Vasopressin, Central Autonomic Control and Blood Pressure Regulation.

PURPOSE OF REVIEW: We present recent advances in understanding of the role of vasopressin as a neurotransmitter in autonomic nervous system control of the circulation, emphasizing hypothalamic mechanisms in the paraventricular nucleus (PVN) involved in controlling sympathetic outflow toward the cardiovascular system. RECENT FINDINGS: Suggest that somato-dendritically released vasopressin modulates the activity of magnocellular neurons in the PVN and SON, their discharge pattern and systemic release. Advances have been made in uncovering autocrine and paracrine mechanisms controlling presympathetic neuron activity, involving intranuclear receptors, co-released neuroactive substances and glia. It is now obvious that intranuclear release of vasopressin and the co-release of neuroactive substances in the PVN, as well as the level of expression of vasopressin receptors, modulate sympathetic outflow to the cardiovascular system and determine vulnerability to stress. Further research involving patho-physiological models is needed to validate these targets and foster the development of more efficient treatment.

Vasopressin-Dependent Disorders: What Is New in Children?

Arginine vasopressin (AVP)-mediated osmoregulatory disorders, such as diabetes insipidus (DI) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are common in the differential diagnosis for children with hypo- and hypernatremia and require timely recognition and treatment. DI is caused by a failure to concentrate urine secondary to impaired production of or response to AVP, resulting in hypernatremia. Newer methods of diagnosing DI include measuring copeptin levels; copeptin is AVP's chaperone protein and serves as a surrogate biomarker of AVP secretion. Intraoperative copeptin levels may also help predict the risk for developing DI after neurosurgical procedures. Copeptin levels hold diagnostic promise in other pediatric conditions, too. Recently, expanded genotype and phenotype correlations in inherited DI disorders have been described and may better predict the clinical course in affected children and infants. Similarly, newer formulations of synthetic AVP may improve pediatric DI treatment. In contrast to DI, SIADH, characterized by inappropriate AVP secretion, commonly leads to severe hyponatremia. Contemporary methods aid clinicians in distinguishing SIADH from other hyponatremic conditions, particularly cerebral salt wasting. Further research on the efficacy of therapies for pediatric SIADH is needed, although some adult treatments hold promise for pediatrics. Lastly, expansion of home point-of-care sodium testing may transform management of SIADH and DI in children. In this article, we review recent developments in the understanding of pathophysiology, diagnostic workup, and treatment of better outcomes and quality of life for children with these challenging disorders.

Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

The syndrome of inappropriate ADH secretion (SIADH), also recently referred to as the "syndrome of inappropriate antidiuresis", is an often underdiagnosed cause of hypotonic hyponatremia, resulting for instance from ectopic release of ADH in lung cancer or as a side-effect of various drugs. In SIADH, hyponatremia results from a pure disorder of water handling by the kidney, whereas external Na+ balance is usually well regulated. Despite increased total body water, only minor changes of urine output and modest edema are usually seen. Renal function and acid-base balance are often preserved, while neurological impairment may range from subclinical to life-threatening. Hypouricemia is a distinguishing feature. The major causes and clinical variants of SIADH are reviewed, with particular emphasis on iatrogenic complications and hospital-acquired hyponatremia. Effective treatment of SIADH with water restriction, aquaretics, or hypertonic saline + loop diuretics, as opposed to worsening of hyponatremia during parenteral isotonic fluid administration, underscores the importance of an early accurate diagnosis and careful follow-up of these patients.

Management of central diabetes insipidus.

The treatment of central diabetes insipidus has not changed significantly in recent decades, and dDAVP and replacement of free water deficit remain the cornerstones of treatment. Oral dDAVP has replaced nasal dDAVP as a more reliable mode of treatment for chronic central diabetes insipidus. Hyponatraemia is a common side effect, occurring in one in four patients, and should be avoided by allowing a regular break from dDAVP to allow a resultant aquaresis. Hypernatraemia is less common, and typically occurs during hospitalization, when access to water is restricted, and in cases of adipsic DI. Management of adipsic DI can be challenging, and requires initial inpatient assessment to establish dose of dDAVP, daily fluid prescription, and eunatraemic weight which can guide day-to-day fluid targets in the long-term.

GENETICS IN ENDOCRINOLOGY Pathophysiology, diagnosis and treatment of familial nephrogenic diabetes insipidus.

For an endocrinologist, nephrogenic diabetes insipidus (NDI) is an end-organ disease, that is the antidiuretic hormone, arginine-vasopressin (AVP) is normally produced but not recognized by the kidney with an inability to concentrate urine despite elevated plasma concentrations of AVP. Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. For a geneticist, hereditary NDI is a rare disease with a prevalence of five per million males secondary to loss of function of the vasopressin V2 receptor, an X-linked gene, or loss of function of the water channel AQP2. These are small genes, easily sequenced, with a number of both recurrent and private mutations described as disease causing. Other inherited disorders with mild, moderate or severe inability to concentrate urine include Bartter's syndrome and cystinosis. MAGED2 mutations are responsible for a transient form of Bartter's syndrome with severe polyhydramnios. The purpose of this review is to describe classical phenotype findings that will help physicians to identify early, before dehydration episodes with hypernatremia, patients with familial NDI. A number of patients are still diagnosed late with repeated dehydration episodes and large dilations of the urinary tract leading to a flow obstructive nephropathy with progressive deterioration of glomerular function. Families with ancestral X-linked AVPR2 mutations could be reconstructed and all female heterozygote patients identified with subsequent perinatal genetic testing to recognize affected males within 2 weeks of birth. Prevention of dehydration episodes is of critical importance in early life and beyond and decreasing solute intake will diminish total urine output.

Diagnosis and differential diagnosis of diabetes insipidus: Update.

The two main differential diagnoses of central diabetes insipidus are nephrogenic diabetes insipidus and primary polydipsia. Reliable distinction between those entities is essential as treatment differs substantially with the wrong treatment potentially leading to serious complications. Past diagnostic measures using the indirect water deprivation test had several pitfalls, resulting in a low diagnostic accuracy. With the introduction of copeptin, a stable and reliable surrogate marker for arginine vasopressin, diagnosis of diabetes insipidus was new evaluated. While unstimulated basal copeptin measurement reliably diagnoses nephrogenic diabetes insipidus, a stimulation test is needed to differentiate patients with central diabetes insipidus from patients with primary polydipsia. Stimulation can either be achieved through hypertonic saline infusion or arginine infusion. While the former showed high diagnostic accuracy and superiority over the indirect water deprivation test in a recent validation study, the diagnostic accuracy for arginine-stimulated copeptin was slightly lower, but superior in test tolerance. In summary of the recent findings, a new copeptin based diagnostic algorithm is proposed for the reliable diagnosis of diabetes insipidus.

Gestational diabetes insipidus: Diagnosis and management.

In the pregnant patient, hypotonic polyuria in the setting of elevated serum osmolality and polydipsia should narrow the differential to causes related to diabetes insipidus (DI). Gestational DI, also called transient DI of pregnancy, is a distinct entity, unique from central DI or nephrogenic DI which may both become exacerbated during pregnancy. These three different processes relate to vasopressin, where increased metabolism, decreased production or altered renal sensitivity to this neuropeptide should be considered. Gestational DI involves progressively rising levels of placental vasopressinase throughout pregnancy, resulting in decreased endogenous vasopressin and resulting hypotonic polyuria worsening through the pregnancy. Gestational DI should be distinguished from central and nephrogenic DI that may be seen during pregnancy through use of clinical history, urine and serum osmolality measurements, response to desmopressin and potentially, the newer, emerging copeptin measurement. This review focuses on a brief overview of osmoregulatory and vasopressin physiology in pregnancy and how this relates to the clinical presentation, pathophysiology, diagnosis and management of gestational DI, with comparisons to the other forms of DI during pregnancy. Differentiating the subtypes of DI during pregnancy is critical in order to provide optimal management of DI in pregnancy and avoid dehydration and hypernatremia in this vulnerable population.

Acquired forms of central diabetes insipidus: Mechanisms of disease.

Most cases of acquired central diabetes insipidus are caused by destruction of the neurohypophysis by: 1) anatomic lesions that destroy the vasopressin neurons by pressure or infiltration, 2) damage to the vasopressin neurons by surgery or head trauma, and 3) autoimmune destruction of the vasopressin neurons. Because the vasopressin neurons are located in the hypothalamus, lesions confined to the sella turcica generally do not cause diabetes insipidus because the posterior pituitary is simply the site of the axon terminals that secrete vasopressin into the bloodstream. In addition, the capacity of the neurohypophysis to synthesize vasopressin is greatly in excess of the body's needs, and destruction of 80-90% of the hypothalamic vasopressin neurons is required to produce diabetes insipidus. As a result, even large lesions in the sellar and suprasellar area generally are not associated with impaired water homeostasis until they are surgically resected. Regardless of the etiology of central diabetes insipidus, deficient or absent vasopressin secretion causes impaired urine concentration with resultant polyuria. In most cases, secondary polydipsia is able to maintain water homeostasis at the expense of frequent thirst and drinking. However, destruction of the osmoreceptors in the anterior hypothalamus that regulate vasopressin neuronal activity causes a loss of thirst as well as vasopressin section, leading to severe chronic dehydration and hyperosmolality. Vasopressin deficiency also leads to down-regulation of the synthesis of aquaporin-2 water channels in the kidney collecting duct principal cells, causing a secondary nephrogenic diabetes insipidus. As a result, several days of vasopressin administration are required to achieve maximal urine concentration in patients with CDI. Consequently, the presentation of patients with central diabetes insipidus can vary greatly, depending on the size and location of the lesion, the magnitude of trauma to the neurohypophysis, the degree of destruction of the vasopressin neurons, and the presence of other hormonal deficits from damage to the anterior pituitary.

The neuroendocrine thymus: coexistence of oxytocin and neurophysin in the human thymus.

Immunoreactive oxytocin and neurophysin were identified and measured by radioimmunoassay in human thymus extracts. Serial dilutions of extracts paralleled the appropriate standard curves. Thymus-extracted oxytocin and neurophysin eluted in the same positions as reference preparations on Sephadex G-75. Authenticity of oxytocin was confirmed by biological assay and high-performance liquid chromatography analysis. In most instances, thymus contents of oxytocin and neurophysin were far greater than those expected from known circulating concentrations and declined with increasing age. The molar ratio of oxytocin to neurophysin in thymus was similar to that found in the hypothalamo-neurohypophyseal system, which strongly suggested with the other data a local synthesis of oxytocin. These findings indicate the presence of neurohypophyseal peptides in the human thymus and further support the concept of a neuroendocrine function integrated in an immune structure.

Diabetes insipidus.

Diabetes insipidus (DI) is a disorder characterized by excretion of large amounts of hypotonic urine. Central DI results from a deficiency of the hormone arginine vasopressin (AVP) in the pituitary gland or the hypothalamus, whereas nephrogenic DI results from resistance to AVP in the kidneys. Central and nephrogenic DI are usually acquired, but genetic causes must be evaluated, especially if symptoms occur in early childhood. Central or nephrogenic DI must be differentiated from primary polydipsia, which involves excessive intake of large amounts of water despite normal AVP secretion and action. Primary polydipsia is most common in psychiatric patients and health enthusiasts but the polydipsia in a small subgroup of patients seems to be due to an abnormally low thirst threshold, a condition termed dipsogenic DI. Distinguishing between the different types of DI can be challenging and is done either by a water deprivation test or by hypertonic saline stimulation together with copeptin (or AVP) measurement. Furthermore, a detailed medical history, physical examination and imaging studies are needed to ensure an accurate DI diagnosis. Treatment of DI or primary polydipsia depends on the underlying aetiology and differs in central DI, nephrogenic DI and primary polydipsia.

Extracellular volume depletion and resultant hypotonic hyponatremia: A novel translational approach.

Although several methods currently exist to determine that a person is hypovolemic, it often remains very challenging to accurately estimate the effective circulating volume or amount of intravascular volume depletion in a non-controlled setting. This depletion of intravascular volume can have many causes and is frequently accompanied by hypotonic hyponatremia as a result of hypovolemia-induced release of arginine vasopressin (AVP) from the posterior pituitary gland. Here, we derive a novel, comprehensible equation that provides a theoretical insight into the complex interrelationship between the degree of isotonic volume depletion and the resultant change in plasma sodium concentration. We believe that the presented model can prove to be a valuable tool for the analysis of fluid and electrolyte imbalances.

[The pathway of vasopressin as a pharmacological target in nephrology: a narrative review].

ADH is a hormone secreted by neurohypophysis that plays different roles based on the target organ. At the renal level, this peptide is capable of causing electrolyte-free water absorption, thus playing a key role in the hydro-electrolytic balance. There are pathologies and disorders that jeopardize this balance and, in this field, ADH receptor inhibitors such as Vaptans could play a key role. By inhibiting the activation pathway of vasopressin, they are potentially useful in euvolemic and hypervolemic hypotonic hyponatremia. However, clinical trials in heart failure have not given favourable results on clinical outcomes. Even in SIADH, despite their wide use, there is no agreement by experts on their use. Since vaptans inhibit the cAMP pathway in tubular cells, their use has been proposed to inhibit cystogenesis. A clinical trial has shown favourable effects on ADPKD progression. Because vaptans have been shown to be effective in models of renal cysts disorders other than ADPKD, their use has been proposed in diseases such as nephronophthisis and recessive autosomal polycystic disease. Other possible uses of vaptans could be in kidney transplantation and cardiorenal syndrome. Due to the activity of ADH in coagulation and haemostasis, ADH's activation pathway by Desmopressin Acetate could be a useful strategy to reduce the risk of bleeding in biopsies in patients with haemorrhagic risk.

[Small cell lung cancer associated with multiple paraneoplastic syndromes].

We report the case of a patient presenting with multiple severe electrolyte disturbances who was subsequently found to have small cell lung cancer. Upon further evaluation, she demonstrated three distinct paraneoplastic processes, including the syndrome of inappropriate antidiuretic hormone, Fanconi syndrome, and an inappropriate elevation in fibroblast growth factor-23 (FGF23). The patient underwent one round of chemotherapy, but she was found to have progressive disease. After 36 days of hospitalization, the patient made the decision to enter hospice care and later she expired.

Central and peripheral roles of vasopressin in the circadian defense of body hydration.

Vasopressin is a neuropeptide synthesized by specific subsets of neurons within the eye and brain. Studies in rats and mice have shown that vasopressin produced by magnocellular neurosecretory cells (MNCs) that project to the neurohypophysis is released into the blood circulation where it serves as an antidiuretic hormone to promote water reabsorption from the kidney. Moreover vasopressin is a neurotransmitter and neuromodulator that contributes to time-keeping within the master circadian clock (i.e. the suprachiasmatic nucleus, SCN) and is also used as an output signal by SCN neurons to direct centrally mediated circadian rhythms. In this chapter, we review recent cellular and network level studies in rodents that have provided insight into how circadian rhythms in vasopressin mediate changes in water intake behavior and renal water conservation that protect the body against dehydration during sleep.

Hyponatremia, fluid-electrolyte disorders, and the syndrome of inappropriate antidiuretic hormone secretion: diagnosis and treatment options.

OBJECTIVE: To review the types and causes of hyponatremia and examine the various strategies for treatment of this disorder. METHODS: A systematic review of the current literature is provided, targeting endocrinology clinicians who consult with hospital medical and surgical staff when managing patients with hyponatremia. Treatment for euvolemic and hypervolemic hyponatremia with arginine vasopressin receptor antagonists is presented, which provides a new treatment option for patients with disorders of water metabolism. RESULTS: Hyponatremia is recognized as the most common electrolyte disorder encountered in the clinical setting and is associated with a variety of conditions including dilutional disorders, such as congestive heart failure and the syndrome of inappropriate antidiuretic hormone secretion, and depletional disorders, such as diarrhea and vomiting or blood loss. Most cases of mild hyponatremia can be treated effectively. Acute, severe hyponatremia that is untreated or treated ineffectively, however, can lead to serious neurologic outcomes or death. With the poor prognosis for morbidity and mortality in patients with severe hyponatremia, hospital-based clinicians must identify those at risk for hyponatremia and suggest appropriate treatment intervention. A new class of drugs, the arginine vasopressin receptor antagonists, targets receptors on collecting duct cells of the nephron and causes aquaresis, the excretion of free water. This therapy leads to the restoration of sodium-water homeostasis in patients with euvolemic and hypervolemic hyponatremia. CONCLUSION: With many hospitalized patients at risk for hyponatremia, especially elderly patients in critical care and postsurgical units, identification of involved patients, recommendation of appropriate treatment, and awareness of new therapeutic options are critical.

Cord blood copeptin concentrations in fetal macrosomia.

BACKGROUND/AIM: Excessive fetal growth is associated with increased adiposity and reduced insulin sensitivity at birth. Copeptin, a surrogate marker of arginine vasopressin (AVP) secretion, is upregulated in states of hyperinsulinemia and is considered one of the mediators of insulin resistance. We aimed to investigate cord blood concentrations of copeptin (C-terminal fragment of AVP pro-hormone) in healthy large-for-gestational-age (LGA) infants at term. METHODS: This prospective study was conducted on 30 LGA (n=30) and 20 appropriate-for-gestational-age (AGA, n=20) singleton full-term healthy infants. Cord blood copeptin and insulin concentrations were determined by ELISA and IRMA, respectively. Infants were classified as LGA or AGA, based on customized birth-weight standards adjusted for significant determinants of fetal growth. RESULTS: Cord blood copeptin concentrations were similar in LGA cases, compared to AGA controls, after adjusting for delivery mode. However, in the LGA group, cord blood copeptin concentrations positively correlated with birth-weight (r=0.422, p=0.020). In the AGA group, cord blood copeptin concentrations were elevated in cases of vaginal delivery vs elective cesarean section (p=0.003). Cord blood insulin concentrations were higher in LGA cases, compared to AGA controls (p=0.036). No association was recorded between cord blood copeptin concentrations and maternal age, parity, gestational age or fetal gender in both groups. CONCLUSIONS: Cord blood copeptin concentrations may not be up-regulated in non-distressed LGA infants. However, the positive correlation between cord blood copeptin concentrations and birth-weight in the LGA group may point to the documented association between AVP release and increased fat deposition. Vaginal delivery vs elective cesarean section is accompanied by a marked stress-related increase of cord blood copeptin concentrations.

Isolation, radioimmunoassay and physiologic secretion of rat neurophysins.

Rat posterior pituitaries were extracted in acid and total rat neurophysins were isolated. Preparative disc gel electrophoresis separated the total neurophysins into three main peptides of differing electrophoretic mobility. Antisera raised in rabbits recognized a common antigenic site in the three peptides and identical radioimmunoassay standard curves were obtained with each of the isolated rat neurophysins. A homologous rat neurophysin radioimmunoassay was utilized to measure neurophysin in samples of unextracted rat plasma. Basal neurophysin levels, 3.7 +/- 0.2 ng/ml (mean +/- SEM), did not differ in samples collected by decapitation, carotid artery cannulation, or tail vein bleeding. Water-loading caused a significant reduction in neurophysin, 2.8 +/- 0.1 ng/ml, while hypertonic saline and dehydration caused a significant elevation, 10.4 +/- 2.1 and 8.0 +/- 1.4 ng/ml, respectively. A step-wise decrease in blood volume caused a step-wise increase in plasma neurophysin concentrations which returned to baseline with reinfusion of the withdrawn blood. A second hemorrhage caused an even greater release of neurophysin indicating large neurophysin reserve in the pituitary. In periodic tail vein samples over 23 days of pregnancy a rise in plasma neurophysin was found from day 14 continuing to parturition with a peak value of greater than 13 ng/ml by day 21. Two days postpartum the value was 4.6 +/- 0.3 ng/ml. With this homologous assay, the basal levels of plasma neurophysin are lower and the stimulated values higher than with previously reported heterologous assays. Therefore, the relative change with physiologic maneuvers is distinctly increased.

Terminals of reserpine-sensitive vasopressin-neurophysin neurons in the external layer of the rat median eminence.

The indirect immunofluorescence technique was used to examine the pharmacology associated with reserpine-induced alterations in vasopressin and neurophysin (VP/NP) immunoreactivity in the external layer of the median eminence in the rat. Twenty-four hours after injection of reserpine, a selective, marked depletion of VP/NP immunoreactivity from the external layer is apparent. Pretreatment with the monoamine oxidase inhibitors, pargyline and tranylcypromine, prevents the depleting effect of reserpine, indicating that the acute effect of reserpine is mediated by monoamines. Acute intraventricular treatment with 6-hydroxydopamine, but not 5,7-dihydroxytryptamine, mimicked the reserpine effect, suggesting that catecholamines mediate reserpine depletion of VP/NP immunoreactivity from the external layer. The experimental results are consistent with a regulatory model in which catecholamines tonically inhibit VP/NP release from terminals in the external layer of the median eminence. Although the studies do not definitively determine the functional relationship between VP and ACTH, the anatomical location of these terminals, the dramatic change in the VP/NP content of these terminals in response to reserpine, and the lack of a response to dehydration suggest that this pool of vasopressin may contribute to ACTH hypersecretion in response to reserpine.