subjects

CONTEXT: The measurement of arginine vasopressin (AVP) is often cumbersome because it is unstable with a short half-life time. AVP is derived from a larger precursor peptide along with the more stable peptide copeptin. Copeptin is the C-terminal part of provasopressin and has been shown to be a useful tool to indicate AVP concentration in critically ill patients. OBJECTIVE: The objective of the study was to evaluate the clinical usefulness of copeptin as a new marker in disordered states of blood volume and plasma osmolality. DESIGN AND SETTING: This was a prospective observational study in a university hospital. PARTICIPANTS AND MAIN OUTCOME MEASURES: Three techniques with respective control studies were used in 24 healthy adults to produce changes in plasma osmolality and/or volume: 1) a 28-h water deprivation, 2) a 17-h hypertonic saline infusion combined with thirsting, and 3) a hypotonic saline infusion with iv desmopressin administration during free water intake. RESULTS: Water deprivation produced a weight loss of 1.7 kg, an increase in plasma osmolality to 294.8 +/- 4.3 mosmol/kg, and an increase of copeptin from 4.6 +/- 1.7 pmol/liter to 9.2 +/- 5.2 pmol/liter (P < 0.0001). During hypertonic saline infusion and thirsting with a raise of plasma osmolality to 296.1 +/- 3.4 mosmol/kg, copeptin increased from 4.9 +/- 3.0 pmol/liter to 19.9 +/- 4.8 pmol/liter (P < 0.0001). Conversely, during hypotonic saline infusion, plasma osmolality decreased to 271.3 +/- 4.1 mosmol/kg, and copeptin decreased from 6.2 +/- 2.4 pmol/liter to 2.4 +/- 2.1 pmol/liter (P < 0.01). CONCLUSION: Copeptin shows identical changes during disordered water states as previously shown for AVP. It might be a reliable marker of AVP secretion and substitute for the measurement of circulating AVP levels in clinical routine.     

Regulation of vasopressin secretion in a patient with chronic hypernatraemia

A patient with the chronic hypernatraemia syndrome is described. Using a sensitive and specific radioimmunoassay, the plasma arginine-vasopressin (AVP) level was measured under various conditions. With an unrestricted diet, the plasma AVP level was inappropriately low for the degree of plasma hyperosmolality (0.9 pmol/l and 302 mOsm/kg, respectively). After chronic water loading, plasma osmolality was 271 mOsm/kg, plasma AVP level 1.5 pmol/l, and the urine remained hypertonic with respect to the plasma. During hypertonic saline infusion, plasma osmolality increased from 271 to 294 mOsm/kg without a concomitant increase in the plasma AVP concentration. After sc injection of apomorphine and after haemodynamic stimulation, the plasma AVP concentration increased from 0.8 to 36 pmol/l and from 1.2 to 6.3 pmol/l, respectively. These data demonstrate a selective deficiency in the osmoregulation of the AVP secretion. The observed neuroendocrine abnormalities may be linked to a congenital malformation of the brain.     

Increases in plasma ACTH and cortisol after hypertonic saline infusion in patients with central diabetes insipidus.

To clarify the mechanism for the potentiation of CRH-induced ACTH response by the infusion of hypertonic saline, we investigated changes in plasma ACTH concentration after infusion of 5% hypertonic saline in five patients with untreated central diabetes insipidus (DI). Basal levels of plasma ACTH and cortisol in the DI group were not significantly different from those in normal control subjects. The infusion of hypertonic saline produced an increase in plasma arginine vasopressin (AVP) in controls, but did not elevate ACTH. However, in patients with DI, the plasma AVP concentration did not change, but circulating ACTH increased 3.6-fold (7.7 +/- 1.5 to 23.0 +/- 2.7 pmol/liter; P < 0.01), and plasma cortisol also increased significantly (298 +/- 99 to 538 +/- 124 nmol/liter; P < 0.05). Moreover, a positive correlation was observed between plasma ACTH and osmolality (r = 0.72; P < 0.005). These results indicate that ACTH secretion in DI patients is regulated by a mechanism distinct from that in healthy subjects. It seems possible that the increase in plasma osmolality promotes ACTH secretion in DI patients through AVP and/or urocortin via the hypophyseal portal system, independent of the AVP secretion from magnocellular neurons.     

Effects of acute water load, hypertonic saline infusion, and furosemide administration on atrial natriuretic peptide and vasopressin release in humans

A new specific RIA for alpha-human atrial natriuretic hormone (alpha hANP) was used to determine whether changes in plasma volume elicited by acute water loading, hypertonic saline infusion, and furosemide administration caused changes in ANP release and resultant changes in renal and cardiovascular function in normal subjects. In addition, changes in plasma arginine vasopressin (AVP), PRA, and aldosterone concentrations were studied simultaneously. Mean plasma alpha hANP and AVP levels were 51.3 +/- 16.0 (+/- SE) and 3.1 +/- 0.6 pg/ml, respectively, in the basal state. Plasma alpha hANP rose to 77.8 +/- 27.6 in response to a 4.5% increase in plasma volume induced by water loading, increased further to 134.1 +/- 28.9 in response to a 23% volume increase induced by hypertonic saline, and fell to 70.2 +/- 15.8 pg/ml in response to a decrease in plasma volume after furosemide treatment (P less than 0.01-0.05). On the other hand, plasma AVP fell to 1.8 +/- 0.1 pg/ml after the water load, rose to 4.1 +/- 0.6 after hypertonic saline, and rose further to 5.8 +/- 0.8 pg/ml after furosemide (P less than 0.01-0.05). Water and hypertonic saline loading decreased PRA, but plasma aldosterone concentrations did not change; subsequent furosemide administration increased both (P less than 0.01-0.05). Arterial pressure and heart rate did not change significantly. Increases in urinary Na excretion and osmolar clearances were associated with a rise in plasma alpha hANP after water loading and hypertonic saline infusion (P less than 0.01-0.05), but changes in urine flow were mainly associated with alterations in AVP release. associated with alterations in AVP release.     

Prompt recovery of plasma arginine vasopressin in diabetic coma after intravenous infusion of a small dose of insulin and a large amount of fluid

We studied the changes in plasma arginine vasopressin in 5 patients with diabetic ketoacidosis and one patient with non-ketotic hyperosmolar coma who had marked hyperglycemia (36.6 +/- 4.6 mmol/l, mean +/- SEM) and dehydration. Plasma osmolality (Posm) was 342.2 +/- 11.4 mOsm/kg H2O, and hematocrit, serum protein, and blood urea nitrogen were also elevated at hospitalization. Circulating blood volume was decreased by approximately 21% as compared with that on day 7. Plasma AVP level was increased to 8.5 +/- 1.6 pmol/l at hospitalization. When hyperglycemia was improved by iv infusion of a small dose of insulin plus fluid administration, plasma AVP level promptly decreased to 2.4 +/- 0.4 pmol/l within six hours. When plasma AVP level had normalized, Posm was still as high as 305 mOsm/kg H2O, but the loss of circulating blood volume was only 4.2% of the control state. Plasma AVP level was positively correlated with change in hematocrit (plasma AVP = 3.58 + 0.45.hematocrit, r = 0.468, p less than 0.01), serum protein (r = 0.487, p less than 0.01), Posm (r = 0.388, p less than 0.01), and blood glucose (r = 0.582, p less than 0.01). Plasma AVP level was negatively correlated with the change in circulating blood volume (plasma AVP = 3.6 - 0.14.change in circulating blood volume, r = -0.469, p less than 0.01). These results indicate that both non-osmotic and osmotic stimuli are involved in the mechanism for AVP release in patients with diabetic coma, and that the non-osmotic control of AVP may contribute to circulating homeostasis, protecting against severe blood volume depletion in diabetic patients suffering from hyperglycemia and dehydration.     

Programming of hypertonicity in neonatal lambs: resetting of the threshold for vasopressin secretion

Lambs exposed in utero to maternal hypertonicity demonstrate plasma hypertonicity and arterial hypertension. To determine whether hypertonicity is due to an altered osmoregulatory set point, we examined arginine-vasopressin and cardiovascular responses to hypertonic saline infusion in these offspring. Study lambs [dehydrated (Dehy)] were exposed to maternal hypernatremia (8-10 mEq/liter increase; 110-150 d gestation) induced by water restriction. Control singleton and Control twins were born to ewes provided ad libitum water. We anticipated reduced birth weight due to maternal dehydration-induced anorexia and therefore included a Control group of twin gestations to approach a similar birth weight near term. After delivery, ewes from all three groups were provided ad libitum water, and their newborns were allowed ad libitum nursing. At 15 +/- 2 d of age, lambs were prepared with bladder and vascular catheters. At 23 +/- 2 d, after a 2-h basal period, neonatal lambs were iv infused with hypertonic 0.83 m NaCl (0.075 ml/kg x h) for 2 h, followed by a 2-h recovery. Neonatal mean arterial pressure and urine flow were continuously monitored, and blood samples were obtained before, during, and after infusion. During the basal period, Dehy neonates and Control twins demonstrated significantly increased plasma sodium levels and mean arterial pressure than Control singletons. In addition, the Dehy neonates had significantly increased plasma osmolality compared with Control singletons and twins. In response to hypertonic infusion, the Dehy offspring continued to exhibit hypertonicity and hypertension. Importantly, plasma tonicity and blood pressure were greatest in Dehy singletons, lowest in singleton controls, and intermediate in twin controls. Furthermore, the plasma osmolality threshold for AVP secretion was significantly higher in Dehy singletons (290 +/- 2 mOsm/kg) than Control twins (285 +/- 1 mOsm/kg) and Control singletons (280 +/- 2 mOsm/kg), indicating in utero programming of an altered set point for systemic osmolality and blood pressure regulation. Because both twin gestation and dehydration-anorexia incur potential fetal nutritional stress, the results suggest that both in utero hypertonicity and nutrition reduction contribute to offspring programming. We postulate that the nutritional stress associated with twins (as well as dehydration-induced anorexia) contributes to increased plasma sodium levels, whereas the increased plasma osmolality is due to in utero hypertonicity.     

The relationship of saline-induced changes in vasopressin secretion to basal and corticotropin-releasing hormone-stimulated adrenocorticotropin and cortisol secretion in man

To investigate the effect of endogenous arginine vasopressin (AVP) on ACTH secretion, normal subjects were given infusions of either hypertonic saline (HS) or isotonic saline (NS) combined with human corticotropin-releasing hormone (CRH) or placebo. Basal plasma AVP was 2.3 +/- 0.3 (+/- SE) pg/ml, did not change with NS treatment, and rose to 5.4 +/- 0.6 pg/ml during HS infusion (P less than 0.01). Both basal and CRH-stimulated plasma ACTH and cortisol concentrations increased during HS infusion. Peak plasma ACTH and cortisol levels were 11.4 +/- 1.5 pg/ml and 8.6 +/- 0.8 micrograms/dl, respectively, during the HS (plus placebo) infusion. During the NS (plus placebo) infusion, plasma ACTH and cortisol gradually declined to 6.8 +/- 0.5 pg/ml and 2.6 +/- 0.4 micrograms/dl. The timing of the rise in ACTH during the HS infusion paralleled the rise in AVP. When an iv dose of 1 microgram/kg CRH was administered during the saline infusions, peak plasma ACTH and cortisol levels were 27.7 +/- 6.3 pg/ml and 17.5 +/- 1.0 micrograms/dl, respectively, during the HS infusion and 15.6 +/- 1.7 pg/ml and 13.4 +/- 1.2 micrograms/dl during the NS infusion. When the areas under the hormone response curves were compared, CRH stimulated ACTH and cortisol secretion to a greater extent than did HS (P less than 0.05). The hormonal stimulation due to combined CRH and hypertonic saline was greater than that attributable to either factor alone (P less than 0.025), but was not different than the sum of the effects of the individual factors. These results indicate that increases in endogenous AVP produced by HS are associated with increases in both basal and CRH-stimulated ACTH and cortisol release. The effect of HS appears to be additive to but not consistently synergistic with the effect of CRH.     

The interaction of blood osmolality and blood volume in regulating plasma vasopressin in man.

The effect of blood volume on the osmotic control of the antidiuretic hormone, arginine vasopressin (AVP), has been studied in 18 healthy young adults. Changes in blood osmolality and/or volume were produced by each of 3 procedures--fluid deprivation, orthostasis, and hypertonic saline infusion--and the resultant changes in plasma AVP were measured by radioimmunoassay and expressed as a function of the simultaneous level of plasma osmolality. When the subjects were hydropenic and recumbent, a highly significant correlation between plasma AVP and osmolality was observed that was described by the regression equation y = 0.35 (x -281.0) where y represents the plasma AVP concentration in pg/ml and x the plasma osmolality in mosmol/kg. When these same hydropenic subjects were studied in the upright position, a maneuver that reduces intrathoracic blood volume, plasma AVP and osmolality still showed a significant correlation, but the regression equation describing this relation, y = 0.31 (x -277.8), occupied a position significantly to the left of that found during recumbency. Conversely, when the same subjects were studied during infusion of hypertonic saline, a procedure that increases blood volume, plasma AVP and osmolality again correlated significantly but the regression equation describing this relation, y = 0.32 (x -282), now occupied a position significantly to the right of that obtained during recumbent and hydropenic conditions. These results indicate that moderate increases or decreases in blood volume do influence the osmoregulation of AVP in man, but the effects are relatively small and limited to adjustments in the set of the receptor toward higher or lower levels of osmolality.     

A short water deprivation test incorporating urinary arginine vasopressin estimations for the investigation of posterior pituitary function in children

The value of a 7-h water deprivation test incorporating urinary osmolality and urinary arginine vasopressin (AVP) measurements was investigated in 20 children with suspected anterior or posterior pituitary dysfunction (group A) and 11 presenting with polyuria and polydipsia (group B). A control group of 16 healthy children was also studied. Urinary osmolalities in the control subjects after 7 h of water deprivation were 827-1136 mosmol/kg and urinary AVP 114-320 pmol/l. Of the group A patients, 5 had symptomatic diabetes insipidus with urinary osmolalities less than 300 mosmol/kg, and urinary AVP concentrations of less than 10 pmol/l, and 5 had normal urinary concentrating ability. The other 10 patients had varying degrees of partial diabetes insipidus (urinary AVP 6-53 pmol/l) although in 3 urinary concentrating ability was well maintained (osmolality 650-747 mosmol/kg). In group B, a diagnosis of compulsive water drinking was made in 9 patients, 1 had nephrogenic diabetes insipidus (urinary osmolality 68 mosmol/kg, AVP 782 pmol/l), and the final patient had transient diabetes insipidus. The test described was easy to perform and well tolerated even in young children. Using this test alone, it was possible to identify patients with partial defects of posterior pituitary function even when urinary concentrating ability was maintained, as well as those with complete cranial diabetes insipidus, nephrogenic diabetes insipidus, and compulsive water drinking.     

Pathophysiology of transient cranial diabetes insipidus during pregnancy

OBJECTIVE We investigated the possible mechanisms underlying transient cranial diabetes insipidus during pregnancy. DESIGN AND PATIENTS A woman who developed clinical diabetes insipidus during the third trimester of pregnancy was studied through a total of three pregnancies and postpartum MEASUREMENTS Plasma AVP, urine and plasma osmolality, urine volume and specific gravity were measured during water deprivation tests and hypertonic saline infusion. Plasma and urine osmolality were measured after subcutaneous injection of AVP. The water deprivation and AVP test were repeated after proven inhibition of urinary PGE₂ with aspirin. Serum vasopressinase activity was measured during one of the pregnancies affected with diabetes insipidus and compared with that obtained between 26 and 38 weeks from 13 normal pregnancies. RESULTS The patient was found to have cranial diabetes insipidus which responded to low dose intranasal 1-desamino-8-D-arginine vasopressin. Inhibition of PGE2 with aspirin did not enhance urine concentrating ability or the response to a test dose of subcutaneous AVP. Plasma levels of vasopressinase remained within the physiological range for normal pregnancy. CONCLUSIONS These studies indicate that subclinical cranial diabetes insipidus may be unmasked in late pregnancy. This effect is not related to AVP resistance resulting from PGE₂ production or excessive vasopressinase activity, but may be due to a combination of physiological vasopressinase secretion with reduced AVP secretory capacity and reduction in the thirst threshold that accompanies normal pregnancy. We relate these findings to a previously described group of women with transient diabetes insipidus during pregnancy who had impaired liver function     

Novel mutant vasopressin-neurophysin II gene associated with familial neurohypophyseal diabetes insipidus

We describe a novel missense mutant of arginine vasopressin (AVP)-dependent neurohypophyseal diabetes insipidus in an autosomal dominant family. A 54-year-old woman was admitted to our hospital because of thyroidectomy for thyroid cancer. After thyroidectomy she was found to have hypernatremia and polyuria and polydipsia both of which had been present from childhood. She had no obstructive hydronephrosis. Her father, father's younger sister and her third son also had polyuria and polydipsia. Basal plasma AVP concentration at normal plasma osmolality was normal but did not respond to increased plasma osmolality despite hyperosmolality during infusion of hypertonic saline infusion, indicating that plasma AVP secretion was impaired. Sodium concentration in urine and urine osmolality were low and increased after nasal administration of DDAVP. There was a diminished but bright signal of pituitary posterior gland on magnetic resonance T1 weighted image. Molecular genetic analysis demonstrated that the patient and her son had a single heterozygous missense mutation (G-->A) at nucleotide 1829 in 1 AVP allele, yielding an abnormal AVP precursor with lacking Glu-47 in its neurophysin II moiety. The abnormal AVP precursor may be related to the impaired AVP secretion.     

Interference in the cytochemical assay of plasma vasopressin by a circulating factor induced by salt-loading in man

Infusion of hypertonic saline into six normal volunteers caused an increase in plasma osmolality from 286.8 +/- 1.7 (mean +/- S.E.M.) to 307.6 +/- 2.6 mosmol/kg (P less than 0.001), a 7.1% increase in estimated blood volume, a rise in plasma immunoreactive arginine vasopressin (AVP) concentrations from 1.3 +/- 0.2 to 12.7 +/- 3.6 pmol/l (P less than 0.001) but no change in plasma AVP concentrations (2.1 +/- 0.9 and 1.9 +/- 1.3 pmol/l) as measured by a cytochemical technique based on the ability of AVP to stimulate rat renal medullary Na+/K+-ATPase activity. Addition of synthetic AVP to plasma obtained before, during and after hypertonic saline infusion also failed to stimulate Na+/K+-ATPase activity. The results suggest that infusion of hypertonic saline interfered with the cytochemical assay for AVP by inhibiting AVP-stimulated medullary Na+/K+-ATPase activity. We conclude that the use of this cytochemical method to detect plasma AVP has severe limitations under these experimental conditions.     

Secretion of atrial natriuretic peptide in patients with non-insulin-dependent diabetes mellitus and effect of autonomic neuropathy

In order to clarify the mode of atrial natriuretic peptide (ANP) release and the effect of autonomic nerve function on ANP release, we measured plasma ANP concentrations in response to hypertonic saline infusion in patients with non-insulin-dependent diabetes mellitus (NIDDM) having or not having autonomic neuropathy (AN). Studies were made on 72 normal subjects (male 44, female 28; 53.0 +/- 0.9 yr.), and 63 patients with NIDDM (male 36, female 27; 56.9 +/- 2.1 yr.). The patients with NIDDM were divided into two groups: Group A was 48 diabetics without AN, and Group B was 15 diabetics with AN. Six patients selected randomly from each group and 6 normal subjects were given an infusion of hypertonic saline (2.5% NaCl) at a rate of 0.25 ml/min/kg over 45 min. Autonomic nerve function was estimated by clinical symptoms, coefficient of variation of R-R intervals (CVR-R), Valsalva test and Schellong test. Plasma ANP concentration was measured by a sensitive and specific radioimmunoassay (RIA) after extraction using SEP-PAK C18 cartridge reported previously. The mean plasma concentration of ANP was 20.7 +/- 1.8 pg/ml (mean +/- SEM) in normal subjects, 24.3 +/- 2.4 pg/ml in NIDDM patients without AN, and 26.4 +/- 3.6 pg/ml in NIDDM patients with AN. There was no significant difference in these levels among the 3 groups. The fasting plasma concentration of ANP in diabetics as well as in normal subjects increased parallel with age. In 12 diabetics, plasma concentrations of ANP significantly elevated from 27.6 +/- 2.0 pg/ml to 149.4 +/- 29.8 pg/ml at 60 min after start of hypertonic saline infusion as compared with 6 normal subjects in whom the levels increased from 15.6 +/- 2.9 pg/ml to 34.1 +/- 5.7 pg/ml at 75 min. On the other hand, the plasma ANP concentration in response to hypertonic saline infusion in NIDDM patients with AN (71.8 +/- 14.4 pg/ml, at 60 min) was lower than that in NIDDM patients without AN (224.2 +/- 38.2 pg/ml, at 60 min). Area under the curve (AUC) of plasma ANP of NIDDM patients with AN after hypertonic saline infusion was 6560 +/- 879.6 pg.min/ml (normal subjects, 2575.6 +/- 444.6 pg.min/ml), which was significantly lower than that of NIDDM patients without AN (13757.8 +/- 1148.4 pg.min/ml). Moreover, there was a positive correlation between AUC and CVR-R in patients with NIDDM. These results indicate that the response of plasma ANP to hypertonic saline infusion in NIDDM patients is significantly higher than in normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Vasopressin secretion during hyperglycemia in insulin-dependent diabetics

Plasma levels of vasopressin (AVP) were measured in ten insulin-dependent diabetic patients before and during intravenous administration of hypertonic glucose. Plasma glucose and plasma osmolality increased from 12.4 +/- 1.2 to 47.0 +/- 2.3 mmol/l and from 293 +/- 2.0 to 307 +/- 2.8 mosm/kg respectively. Plasma vasopressin increased in parallel from 5.6 +/- 0.6 to 7.7 +/- 0.6 pg/ml. The present results demonstrate that hyperglycemia may be an effective stimulus for AVP secretion in insulin-deficient diabetics.