Vasopressin Deficiency Research Articles

Selective V1a receptor agonist FE 202158 reverses platelet-activating factor-induced hypotension, vascular leak, impaired tissue perfusion, and mortality in rats

Platelet-activating factor (PAF) is a phospholipid autacoid inducing peripheral vasodilation and vascular leak, both pathophysiological hallmarks of sepsis-induced cardiovascular dysfunction resulting in hypotension [1]. Indeed, PAF has been implicated in various animal models of sepsis and in septic humans [2]. A deficiency in the vasopressor hormone arginine vasopressin (AVP), a mixed V1a/V2 receptor agonist, also contributes to the cardiovascular dysfunction of septic shock, leading to clinical use of AVP for this condition [3,4]. These various findings led us to hypothesize that the selective V1a receptor agonist FE 202158 would be effective in a rat model of PAF-induced hypotension.

Le diabète insipide central chez l'enfant : étude de six observations

Introduction The central insipid diabetes (DIC) is defined by the excretion — abnormally important — of dilute urines at an absolute or relative deficiency in endogen vasopressin and susceptible to exogen vasopressin. Patients and methods The authors have studied retrospectively 6 cases of DIC hospitalised in the CHU Hédi Chaker of Sfax pediatrics service over a period of 19 years starting from the 1st of January 1987 though the 31st of December 2005. They have studied in our patients the clinic, biologic, neuroradiologic and etiologic particularities. Results During the period of study, the authors have studied 6 cases of DIC. The average age was of 7 years (1 year 9 months–13 years 3 months). The polyuropolydipsic syndrome represented the reason of consultation of all our patients. Hypotonic polyurie was constant with all children, it was about an average of 12,2 ml/kg/h. The test of hydrous restriction coupled with the Minirin ® test has allowed us to perform the diagnosis of the DIC in all cases. The etiologic analyses including a neuroradiologic imagery (IRM and/or cerebral scanner) has permitted to show an expansive process of the median line (germinome) with one patient, an growth of the pituitary stem one patient, the cerebral scanner has been done to 2 children and it was normal. A patient was lost before doing the imagery. The thoracic scanner realized for one patient presenting dyspnoea showed pulmonary emphysema with an interstitial syndrome in aid of a langherancienne histiocytose. The coetaneous biopsy made on another patient having presented cuteness lesions confirmed too the diagnosis of Histiocytose. The DIC is idiopathic with the two other patients. The evolution has been marked by the death in one case, a progressive aggravation dyspnoea with 1 patient; otherwise, it was favourable for the other patients. Conclusion The DIC is rare in the child, the historic clinic brutal making the diagnostic easy; it is not the case with the investigations permitting to discover an etiology that can unmask over a long period justifying a prolonged supervision.

Congenital vasopressin deficiency and acute and chronic opiate effects on hypothalamo-pituitary–adrenal axis activity in Brattleboro rats

A growing body of evidence suggests that vasopressinergic activity in the hypothalamus is important in stress-related behaviors (like drug abuse) in line with a role in the regulation of the hypothalamo-pituitary-adrenal axis (HPA). We hypothesized that in the naturally vasopressin-deficient Brattleboro rat, acute and chronic morphine treatment may lead to reduced HPA axis activity. Rats were treated either with a single dose of morphine (10 mg/kg subcutaneously) and serial blood samples were taken or were treated twice daily with increasing doses of morphine (10-100 mg/kg subcutaneously) for 16 days and animals were killed by decapitation 4 or 16 h after the last injection. Single morphine injection induced a biphasic ACTH and corticosterone elevation with smaller increases in vasopressin-deficient rats. Chronic morphine treatment induced the typical somatic and HPA axis changes of chronic stress; the absence of vasopressin did not prevent these changes. In rats repeatedly treated with morphine plasma, ACTH and corticosterone levels were elevated both 4 and 16 h after the last injection (short and long withdrawal) and the absence of vasopressin attenuated this response. Our data suggest that vasopressin plays a prominent role in morphine treatment and withdrawal-induced acute hormonal changes, but does not affect development of chronic hyperactivity of the HPA axis.

Vasopressin in vasodilatory and septic shock

The aim of this article is to review mechanisms of action of vasopressin and clinical studies of vasopressin in septic shock. Arginine vasopressin is an important stress hormone that has both vasoactive and antidiuretic properties. The vasoactive properties of vasopressin have been more applicable clinically because of the discovery by Landry and colleagues that there is a deficiency of vasopressin in septic shock and that infusion of relatively low doses of vasopressin improves responsiveness to infused catecholamines (such as norepinephrine). There are at least 16 clinical studies of infusion of vasopressin in patients who have septic shock. The majority of studies found that vasopressin infusion increased blood pressure and urine output, and decreased the dose requirement of norepinephrine. Several studies showed that vasopressin infusion increased urine output. Both vasopressin and norepinephrine have important adverse effects including decreased cardiac output, decreased heart rate, arrhythmias, myocardial ischemia, mesenteric ischemia, and digital ischemia. It is still unclear whether there is net benefit from low dose vasopressin infusion in patients who have septic shock. There may be certain patients who benefit but there are few studies of a prolonged vasopressin infusion to determine which patients benefit.

Endogenous and exogenous vasopressin in shock

Vasopressin is critical for blood pressure regulation when cardiovascular homeostasis is threatened and some patients with shock have inappropriately low levels of hormone in plasma. The present review focuses on recent work that addresses the role of endogenous vasopressin in the pathogenesis of shock and the potential therapeutic indications and secondary effects of exogenous hormone in patients with shock. Examples of types of shock resistant to catecholamine pressors in which exogenous vasopressin was effective in restoring arterial pressure continued to accumulate. Widespread determinations of plasma vasopressin in patients with shock suggest that endogenous vasopressin deficiency may be more frequent than previously thought. The generation of mice with deletion of vasopressin's V1a receptor highlighted the important role of the hormone on cardiovascular homeostasis. Vasopressin administration is very effective in restoring arterial pressure in many forms of shock and this appears to be due, at least in part, to deficiency of endogenous hormone. Generation of mice lacking vasopressin V1a receptor open new and exciting avenues of inquiry to clarify the role of the hormone in cardiovascular homeostasis.

Author’s reply to the correspondence letter from Dr. S. Meyer et al. entitled arginine-vasopressin as a rescue therapy in children and neonates for catecholamine-resistant shock

We appreciate the interest in our study and the comments by Dr. Meyer and would like to respond to them. Our study reported the retrospectively analysed data of 17 neonates, who developed systemic inflammatory response syndrome (SIRS) with catecholamineresistant vasodilatory shock following open-heart surgery and were treated with lowdose continuous infusion of arginine-vasopressin (AVP). Despite the use of modified ultrafiltration uncontrolled release of proinflammatory cytokines may lead to SIRS after cardiopulmonary bypass. Especially neonates who undergo cardiac surgery with long bypass duration are at high risk to develop post bypass SIRS [2, 7]. This syndrome is not necessarily associated with cardiac dysfunction or cardiogenic shock. Both septic as well as post cardiopulmonary bypass-induced severe vasodilatation are associated with inappropriately low vasopressin plasma levels; so this vasopressin deficiency may contribute to the hypotension of vasodilatory shock [3, 4, 6]. Low dose continuous infusions of vasopressin have been successfully used in several trials in adults and children with vasodilatory shock secondary to open-heart surgery [1, 5, 6]. In accordance with these findings, our study showed that in neonates with vasodilatory shock refractory to traditional vasopressors after cardiac surgery vasopressin seems to be a potent agent to increase blood pressure and avoid end-organ failure. Because vasopressin is less appropriate for neonates with ventricular dysfunction [6], we took care not to use AVP in patients with cardiac dysfunction. One major limitation of our study was that we did not measure endogenous vasopressin levels prior to the initiation of AVP. We fully agree with the suggestion of Dr. Meyer that future clinical studies should assess endogenous vasopressin levels prior to the administration of exogenous AVP.

Vasopressin administration facilitates fluid removal during hemodialysis

Inadequate secretion of vasopressin during fluid removal by hemodialysis may contribute to the cardiovascular instability that complicates this therapy and administration of exogenous hormone, by supporting arterial pressure, may facilitate volume removal. To test this, we measured plasma vasopressin in patients with end-stage renal disease (ESRD) during hemodialysis and found that despite significant fluid removal, plasma vasopressin concentration did not increase. We further found that ESRD did not alter the endogenous removal rate of plasma vasopressin and that plasma hormone is not dialyzed. Finally, in a randomized, double-blinded, placebo-controlled trial in 22 hypertensive patients, we examined the effect of a constant infusion of a non-pressor dose of vasopressin on the arterial pressure response during a hemodialysis in which the target fluid loss was increased by 0.5 kg over the baseline prescription. We found that arterial pressure was more stable in the patients receiving vasopressin and that while only one patient (9%) in the vasopressin group had a symptomatic hypotensive episode, 64% of the patients receiving placebo had such an episode (P=0.024). Moreover, increased fluid removal was achieved only in the vasopressin group (520+/-90 ml vs 64+/-130 ml, P=0.01). Thus, administration of non-pressor doses of vasopressin to hypertensive subjects improves cardiovascular stability during hemodialysis and allows increased removal of excess extracellular fluid. Inadequate vasopressin secretion during hemodialysis-induced fluid removal is a likely contributor to the intradialytic hypotension that limits fluid removal.

Hormone Replacement Therapy and Vascular Risk Disorders in Adult Hypopituitarism

Adult patients with hypopituitarism are treated by the replacement of deficient hormones, although GH has not been substituted until March 2006 in Japan except for clinical trial. This study examines which hormonal status influences the prevalence of vascular risk disorders in hypopituitary adults. A sample of 263 adult patients with hypopituitarism was studied, among whom there were various hormonal status such as no deficiency, treated or untreated deficiency of each pituitary hormone. Analysis of adult patients with hypopituitarism showed that hypertension was more prevalent in the older than in younger patients and in male than in female patients. Hypercholesterolemia and hypertriglyceridemia were more prevalent in patients with TSH deficiency even with thyroxine substitution than those without TSH deficiency. Both obesity and hypertension were less prevalent in patients with treated ACTH deficiency than those without ACTH deficiency. Obesity was more prevalent in patients with treated vasopressin deficiency than those without vasopressin deficiency. These results provide evidence that glucocorticoid substitution in ACTH deficient adults was favorable to prevent obesity and hypertension but that the thyroxine substitution in TSH deficient adults appeared rather insufficient to prevent hyperlipidemia.

A Case of Idiopathic Central Diabetes Insipidus together with Primary Empty Sella and Combined Pituitary Hormone Deficiency

Central diabetes insipidus is a heterogeneous condition that is characterized by polyuria and polydipsia, and this is due to a deficiency of arginine vasopressin. Central diabetes insipidus is rare in children and young adults, and up to 50 percent of cases are idiopathic. Genetic abnormalities in the homeobox genes have recently been shown, on sellar magnetic resonance imaging, to be associated with combined pituitary hormone deficiency with pituitary defect. We report here on a 44-year-old female who suffered from polydipsia, polyuria and primary amenorrhea since childhood. She was diagnosed with idiopathic central diabetes insipidus together with primary empty sella and combined pituitary hormone deficiency. On the genetic analysis, she was proven to have a point mutation of the PROP-1 gene, which is known as a cause of combined pituitary hormone deficiency.

Vasopressin: Mechanisms of action on the vasculature in health and in septic shock

Vasopressin is essential for cardiovascular homeostasis, acting via the kidney to regulate water resorption, on the vasculature to regulate smooth muscle tone, and as a central neurotransmitter, modulating brainstem autonomic function. Although it is released in response to stress or shock states, a relative deficiency of vasopressin has been found in prolonged vasodilatory shock, such as is seen in severe sepsis. In this circumstance, exogenous vasopressin has marked vasopressor effects, even at doses that would not affect blood pressure in healthy individuals. These two findings provide the rationale for the use of vasopressin in the treatment of septic shock. However, despite considerable research attention, the mechanisms for vasopressin deficiency and hypersensitivity in vasodilatory shock remain unclear. To summarize vasopressin's synthesis, physiologic roles, and regulation and then review the literature describing its vascular receptors and downstream signaling pathways. A discussion of potential mechanisms underlying vasopressin hypersensitivity in septic shock follows, with reference to relevant clinical, in vivo, and in vitro experimental evidence. Search of the PubMed database (keywords: vasopressin and receptors and/or sepsis or septic shock) for articles published in English before May 2006 and manual review of article bibliographies. The pathophysiologic mechanism underlying vasopressin hypersensitivity in septic shock is probably multifactorial. It is doubtful that this phenomenon is merely the consequence of replacing a deficiency. Changes in vascular receptors or their signaling and/or interactions between vasopressin, nitric oxide, and adenosine triphosphate-dependent potassium channels are likely to be relevant. Further translational research is required to improve our understanding and direct appropriate educated clinical use of vasopressin.

Is the cyclic GMP system underestimated by intensive care and emergency teams?

At present, the clinical management inflammatory vasoplegia associated to sepsis or anaphylaxis is symptomatic. Volume is expanded by means of administration of fluids, and low blood pressure is managed by means of administration of positive inotropes and vasoconstrictors. This therapeutic approach is mainly associated to the cyclic AMP (cAMP) and, many times the circulatory shock is refractory to high amines concentrations. However, beside of cAMP-dependent vasoreactivity mechanisms there are other two known vasoplegia involved mechanisms: cyclic GMP (cGMP) and hyperpolarization that is less clinically considered. Also, it is possible to speculate about 'probable vasopressin deficiency'. Methylene blue (MB) is the most useful and clinically safe cGMP blocker. We propose a decision tree for diagnosis and institution of this therapeutical approach many times underestimate by intensive care and emergency teams.

Signs of attenuated depression-like behavior in vasopressin deficient Brattleboro rats

Vasopressin, a peptide hormone functioning also as a neurotransmitter, neuromodulator and regulator of the stress response is considered to be one of the factors related to the development and course of depression. In the present study, we have tested the hypothesis that congenital deficit of vasopressin in Brattleboro rats leads to attenuated depression-like behavior in tests modeling different symptoms of depression. In addition, hypothalamic–pituitary–adrenocortical axis activity was investigated. Vasopressin deficient rats showed signs of attenuated depression-like behavior in forced swimming and sucrose preference tests, while their behavior on elevated plus maze was unchanged. Vasopressin deficiency had no influence on basal levels of ACTH and corticosterone and had only mild impact on hormonal activation in response to forced swimming and plus-maze exposure. However, vasopressin deficient animals showed higher level of dexamethasone induced suppression of corticosterone response to restraint stress and higher basal levels of corticotropin-releasing hormone mRNA in the hypothalamic paraventricular nucleus. In conclusion, present data obtained in vasopressin deficient rats show that vasopressin is involved in the development of depression-like behavior, in particular of the coping style and anhedonia. Moreover, behavioral and endocrine responses were found to be dissociated. We suggest that brain vasopressinergic circuits distinct from those regulating the HPA axis are involved in generating depression-like behavior.

The Vasopressin System

Vasopressin, synthesized in the hypothalamus, is released by increased plasma osmolality, decreased arterial pressure, and reductions in cardiac volume. Three subtypes of vasopressin receptors, V1, V2, and V3, have been identified, mediating vasoconstriction, water reabsorption, and central nervous system effects, respectively. Vasopressin and its analogs have been studied intensively for the treatment of states of "relative vasopressin deficiency," such as sepsis, vasodilatory shock, intraoperative hypotension, and cardiopulmonary resuscitation. Infusion of vasopressin (0.01-0.04 U/min) decreases catecholamine requirements in patients with sepsis and other types of vasodilatory shock. Bolus application of 1 mg terlipressin, the V1 agonist, reverses refractory hypotension in anesthetized patients and has been studied in patients with septic shock and chronic liver failure. During cardiopulmonary resuscitation, a 40-U bolus dose of vasopressin may be considered to replace the first or second bolus of epinephrine regardless of the initial rhythm. The side effects of vasopressin and its analogs must be further characterized.

Serial circulating vasopressin levels in children with septic shock*

Septic shock is an important cause of death in pediatric intensive care units. Initial evaluations have shown that vasopressin may have a role in catecholamine refractory shock in adults. It is important to determine whether children with septic shock have deficiency of vasopressin. This will help in defining the role of vasopressin in septic shock. Prospective cohort study. Pediatric intensive care unit of a tertiary care hospital in north India. Patients were children with septic shock, and controls were children with sepsis but no shock. Vasopressin levels in plasma were determined by enzyme-linked immunosorbent assay for children with septic shock at diagnosis (baseline) and thereafter at 24, 48, and 96 hrs to determine the time trends. The baseline vasopressin values for children with septic shock were compared with those for children without shock. The median (95% confidence interval) vasopressin level at baseline in children with septic shock was 116 (63.3-130.7) pg/mL, and in children with sepsis but no shock it was 106 (61.7-131.77) pg/mL. The median value for survivors was 76 (44.6-130.9) pg/mL, and for nonsurvivors, 118 (81.7-259) pg/mL (p = .16). The serial values also did not show any significant changes; the values at 24 hrs (n = 17), 48 hrs (n = 16), and 96 hrs (n = 15) were 105 (76.1-125.9), 105 (41.4-155.5), and 109.5 (54.9-154.8) pg/mL, respectively. The results of our study suggest that vasopressin levels are elevated in children with septic shock and that serial values up to 96 hrs do not show any decline.

Decreased vasopressin responsiveness in vasodilatory septic shock–like conditions*

To determine the effect of vasodilatory septic shock-like conditions on vasoconstricting responses to vasopressin and norepinephrine in isolated resistance arteries. Prospective, randomized animal study. University research laboratory. Male adult Sprague-Dawley rats. Small mesenteric arteries (outside diameter, 50-150 microm) were cannulated and studied in vitro under physiologic conditions. A vasodilatory septic shock-like state was produced by treatment with the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine (SNAP), and the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). Vasoconstricting concentration-response relationships were determined for norepinephrine and vasopressin before and after application of SNAP or SNAP+ IBMX. Synergism between low-dose vasopressin and norepinephrine and between low-dose norepinephrine and vasopressin was determined before and after SNAP or SNAP+IBMX. Norepinephrine and vasopressin produced concentration-dependent contractions (half-maximal effective concentration [EC(50)] = 2.5 microM and 3.9 nM, respectively) that were significantly inhibited by 1 microM SNAP (EC(50) = 3.6 microM and 8.1 nM, respectively) or 100 microM SNAP + 10 microM IBMX (EC(50) = 10 microM and 8.2 nM, respectively). Low-dose vasopressin significantly increased the responsiveness to norepinephrine (EC50 = 0.5 microM) just as a low-dose norepinephrine significantly enhanced the vasopressin response (EC(50) = 2.3 nM). The synergistic effects of low-dose vasopressin and norepinephrine, or low-dose norepinephrine and vasopressin, were also significantly inhibited by 1 microM SNAP (EC(50) = 2.5 microM and 4.2 nM, respectively) or 100 microM SNAP + 10 microM IBMX (EC(50) = 9 microM and 8.4 nM, respectively). Vasoconstriction produced by vasopressin or norepinephrine, and the synergistic vasoconstriction produced by the combinations, was inhibited in vasodilatory septic shock-like conditions. Thus, in addition to the well-described vasopressin deficiency in vasodilatory septic shock, these studies indicate that decreased vasopressin responsiveness further contributes to a state of relative vasopressin insufficiency in this condition.

Functional and Morphological Changes in the Hypothalamus-Pituitary Posterior Lobe System after Hypophysectomy in the Dog

Acute diabetes insipidus-like symptoms have been reported as a complication after hypophysectomy in dogs. These symptoms are believed to be the consequence of deficiency of arginine vasopressin (AVP) secretion. The symptoms spontaneously resolve within 2 weeks, but the mechanism is unclear. In the present study, AVP secretion related to increases in Na+ concentration and serum osmotic pressure was measured, and immunohistochemical analysis in the paraventricular and supraoptic nuclei was performed after hypophysectomy in normal dog. In the hypertonic saline test, the plasma AVP concentration slightly increased in hypophysectomized dogs, although the increase was markedly smaller than that in normal dogs. An immunohistochemical study of the hypothalamus nucleus revealed that, AVP-positive cells tended to decrease after hypophysectomy. It suggests that excision of the posterior lobe by surgery injured the axon of magnocellular neuron in the hypothalamus. A decrease in the function and the number of AVP-producing and -secreting magnocellular neurons after hypophysectomy, suggests that the clinical improvement of postoperative diabetes insipidus-like symptoms may not be related to the recovery of AVP secretion.

Haploinsufficiency of the arginine–vasopressin gene is associated with poor spatial working memory performance in rats

Behavioral pharmacological studies have implicated a role for the neurophysin arginine–vasopressin in learning and memory. Vasopressin, and its analogues, can produce either improvements or impairments in mnemonic functions, effects that depend upon the agent administered, the memory process measured and the task employed. As recent data have implicated vasopressin in regulating the cognitive functions of the prefrontal cortex, we sought to determine whether changes in vasopressinergic tone would affect a form of memory that is dependent upon this brain region. To that end, we used a genetic approach to examine how haploinsufficiency of the vasopressin gene affects working memory performance. Specifically, we tested a naturally occurring null-mutant rat on an operant delayed-non-match-to-position task. Male and female heterozygous and wild-type rats were trained to perform this working memory task, and the effects of varying the delay across which they had to maintain task information were systematically varied. Although vasopressin-deficient rats omitted fewer trials and completed trials more quickly, they exhibited delay-dependent deficits of choice accuracy. The genotype effects were not modified by sex. Collectively, these data indicate that even partial vasopressin deficiency can trigger deficits of spatial working memory performance and add to the growing body of results supporting a regulatory control of neocortical-dependent cognitive functions by this neurohormone.

Serial T1-weighted magnetic resonance imaging changes in a patient with central diabetes insipidus, possibly due to lymphocytic infundibuloneurohypophysitis

Central diabetes insipidus (CDI), characterized by polydipsia and polyuria due to vasopressin deficiency, is familial, idiopathic or secondary. Idiopathic CDI, which accounts for 10% to 30% of cases of CDI (1), is characterized by selective hypofunction of the hypothalamic‐neurohypophysial system. Idiopathic CDI could be an autoimmune disorder (2). Imura et al. (3) studied the processes of idiopathic CDI by magnetic resonance imaging (MRI), found abnormalities in the pituitary stalk and neurohypophysis, and performed biopsies that demonstrated lymphocytic inflammation. Their cases were diagnosed with CDI due to lymphocytic infundibuloneurohypophysitis. Their study provided new insight into the pathogenesis of CDI. However, they did not demonstrate the serial changes by MRI. We demonstrate the serial T1-weighted MRI changes in a 52-year-old woman with CDI possibly due to lymphocytic infundibuloneurohypophysitis. The initial MRI findings on admission were prominent pituitary-stalk thickening and neurohypophysial enlargement. These findings suggested that the patient had lymphocytic infundibuloneurohypophysitis (3‐5). The serial T1weighted MRI changes which occurred over the years were (i) prominent pituitary-stalk thickening and neurohypophysial enlargement, (ii) their improvement, and finally (iii) empty sella. The MRI changes are associated with the clinical course of the disease. Steroids were not administered to the patient; she recovered from CDI spontaneously. This is the first report to demonstrate the natural course of serial MRI changes in a patient with CDI possibly due to lymphocytic infundibuloneurohypophysitis. A 52-year-old woman had been well until 27 October 2002, when she began to have extreme thirst and excessive urine output. She visited us on 2 December 2002. She had extreme thirst and had started to drink more than 2literswater aday.Shehad decreased anti-diuretic hormone (ADH) levels (0.3ng/l, reference range 0.3‐ 3.5ng/l) with a low urine osmolality of 100mOsm/kg, high plasma osmolality of 310mOsm/kg (reference range 278‐305mOsm/kg), and a high serum

Pituitary hormone replacement

<h2>Abstract</h2> Hormone replacement therapy is available for patients suffering diabetes insipidus and all the anterior pituitary hormone deficiencies, with the exception of prolactin. In patients with adrenocorticotrophic hormone and thyroid-stimulating hormone deficiencies, replacement is with the target-gland hormone products cortisol (hydrocortisone) and thyroxine, respectively. Sex steroid replacement therapy is offered to patients with gonadotrophin deficiency to deal with the sex steroid deficiency, but if fertility is desired gonadotrophin therapy is required. Growth hormone (GH) deficiency requires GH replacement, but only adult patients with severe GH deficiency are considered for replacement and, in the UK, such patients are chosen by virtue of severe impairment of quality of life; strict criteria must be satisfied before the 9-month trial of therapy can be extended to lifelong GH replacement. Desmopressin, a synthetic analogue of arginine vasopressin, is the drug of choice for the treatment of antidiuretic hormone deficiency; it is available in several different preparations.

A novel splice site mutation of the arginine vasopressin–neurophysin II gene identified in a kindred with autosomal dominant familial neurohypophyseal diabetes insipidus

Autosomal dominant familial neurohypophyseal diabetes insipidus is an inherited deficiency of arginine vasopressin (AVP), and this is caused by mutations in the AVP–neurophysin II (AVP–NP II) gene. Most of these mutations have been located in the signal peptide or in the NP II moiety. In the present study, we have analyzed the AVP–NP II gene in a Korean family. Clinical and genetic studies were performed on three members of the family, and on a normal healthy unrelated individual. The diagnosis of neurohypophyseal diabetes insipidus was done by performing a fluid deprivation test and a vasopressin challenge. For genetic analysis, the genomic DNA was extracted and the AVP–NP II gene was amplified by polymerase chain reaction (PCR). Clinical assessment of the affected individuals confirmed the diagnosis of neurohypophyseal diabetes insipidus. Genetic analysis of the AVP–NP II gene revealed a novel deletion mutation of a single nucleotide (guanine) within the splice acceptor site of intron 2 (IVS2 +1 delG). The affected individuals were heterozygous for this mutation. We also demonstrated through RT-PCR analysis of the mutant gene that this mutation resulted in the retention of intron 2 during pre-mRNA splicing. We concluded that a novel splicing mutation in the AVP–NP II gene causes neurohypophyseal diabetes insipidus in this family.