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.     

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.     

Effect of an osmotic stimulus on the secretion of arginine vasopressin and adrenocorticotropin in the horse

Arginine vasopressin (AVP) is released in response to changes in blood osmolality and is also a putative secretagogue for ACTH. However, it is unclear whether osmotically generated increases in AVP in the physiological range influence ACTH secretion. We have studied this question using our unique noninvasive technique for collecting pituitary venous blood in six normal conscious horses that received an iv infusion of hypertonic saline (HS; 5%, 0.07 ml/kg.min) for 45-60 min. Pituitary and jugular venous samples were collected every 5 min for 40 min before, during, and for 20 min after HS. During HS, mean blood osmolality rose (P less than 0.01), with a mean peak increase of 14.8 mosmol/kg (range, +6-+37 mosmol/kg). Jugular AVP rose (P less than 0.01) from 0.56 +/- 0.18 pmol/liter (mean +/- SEM) before HS to 2.16 +/- 0.86 pmol/liter during HS. Mean jugular AVP and osmolality were correlated (r = 0.82; P less than 0.05) during HS. Mean jugular ACTH concentrations increased (P less than 0.01) from 49 +/- 9 ng/liter before HS to 148 +/- 54 ng/liter during HS, while mean cortisol levels during and after HS exceeded basal levels (P less than 0.05). Pituitary AVP and ACTH concentrations exceeded jugular concentrations by up to 100-fold, and mean (P less than 0.01 for both) and peak (P less than 0.001 for both) levels increased during HS. AVP and ACTH secretion during HS were pulsatile. The mean and peak changes in pituitary AVP were significantly correlated with those in ACTH. For the six horses together, pituitary ACTH and AVP concentration changes occurred synchronously during the experiment (P less than 0.001), and the paired AVP and ACTH concentrations were highly correlated (r = 0.73; n = 129 pairs; P less than 0.001). We conclude that 1) physiological changes in AVP secretion are closely associated with comparable changes in ACTH secretion, and 2) osmotic signals that presumably activate the magnocellular neurons of the supraoptic and paraventricular nuclei may be physiologically relevant regulators of corticotrope function.     

The physiological significance of arginine vasopressin in potentiating the response to corticotrophin-releasing factor in sheep

In order to assess the physiological importance of endogenous arginine vasopressin (AVP) in augmenting the ACTH response to corticotrophin-releasing factor (CRF), the response to CRF during hypertonic saline infusion in six Coopworth sheep was examined. A 4-h infusion of 5% (w/v) NaCl (3.8 ml/min) resulted in significantly (P less than 0.01) greater rises in ACTH and cortisol, but not aldosterone, than were observed after CRF alone. Infusion of hypertonic saline without CRF resulted in a highly significant (P less than 0.001) rise in plasma osmolality and AVP but no significant change in plasma ACTH, cortisol or aldosterone. It is concluded that a marked but physiological increase in peripheral (and presumably central) levels of AVP does not result in any demonstrable change in plasma ACTH concentration. However, under these conditions, the ACTH and cortisol responses to CRF are considerably augmented.     

Effects of incremental infusions of arginine vasopressin on adrenocorticotropin and cortisol secretion in man

Arginine vasopressin (AVP) regulates ACTH release under certain conditions, and exogenously administered AVP is used clinically to stimulate ACTH secretion. We attempted to determine at what plasma concentration AVP can stimulate ACTH release. Six normal men were given infusions of AVP (Ferring) or vehicle between 1600 and 1700 h on five occasions: 1) saline (30 mL/h); 2) 10 ng AVP/min; 3) 30 ng AVP/min; 4) 100 ng AVP/min; and 5) 300 ng AVP/min. Plasma AVP, ACTH, and cortisol concentrations were measured every 10 min during the infusions. Basal plasma AVP levels were less than 1 ng/L (less than 0.92 pmol/L). The lowest AVP dose raised plasma AVP into the range found in fluid-deprived subjects (7-8 ng/L;6.5-7.3 pmol/L), but had no effect on plasma ACTH concentrations. AVP in a dose of 30 ng/min also had no effect. The 100 ng AVP/min dose raised plasma AVP concentrations to 51.4-65.5 ng/L (46-60 pmol/L). This increase led to a transient insignificant increase in plasma ACTH from 13.9 +/- 1.2 (+/- SEM) ng/L (3.1 +/- 0.3 pmol/L) to 20.0 +/- 1.4 ng/L (4.4 +/- 0.3 pmol/L), while plasma cortisol rose significantly from 146 +/- 10 to 209 +/- 19 nmol/L (P less than 0.01) after 60 min of infusion. The 300 ng AVP/min dose raised plasma AVP levels to about 260 ng/L (239 pmol/L); the maximal plasma ACTH and cortisol levels were 39.5 +/- 5.0 ng/L (8.7 +/- 1.1 pmol/L; P less than 0.01) and 348 nmol/L (P less than 0.01), respectively. Thus, peripheral plasma AVP levels have to be raised high above the physiological range before ACTH release is stimulated. We conclude that any AVP reaching the adenohypophysis through the peripheral circulation is of much less importance for the regulation of ACTH secretion than is AVP derived from the pituitary portal circulation.     

Clinical assessment of posterior pituitary function by direct measurement of plasma vasopressin levels during hypertonic saline infusion

Clinical usefulness of a radioimmunoassay of plasma arginine vasopressin concentration (AVP) during hypertonic saline infusion for the assessment of posterior pituitary function was studied in comparison with the conventional water deprivation test. Infusion of 5% saline at a rate of 0.05 ml/kg/min for 120 min in 15 normal subjects induced an elevation of plasma osmolality (Posm) from 290.3 +/- 0.7 to 307.5 +/- 2.1 mOsm/kg with a resultant increase in AVP from 2.4 +/- 0.4 to 9.9 +/- 2.2 pg/ml. During the infusion, a highly significant correlation between AVP and Posm was observed with a regression line expressed as AVP = 0.40 (Posm - 283.0). In 22 polyuric patients, on the other hand, the infusion induced a marked elevation of Posm from 302.6 +/- 2.5 to 321.3 +/- 2.9 mOsm/kg, but caused a slight (less than 5.8 pg/ml) or no increase in AVP from the basal levels (0.5 +/- 0.1 pg/ml). A conventional water deprivation test was carried out in ten patients with neurogenic diabetes insipidus, including one who had coincidental nephrogenic diabetes insipidus. As would be expected, urine osmolality (Uosm) did not rise beyond Posm in seven of them. However, two of three other patients, who had a complete lack of AVP response to the hypertonic saline, were able to concentrate their urine with a maximal Uosm/Posm of 1.3 and 1.1 respectively. The concurrent decrease in creatinine clearance to 49 and 57% of the initial values, respectively, indicated that a marked reduction in glomerular filtration rate due to severe dehydration was responsible for the unexpected concentration of urine in the patients with totally impaired AVP secretion. Based on these results, we conclude that the direct measurement of AVP during hypertonic saline infusion is an essential procedure for the accurate evaluation of posterior pituitary function.     

Effects of free fatty acids on ACTH and cortisol secretion in anorexia nervosa

OBJECTIVE: Free fatty acids (FFAs) exert a stimulatory effect on the hypothalamic-pituitary-adrenal (HPA) axis in animals and inhibit spontaneous ACTH and cortisol secretion in humans. Patients with anorexia nervosa display concomitant HPA axis hyperactivity and increased lipolysis. We studied the effects of a lipid load on ACTH and cortisol secretion in patients with anorexia nervosa in comparison with normal subjects. DESIGN: Eight women with anorexia nervosa (ANW; means +/- s.e.m.: 23.9 +/- 2.3 years of age; body mass index (BMI): 14.9 +/- 0.6 kg/m2) and seven normal women (NW; 25.6 +/- 2.3 years of age; BMI: 22.8 +/- 1.9 kg/m2) had FFA, ACTH, cortisol, glucose and insulin levels measured in the morning every 30 min for 180 min during i.v. saline or lipid-heparin emulsion (LHE) infusion. RESULTS: During saline infusion, ACTH and cortisol levels decreased spontaneously in both groups, ACTH and cortisol levels in ANW being higher than in NW. LHE infusion led to increased FFA levels in both groups (P < 0.005). The ACTH and cortisol decrease in NW was more marked than during saline infusion (P < 0.05). LHE infusion in ANW was associated with a more pronounced decrease in ACTH levels than during saline infusion (P < 0.05), while cortisol levels were unchanged. At the end of the LHE infusion, a progressive decrease in FFA levels was associated with an increase in ACTH and cortisol concentrations in NW (P < 0.05) but not in ANW in whom FFA levels decreased to a lesser extent (P < 0.05). CONCLUSIONS: This study showed that corticotroph sensitivity to the inhibitory effect of an FFA load is preserved in patients with anorexia nervosa, in spite of persistent adrenal hyperactivity.     

Effect of administration of corticotropin-releasing hormone and glucocorticoid on arginine vasopressin response to osmotic stimulus in normal subjects and patients with hypocorticotropinism without overt diabetes insipidus

We examined the effect of CRH administration on the response of plasma arginine vasopressin (AVP) induced by an osmotic stimulus in six normal subjects and five patients with hypocorticotropinism without overt diabetes insipidus (four patients with Sheehan's syndrome and one with idiopathic pituitary dwarfism with ACTH deficiency). Hypertonic saline infusion (855 mmol/L saline solutions at a rate of 205 mumol/kg.min for 10 min) increased plasma AVP 5.7-fold (P less than 0.01) in normal subjects and 2.4-fold (P less than 0.05) in the patients. CRH administration significantly augmented the plasma AVP response to the osmotic stimulus in the normal subjects, but not in the patients with hypocorticotropinism. CRH administration alone did not influence plasma AVP. These findings suggest that a central CRH-related mechanism(s) was at least partly involved in the augmentation of AVP release. Based on the relatively low plasma AVP response to the osmotic stimulus in patients and their lower plasma AVP levels and higher plasma osmolality under basal conditions, we suggest that patients with hypocorticotropinism have partial diabetes insipidus, in which impairment of central CRH action might be, at least in part, involved. The response of plasma AVP to the osmotic stimulus was attenuated significantly when the patients were given cortisol. Since basal PRA, plasma aldosterone, plasma osmolality, hematocrit, body weight, mean blood pressure, and heart rate were similar with and without cortisol administration, this effect of cortisol may have been due to central suppression of the AVP response to the osmotic stimulus.     

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.     

AUGMENTATION OF THE RESPONSE TO CRF IN MAN: RELATIVE CONTRIBUTIONS OF ENDOGENOUS ANGIOTENSIN AND VASOPRESSIN

The plasma ACTH response to corticotrophin releasing factor (CRF) was studied in seven normal individuals. Five subjects were restudied following 4 d of salt restriction which resulted in raised endogenous plasma angiotensin II secretion. In a third experiment six subjects were given CRF following pre-infusion of hypertonic saline which significantly increased endogenous plasma vasopressin (AVP) levels. We were unable to demonstrate that high endogenous plasma AII levels were associated with a significant change in the plasma ACTH or cortisol responses to CRF. However there was an almost three-fold increase in the ACTH response when endogenous plasma AVP was elevated by hypertonic saline. It is concluded that AVP is likely to be of physiological importance in potentiating the ACTH response to CRF and that AVP and CRF together may provide a better test of pituitary ACTH secretion than either peptide alone.     

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.     

Effects of the nonpeptide V(1) vasopressin receptor antagonist SR49059 in hypertensive patients

We assessed the clinical and pharmacological profile of the orally active V(1) vascular vasopressin (AVP) receptor nonpeptide antagonist SR49059 (SR) during the osmotic stimulation of AVP release in hypertensive patients. In a double-blind crossover-versus-placebo study, 24 untreated stage I or II essential hypertensive patients (12 whites and 12 blacks) received a single 300 mg oral dose of SR 2 hours before the stimulation of AVP secretion with a 5% hypertonic saline infusion. Hemodynamic, humoral, and hormonal parameters were monitored for up to 28 hours after drug administration. SR did not alter blood pressure or heart rate before the saline infusion and did not reduce the blood pressure increment induced by the hypertonic saline infusion. However, the blood pressure peak at the end of the hypertonic saline infusion was slightly lower in the presence of SR (P=0.04). Heart rate was significantly faster between 4 and 6 hours after SR administration (P=0.02). The rise in plasma sodium and osmolality triggered by the saline infusion was not modified by SR, but AVP release was slightly greater in the presence of SR (P<0.0003). AVP-induced aggregation of blood platelets in vitro was significantly reduced by SR, with a peak effect 2 hours after drug administration that coincided with the SR peak plasma concentration. Plasma renin activity and aldosterone before and after the saline infusion were not modified by SR. Urine volume and osmolality were not altered by SR administration. SR effects were similar in the 2 ethnic groups as well as in salt-sensitive versus salt-resistant patients. In a situation of AVP osmotic release and volume expansion in hypertensive patients, a single oral dose of the V(1) vascular AVP receptor nonpeptide antagonist SR49059, which is able to block AVP-induced platelet aggregation, exerts a transient vasodilation effect that is not associated with a sustained blood pressure reduction. SR49059 is a pure V(1) vascular receptor antagonist that is devoid of V(2) renal receptor actions.     

No effect of free fatty acids on adrenocorticotropin and cortisol secretion in healthy young men

Free fatty acids (FFAs) affect anterior pituitary function. However, the effect of FFAs on corticotropin (ACTH) and cortisol in humans is controversial. Thus, we assessed the effect of a pronounced increase in circulating FFA levels induced by infusion of lipid/heparin on ACTH and cortisol secretion in young men. Eight healthy male volunteers who underwent a 10-hour overnight fast were investigated. A 20% lipid/heparin or saline/heparin infusion was given at a rate of 1.5 mL/min for 6 hours. A euglycemic hyperinsulinemic clamp was performed in 6 subjects 4 hours after the start of infusion. To assess steroid metabolism, we measured ACTH, cortisol, FFAs, and urinary steroids. Lipid infusion increased FFAs (6.06 +/- 0.52 vs 0.70 +/- 0.23 mmol/L; P < .005) and induced insulin resistance (glucose infusion rate, 4.08 +/- 2.15 vs 6.02 +/- 2.60 mg/kg per minute; P < .005). Serum cortisol and plasma ACTH decreased independent of lipid/heparin or saline/heparin infusion. In addition, we found no effect of hyperinsulinemia on ACTH and cortisol levels. There were no differences in urinary free cortisol, urinary free cortisone, 5beta-tetrahydrocortisol, 5alpha-tetrahydrocortisol, and tetrahydrocortisone. In conclusion, FFAs had no effect on basal ACTH and cortisol secretion in normal-weight young men. In addition, no alterations in urinary glucocorticoid metabolites were detected, suggesting unchanged cortisol metabolism during lipid infusion.     

Role of endogenous arginine vasopressin in potentiating corticotropin-releasing hormone-stimulated corticotropin secretion in man

Exogenously administered vasopressin (VP) augments ACTH secretion stimulated by CRH. This study was performed to elucidate the role of endogenous VP in potentiating CRH-induced ACTH secretion in man. Synthetic human CRH (100 micrograms) was injected iv into seven normal men after they had been water loaded (20 mL/kg; 60 and 30 min before CRH injection; WL-CRH test) and water deprived (water restriction for 18 h before CRH injection; WD-CRH test). Blood samples were obtained before and 5, 15, 30, 60, 90, and 120 min after CRH injection at 0900 h for determination of plasma ACTH, cortisol, arginine vasopressin (AVP), CRH, and catecholamine levels and osmolality. Urine was obtained immediately before and 120 min after CRH injection for determination of osmolality. The mean plasma AVP levels were significantly higher during the WD-CRH test [1.8 +/- 0.4 (+/- SE) to 1.9 +/- 0.4 pmol/L] than during the WL-CRH test (0.6 +/- 0.1 to 0.9 +/- 0.1 pmol/L). The mean plasma ACTH and cortisol levels rose significantly from basal (4.5 +/- 0.6 pmol/L and 320 +/- 20 nmol/L, respectively) to peak values of 14.0 +/- 2.1 pmol/L at 30 min and 700 +/- 50 nmol/L at 60 min, respectively, during the WD-CRH test. During the WL-CRH test, mean basal plasma ACTH and cortisol levels were 3.5 +/- 0.7 pmol/L and 420 +/- 50 nmol/L, respectively, and reached peak values of 7.7 +/- 1.1 pmol/L at 60 min and 550 +/- 40 nmol/L at 30 min, respectively. Both the mean peak levels and integrated ACTH and cortisol responses were significantly higher during the WD-CRH than during the WL-CRH test. There was no significant difference between the plasma CRH and catecholamine concentrations in both tests. These results suggest that endogenous AVP potentiates CRH-stimulated ACTH secretion and, thus, plays a physiologically significant role in regulating CRH-stimulated ACTH and cortisol secretion in man.     

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)     

Baroregulation of vasopressin release in adipsic diabetes insipidus

Adipsic diabetes insipidus (ADI) occurs in association with a heterogeneous group of conditions. We report vasopressin (AVP) responses to hypotension in nine patients with ADI and nine controls. Hypertonic saline infusion produced absent thirst (1.7 +/- 1.7 to 1.5 +/- 1.7 cm, P = 0.99) and AVP responses (0.3 +/- 0.1 to 0.4 +/- 0.1 pmol/liter, P = 0.99) in the ADI group, who also drank less than the control group (258 +/- 200 ml vs. 1544 +/- 306 ml, P < 0.001). Intravenous infusion of trimetaphan camsylate produced a fall in mean arterial pressure of 31.6% +/- 8.9% in patients and 29.4% +/- 6.1% in controls. Plasma AVP concentrations rose from 1.4 +/- 0.8 to 340.3 +/- 497.4 pmol/liter (P < 0.001) in the control group. In three patients with craniopharyngioma, there was no rise in plasma AVP concentrations (0.3 +/- 0.1 to 0.3 +/- 0.1 pmol/liter, P = 0.96), but plasma AVP rose significantly in response to hypotension in the other six patients (0.4 +/- 0.2 to 204.5 +/- 223.2 pmol/liter, P < 0.001). We concluded that the AVP responses to hypotension in ADI are heterogeneous and reflect the site of the lesion causing the diabetes insipidus.     

Hyponatremia-induced inhibition of magnocellular neurons causes stressor-selective impairment of stimulated adrenocorticotropin secretion in rats.

Chronically hyponatremic rats were subjected to various stressors in order to evaluate the possible contribution of magnocellular neurons to the regulation of ACTH secretion, since such rats have markedly inhibited secretion and synthesis of magnocellular arginine vasopressin (AVP) and oxytocin (OT). Stress caused by a novel environment or by insulin-induced hypoglycemia resulted in moderate increases in plasma ACTH, which were of similar magnitude in both hyponatremic and normonatremic rats, and these stressors caused no increase in plasma AVP and OT levels in either group of rats. However, when exposed to ether, hyponatremic rats exhibited a significantly blunted ACTH response compared to normonatremic controls (331 +/- 49 vs. 740 +/- 124 pg/ml; P less than 0.01, respectively), and plasma AVP levels were markedly increased in the normonatremic, but not in the hyponatremic, rats. Intravenous infusion of 2 M NaCl also caused an ACTH release in hyponatremic rats that was significantly smaller than that in their normonatremic counterparts (228 +/- 52 vs. 479 +/- 85 pg/ml; P less than 0.05, respectively), and in this case both plasma AVP and OT levels were markedly increased in the normonatremic, but not in the hyponatremic, rats. However, hyponatremic rats exhibited greatly increased plasma ACTH levels 2 and 96 h after adrenalectomy (ADX), which were statistically equivalent to the increases in ACTH levels in normonatremic rats after ADX. Seven days after ADX parvocellular neurons of the paraventricular nucleus showed strongly increased CRF-41 and AVP-neurophysin, but not OT-neurophysin, immunoreactivities in both normonatremic and hyponatremic rats. These results show that parvocellular CRF-41/AVP-producing neurons in the paraventricular nucleus are not inhibited by chronic hyponatremia, in contrast to magnocellular neurons, and suggest that ACTH secretion induced by ether or hypertonic saline, but not by novel environment or insulin-induced hypoglycemia, is partially mediated by magnocellular AVP and/or OT.     

Impaired vasopressin secretion in patients with myotonic dystrophy

Hypernatremia has occasionally been observed in patients with myotonic muscular dystrophy (MyD). To elucidate the possibility of osmoregulatory dysfunction, we investigated hypothalamo-posterior pituitary function as well as serum electrolytes in eight patients with MyD. Blood samples were obtained early in the morning after overnight dehydration. Renal function was estimated by blood urea nitrogen, serum creatinine and creatinine clearance. Posterior pituitary function was evaluated by direct measurement of plasma vasopressin (AVP) during a 5% hypertonic saline infusion. Plasma AVP concentrations were determined by sensitive radioimmunoassay. In five patients, circulating blood volume (CBV), plasma renin activity (PRA) and serum aldosterone (S-Aldo.) were also measured. The mean serum sodium level (143.9 +/- 1.7mEq/1: Mean +/- SD) was significantly higher than in the controls (139.4 +/- 2.2mEq/1). A 5% hypertonic saline infusion showed a subnormal increase in AVP and diminished thirst, despite sufficient elevation of plasma osmolality, in all patients as compared with healthy adults. Renal function was intact. Biochemical evidence of dehydration, estimated by PRA, S-Aldo and CBV, was unremarkable in four of the five patients. These findings suggest that patients with MyD have neurogenic disorders of osmoregulation in addition to previously reported endocrine abnormalities. Impaired AVP secretion in response to osmotic stimuli and reduced thirst might be responsible for such failure.     

Neurohypophyseal function in postpartum hypopituitarism: impaired plasma vasopressin response to osmotic stimuli

We studied neurohypophyseal function in 12 women with postpartum hypopituitarism (Sheehan's syndrome) by measuring plasma arginine vasopressin concentrations during 5% hypertonic saline infusions. All patients had a history of obstetric shock or massive bleeding, and were receiving cortisol and/or L-T4 replacement therapy. None had any symptoms of diabetes insipidus. The mean basal plasma vasopressin level in the patients [0.6 +/- 0.1 (+/- SE) pmol/L] was significantly lower (P less than 0.01) than that in normal adults (2.5 +/- 0.5 pmol/L; n = 12), whereas mean plasma osmolality values were similar in the two groups. During hypertonic saline infusion, the 10 hypopituitary patients had varying degrees of subnormal arginine vasopressin responses to the increase in plasma osmolality. Urine-concentrating ability after dehydration also was lower in the patients, although overt polyuria was absent at the time of this study. These results indicate that the osmoregulation of arginine vasopressin secretion is frequently impaired in postpartum hypopituitarism, suggesting neurohypophyseal damage.     

Impairment of AVP regulation in 17alpha-hydroxylase deficiency,a unique form of adrenal insufficiency

17alpha-hydroxylase deficiency (17alpha-OHDS) results in decreased production of cortisol and sex steroids and hypokalemia secondary to excess mineralocorticoids. It has long been known that glucocorticoid deficiency is associated with impaired urinary dilution and increased secretion of vasopressin (AVP). On the other hand, chronic hypokalemia is a well-established cause of nephrogenic diabetes insipidus. We evaluated the status of AVP secretion in a patient with 17alpha-OHDS and in 8 normokalaemic control subjects during hypertonic saline infusion (5% NaCl 0.06 ml.kg.min.120 min). The patient was evaluated on 3 separate occasions: pre-treatment (PT), and daily treatment with 0.375 mg (T1) and 0.5 mg (T2) dexamethasone. Blood was collected for AVP, corticosterone (B), plasma osmolality (pOsm) and electrolyte determination. In the control group plasma AVP levels increased from 0.8 +/- 0.1 to 4.1 +/- 0.6 pmol/l and pOsm increased from 282 +/- 2 to 302 +/- 11.5 mosmol/kg. In the patient, plasma AVP levels increased from 9.3 to 12.3; 4.5 to 6.2; and 2.5 to 6.2 pmol/l, and pOsm increased from 282 to 302, from 290 to 307, and from 291 to 311 mosmol/kg during the PT, T1 and T2 conditions, respectively. Serum potassium levels were low (2.6 mmol/l) during PT and reached normal values after treatment. There was a significant negative correlation between plasma AVP and serum potassium levels (r=-0.71; p<0.001). The results originally indicate that high plasma AVP levels may be found in 17alpha-OHDS, suggesting an effect of F deficiency per se. In addition, a concealed partial nephrogenic diabetes insipidus secondary to chronic hypokalemia cannot be excluded.