Evidence for dopaminergic regulation of vasopressin release in the anephric rat

Arginine vasopressin (AVP) release elicited by osmotic stimuli induces variable hypertensive responses. In normotensive anephric rats, a significantly greater blood pressure response was elicited by hypertonic saline than by mannitol infusion, and was further enhanced by previous dopaminergic receptor blockade. Plasma levels of AVP were significantly more elevated after saline than after mannitol despite more pronounced elevation of plasma osmolality in the latter animals, and were the highest in dopaminergically blocked animals. These findings indicate that dopamine exerts an inhibitory effect on the release of AVP.     

Effects of central osmotic stimulation on vasopressin and enkephalin release into the blood and cerebrospinal fluid and blood pressure

To assess the central effect of hypertonic NaCl on the release of vasopressin (AVP) and methionine enkephalin-like substances into the blood and cerebrospinal fluid, and on blood pressure, ventriculocisternal perfusion (0.25 ml/min, 60 min) was performed in anesthetized dogs with artificial cerebrospinal fluid (CSF), either isotonic (300 mosmol/kg) or hypertonic (600 and 1200 mosmol/kg). The effect of central administration of a V1-AVP antagonist on the central osmotic challenge was also studied. In dogs, given 600 mosmol/kg, CSF osmolality increased with a concomitant rise in mean arterial pressure and plasma AVP concentrations. Plasma osmolality, heart rate, CSF AVP and plasma and CSF methionine enkephalin-like substances showed no significant change. In dogs, given 1200 mosmol/kg, the CSF osmolality increase was accompanied by a rise in mean arterial pressure, heart rate, plasma AVP and CSF AVP. Plasma osmolality and plasma and CSF methionine-enkephalin-like substances did not change significantly. A V1-AVP antagonist given centrally attenuated the rise in mean arterial pressure induced by osmotic challenge. In dogs, given 300 mosmol/kg, no parameters changed significantly except for a gradual fall in heart rate. These results suggest that central osmotic stimulation by hypertonic NaCl increases blood pressure, heart rate and the release of AVP, but not methionine enkephalin-like substances, into the blood and CSF, and a V1-blocker given centrally attenuates the pressor response.     

Vasopressin-induced presynaptic facilitation of sympathetic neurotransmission in the pithed rat

OBJECTIVE : Several studies have shown that arginine vasopressin (AVP) potentiates the sympathetic nervous transmission in isolated vessels. The present study investigates such a potentiation in the pithed rat model. METHODS : Male Wistar rats weighing 270-310 g were used. Spinal-cord stimulation was applied, with frequencies of 0.25-4 Hz, in the presence or absence of a subpressor dose of intravenous (i.v.) AVP (1 pmol/kg per min). In addition, the effect of AVP on postsynaptic alpha-adrenoceptor-mediated responses was studied using exogenously administered noradrenaline (NA). For this purpose dose-response curves (DRCs) for NA (i.v.) were constructed. RESULTS : In the pithed rat model endogenously generated angiotensin II facilitates neurally mediated increments in vascular resistance. Without the administration of the angiotensin II type 1 (AT1) antagonist, irbesartan, the facilitating effect of AVP was not visible. However, after the administration of the AT1 antagonist, irbesartan, the facilitating effect of AVP became apparent. The stimulation-induced rise in diastolic blood pressure (DBP) was enhanced in the presence of AVP from 63.7 +/- 4.5 to 78.6 +/- 4.2 mmHg, at a stimulation frequency of 4 Hz. The vasopressin receptor V1 antagonist, SR-49059, completely inhibited this AVP-induced facilitation, whereas the V2 antagonist, SR-121463B, or the V2 agonist, desmopressin, did not. The DRC of exogenously administered NA was not influenced by AVP. CONCLUSION : The stimulating effect of AVP on sympathetic neurotransmission is completely dependent on the stimulation of presynaptically located V1 receptors. The facilitating effect of angiotensin II on the sympathetic nervous system (SNS) in the pithed rat model masks the facilitating effect of AVP in this preparation.     

Mechanisms underlying arginine vasopressin-induced relaxation in monkey isolated coronary arteries.

OBJECTIVE: The present study was undertaken to examine whether arginine vasopressin (AVP) relaxes primate coronary artery and to analyse the mechanisms of its action in reference to endothelial nitric oxide and AVP receptor subtype. METHODS: Isometrical tension responses to AVP and desmopressin were recorded in isolated monkey coronary arteries. RESULTS: AVP (10(-9) to 10(-7) mol/l) induced a concentration-related relaxation; endothelium-denudation abolished the response. Treatment with N(G)-nitro-L-arginine, but not the D-enantiomer, abolished the endothelium-dependent relaxation, which was restored by L-arginine. Treatment with SR49059 and [Pmp1,Tyr(Me)2]-Arg8-vasopressin, selective inhibitors of V1 receptor subtype, attenuated the relaxant response to AVP, whereas the relaxation induced by sodium nitroprusside was not affected by SR49059. Desmopressin, a V2 receptor agonist, up to 10(-8) mol/l did not elicit relaxation. CONCLUSIONS: It is concluded that AVP-induced monkey coronary arterial relaxation is mediated via nitric oxide synthesized from L-arginine in association with stimulation of V1 receptor subtypes in the endothelium.     

Vasopressin does not effect hypertension caused by long-term nitric oxide inhibition

Nitric oxide attenuates both vasopressin-induced vasoconstriction and vasopressin release. We tested whether hypertension and renal dysfunction elicited by chronic inhibition of nitric oxide (NO) synthesis using N(G)-nitro-L-arginine (L-NNA) could be mediated in part by vasopressin V(1A) receptors. Male rats were treated orally for 6 weeks with L-NNA (15 mg/kg per day), a nonpeptide V(1A) receptor antagonist (2S)-1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3, 4-dimethoxybenzene-sulfonyl)-3-hydroxy-2, 3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide (SR 49059, 30 mg/kg per day), or a combination of SR 49059 and L-NNA (same doses), or they received no treatment. Both drugs were added to the food. Measurements were performed in conscious rats (urine collection in metabolic cages, tail-cuff arterial pressure) and at the end of the study in anesthetized rats (clearance measurements). L-NNA produced sustained hypertension, decreased glomerular filtration rate, and increased renal vascular resistance, plasma renin activity, and urinary albumin excretion. SR 49059 had no effect per se on these parameters and also did not attenuate the hypertension and renal dysfunction induced by L-NNA. Surprisingly, SR 49059 potentiated L-NNA-induced hypertension at the end of the 6-week treatment. However, the blood pressure response and the renal and mesenteric vasoconstriction elicited by exogenous vasopressin were attenuated in rats treated with SR 49059. L-NNA did not change plasma vasopressin concentration or 24-hour urinary vasopressin excretion. Our findings suggest that activation of vasopressin V(1A) receptors does not contribute to the hypertension and renal dysfunction induced by chronic NO synthesis inhibition. They also document unchanged plasma vasopressin concentration in NO-deficient hypertension.     

INFLUENCE OF NIFEDIPINE AND ENALAPRIL ON OSMOREGULATION OF VASOPRESSIN

To determine whether calcium fluxes and angiotensin II influence osmoregulation of vasopressin (AVP) secretion, the effects of the calcium antagonist nifedipine and of the converting enzyme inhibitor enalapril on the AVP response to an osmotic load were compared to those of a placebo in seven normal female subjects. Plasma and urinary AVP were measured before and during a 3-h infusion of 2.5% hypertonic saline. Nifedipine (10 mg orally 2 h before and 10 mg at the start of the infusion) increased heart rate but did not change blood pressure. The changes in free water clearance and in urinary AVP induced by hypertonic saline under nifedipine were greater than in the control test, but the slope and the intercept of the regression line of plasma AVP upon plasma osmolality were not significantly different. Enalapril (10 mg 3 h before the infusion) did not change heart rate or blood pressure. Free water clearance and urinary AVP did not differ from the control test, but the slope of the regression line was less steep. These slight modifications of the response to an osmotic load suggest that calcium fluxes and angiotensin II only exert a limited influence on AVP osmoregulation in normal females.     

Osmoregulation of vasopressin secretion in patients with the syndrome of inappropriate antidiuresis associated with central nervous system disorders.

To clarify the characteristics of vasopressin (AVP) secretion in patients with the syndrome of inappropriate antidiuresis (SIAD) related to central nervous system disorders, we examined the response of AVP secretion to osmotic stimulus by hypertonic saline infusion and analyzed the possible causative factors in six patients with SIAD associated with head trauma or cerebral infarction. Hyponatremia developed after head trauma in four patients and cerebral infarction in two patients. In all patients the clinical state and laboratory findings fulfilled the criteria for SIAD, which was supported by either nonsuppressible plasma AVP levels or effectiveness of treatments with water restriction, demeclocycline, nonpeptide V2 AVP antagonist or diphenylhydantoin. Although patterns of plasma AVP response to the osmotic stimulus varied, plasma AVP concentrations neither increased nor decreased to undetectable levels with a rise in plasma osmolality. In one patient, plasma AVP levels responded to increasing plasma osmolality when plasma osmolality normalized; in which the threshold and the sensitivity of osmostat were normal. In two other patients, AVP secretion responded to plasma osmolality after the treatment. The changes in AVP secretion were not due to nonosmotic stimuli for AVP release. In conclusion, this study shows that patients with SIAD and central nervous system disorders may have persistent AVP secretion with a loss of hypotonic suppression such as found in patients with adrenal insufficiency or depletional hyponatremia in central nervous system disorders, indicating that careful evaluation is necessary to determine the relationship between persistent AVP secretion and the pathogenesis of hyponatremic disorders.     

Chronic Cardiovascular Effects of Central Vasopressin in Conscious Rats

To clarify the cardiovascular effects of central vasopressin (AVP), a chronic intracerebroventricular (ICV) infusion of AVP was performed in conscious Wistar normotensive rats. Animals were divided into 3 groups: 1) AVP 1 ng/hr (Low), 2) AVP 100 ng/hr (High), and 3) saline (control) ICV infusion. After a 6 day control period, AVP or saline was continuously infused into the lateral cerebroventricle at a rate of 1 μ/hr using osmotic minipump for 7 days. As a result, a dose-related elevation of AVP concentration in CSF was achieved. Systolic blood pressure in both Low and High AVP infusion was slightly (7-12 mmHg) but significantly higher than that in control. ICV infusion of AVP did not alter urine volume, electrolytes excretion or osmolality, and AVP vascular antagonist injected intravenously failed to affect mean arterial pressure. Furthermore, plasma catecholamines and renin activity did not differ significantly among the groups. Thus, chronic ICV infusion of AVP induced the elevation of blood pressure, which is due to centrally mediated effect of AVP.     

Evidence for a role of vasopressin in the control of aldosterone secretion in primary aldosteronism: in vitro and in vivo studies

CONTEXT: Arginine vasopressin (AVP) stimulates steroid secretion from the normal human adrenal gland and some cortisol-producing adrenocortical tumors or hyperplasia through activation of the V(1a) receptor. OBJECTIVE: The objective of the study was to investigate in vitro and in vivo the possible involvement of AVP in the physiopathology of primary aldosteronism. DESIGN: The design of the study included immunohistochemical, pharmacological, and molecular studies on aldosterone-producing adenoma (APA), followed by a monocentric, crossover trial of the orally active V(1a) receptor antagonist, SR 49059, in a double blind, randomized, and placebo-controlled fashion. SETTING: The study was conducted at a university hospital and research laboratory. PATIENTS: The study population included eight untreated patients with primary aldosteronism, four with APA and four with idiopathic hyperaldosteronism. MAIN OUTCOME MEASURES: Aldosterone secretion of APA cells in vitro and plasma aldosterone, renin, and ACTH were measured. INTERVENTION: SR 49059 (200 mg once daily) or placebo was administered during two 1-wk treatment periods separated by a 2-wk washout. RESULTS: We observed the occurrence of AVP-containing cells in APA tissues. Administration of AVP to perifused APA cells induced an increase in aldosterone production, which was inhibited by a specific V(1a) antagonist. RT-PCR analysis showed the expression of V(1a) receptor mRNA in most APAs studied. In APA patients, SR 49059 did not induce any effect on basal aldosterone secretion but provoked a plasma aldosterone response to orthostatism (P < 0.03) and strengthened the positive correlation between plasma aldosterone and ACTH. CONCLUSIONS: The present study indicates that functional V(1a) receptors are present in APA and suggests that AVP may exert an autocrine/paracrine control of aldosterone secretion in APA tissues.     

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.     

Changes in vasopressin release and autonomic function induced by manipulating forebrain GABAergic signaling under euvolemia and hypovolemia in conscious rats

The anteroventral third ventricular region (AV3V) is a pivotal area for osmotic responses and integration of autonomic functions. The purpose of this study was to investigate whether the gamma-aminobutyric acid (GABA)-ergic activity in the AV3V may be involved in the regulation of arginine vasopressin (AVP) secretion and related phenomena under the conditions with or without hypovolemia. Experiments were performed in conscious rats. We found that AV3V infusion with the GABA(A) receptor antagonist bicuculline in euvolemic rats caused prompt increases in plasma AVP, osmolality, glucose, arterial pressure and heart rate. The effects of the bicuculline infusion were abolished by prior infusion of a GABA(A) receptor agonist, muscimol. When repeated twice with a 10-min interval, removal of systemic blood (10 mL/kg body weight) lowered arterial pressure and enhanced plasma AVP, osmolality, glucose and angiotensin II. Muscimol infusion in the AV3V, but not in the cerebral ventricle, inhibited the responses of plasma AVP and glucose, despite having no effect in a sham hemorrhagic state. The inhibition of the AVP response by the muscimol infusion was also verified in rats given a combined stimulus of bleeding plus an osmotic load. In contrast, AV3V infusion with the GABA(B) receptor agonist baclofen tended to intensify the hemorrhagic responses of plasma AVP and glucose, despite its potency to prevent the hemorrhagic fall in arterial pressure. These results, taken together with our previous data, suggest that hypovolemic stimuli, like hyperosmotic stimuli, may promote AVP secretion by causing the inhibition of AV3V GABA(A)-ergic activity responsible for potentiation of glutamatergic activity.     

Vasopressin and a Nonpeptide Antidiuretic Hormone Receptor Antagonist (OPC-31260)

The development of nonpeptide orally active AVP analogues has provided a new tool with which to assess the physiological and pathophysiological role of vasopressin (AVP). We have previously characterised the nonpeptide vasopressin V1 receptor antagonist OPC-21268, and now report the in vitro characterisation of the nonpeptide V2 receptor antagonist OPC-31260 in the rat. OPC-31260 caused a concentration-dependent displacement of the selective AVP V2 receptor antagonist radioligand, [³H]desGly-NH₂⁹[d(CH₂)₅, D-Ile², Ile⁴] AVP from V2 receptors in rat kidney medulla membranes. The concentration of OPC-31260 that displaced 50% of specific AVP binding (IC₅₀) was 20 ± 2 nmol/l for renal V2 receptors. OPC-31260 also caused a concentration-dependent displacement of the selective AVP V1 receptor antagonist radioligand, [¹²⁵I]-[d(CH₂)₅, sarcosine⁷] AVP from V1 receptors in both rat liver and kidney medulla membranes. The IC₅₀ was 500 ± 30 nmol/ 1 for both renal and liver V1 receptors. After oral administration to rats, OPC-31260 was an effective inhibitor of AVP at renal V2 and liver V1 receptors in a time-dependent manner. In vitro binding kinetic studies showed that OPC-31260 was a competitive antagonist at both the renal V2 receptor and the hepatic V1 receptor. OPC-31260 is a nonpeptide, orally effective competitive inhibitor of AVP with a V2: V1 receptor selectivity ratio of 25:1 indicating relative V2 receptor selectivity.     

Exaggerated Natriuresis in Adult Polycystic Kidney Disease

ABSTRACT. Angiotensin II (AII), aldosterone (Aldo) arginine vasopressin (AVP) in plasma, serum osmolality (S_osm), and renal sodium excretion (U_NaV) were studied before and after infusion of hypertonic sodium chloride solution in 20 patients with adult polycystic kidney disease (PKD) with normal or moderately reduced creatinine clearance (C_Cr) and in 10 healthy control subjects. U_NaV increased after sodium loading in all, significantly more in the PKD patients. AII and Aldo were normal before sodium loading and suppressed after saline in PKD patients and controls. The increase in V_NaV correlated with Aldo in patients but not in controls. AVP before loading was increased in hypertensive PKD patients with reduced C_cr, but not in normotensive patients with normal C_cr. After hypertonic saline, S_osm increased to the same degree both in PKD and control subjects, but AVP increased more in those with PKD. The exaggerated natriuresis of PKD is probably not explained by a change in the activity of the renin-angiotensin-aldosterone system. The enhanced response of AVP to osmotic stimuli in PKD may be a compensatory reaction to a reduced renal tubular effect of AVP.     

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.     

Pretreatment with vasodilator or V1-antagonist abolishes vasopressin withdrawal hypotension in spontaneously hypertensive rats

In spontaneously hypertensive rats (SHR), the cessation of a 3-h intravenous infusion of arginine vasopressin (AVP, 8 mU/kg per min) resulted in a large and prolonged fall in arterial pressure (46 +/- 7.5 mmHg below basal levels). Pretreatment of SHR with the specific V1-receptor antagonist, [1-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid), 2-(O-methyl)-tyrosine] AVP (d(CH2)5Tyr (Me)AVP, 8 micrograms/kg followed by 0.05 micrograms/kg per min) abolished the pressor response to AVP, and markedly reduced the subsequent hypotensive response following the cessation of the AVP infusion. The hypotensive response to AVP withdrawal was abolished also when phenylephrine hydrochloride (PE, 20 nmol/kg per min) elicited a blood pressure rise during the course of AVP infusion in rats with V1-receptor blockade. Finally, the concurrent administration of sodium nitroprusside (30 micrograms/kg per min) not only counteracted the pressure rise during AVP infusion, but also prevented the hypotensive response that normally accompanied the withdrawal of AVP. These findings demonstrate that neither V1-receptor activation nor blood pressure elevation alone was sufficient to generate a hypotensive response to the withdrawal of AVP; rather, both V1-receptor activation and a blood pressure elevation associated with the activation of these receptors were essential to the hypotensive response that followed the withdrawal of AVP in SHR.     

Osmotic stimulation in DOC-salt hypertension: vasopressin and blood pressure

To determine whether there is a change in the sensitivity of the osmotic control of vasopressin release in deoxycorticosterone (DOC)-salt hypertension, experiments were performed in unilaterally nephrectomized rats that were either normotensive or were made hypertensive with DOC and given 1% saline to drink. After 3 weeks of treatment, 2.5 mol/l NaCl was infused i.v. into conscious normotensive and hypertensive rats. Increases in both plasma osmolality and plasma vasopressin concentration were similar throughout the course of this infusion in the two groups of rats. Hypertonic saline infusion increased the mean arterial blood pressure in the two groups of rats, but this increase was partially attenuated by the i.v. injection of a vasopressin pressor antagonist. In conclusion, vasopressin release in response to osmotic stimulation was similar in normotensive and hypertensive rats. The pressor response to hypertonic saline in both groups of rats could be partially attributed to the increased plasma vasopressin concentration.     

Effect of SR 49059, a V1a vasopressin receptor antagonist, in Raynaud's phenomenon

OBJECTIVE: To assess whether vasopressin V1a receptor blockade reduces the abnormal vasoactive response to cold in patients suffering from Raynaud's phenomenon (RP). METHODS: SR 49059, an orally active, non-peptidic vasopressin V1a receptor antagonist, was given orally (300 mg once daily) to 20 patients with RP in a single-centre, double-blind, placebo-controlled, randomized cross-over study with two 7-day periods of treatment separated by 21 days of washout. Bilateral finger systolic blood pressure and skin temperature were assessed before and after immersion of the hand in cold water for 3 min (15 degrees C) during the screening phase and three times (before and 2 and 4 h after drug intake) on days 1 and 7 of each of the two treatment periods. Recovery of digital pressure and skin temperature was measured 0, 10, 20 and 32 min after the end of the cold immersion test. RESULTS: SR 49059 significantly attenuated the cold-induced fall in systolic pressure by 14.5% (95% confidence interval 0-29; P = 0.045) on the most affected hand on day 7 compared with placebo. Temperature recovery after the end of the cold test showed a trend to enhancement 2 and 4 h after SR 49059 on day 7 (P = 0.060 and P = 0.062 respectively). The beneficial effects on finger pressure and temperature recovery were obtained without changes in supine blood pressure or in heart rate. CONCLUSION: SR 49059 given orally once a day for 7 days to patients with RP showed favourable effects compared with placebo on finger systolic pressure and temperature recovery after cold immersion, without inducing side-effects.     

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.     

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.