Vasopressin Research & Studies

Diabetes insipidus is a disorder characterized by hypo-osmotic polyuria secondary to abnormal synthesis, regulation, or renal action of antidiuretic hormone. Recently, an expert group, with the support of patient associations, proposed that diabetes insipidus be renamed to avoid confusion with diabetes mellitus. The most common form of diabetes insipidus is secondary to a dysfunction of the neurohypophysis (central diabetes insipidus) and would be therefore named 'vasopressin deficiency'. The rarer form, which is linked to renal vasopressin resistance (nephrogenic diabetes insipidus), would then be named 'vasopressin resistance'. The etiology of diabetes insipidus is sometimes clear, in the case of a neurohypophyseal cause (tumoral or infiltrative damage) or a renal origin, but in some cases diabetes insipidus can be difficult to distinguish from primary polydipsia, which is characterized by consumption of excessive quantities of water without any abnormality in regulation or action of antidiuretic hormone. Apart from patients' medical history, physical examination, and imaging of the hypothalamic-pituitary region, functional tests such as water deprivation or stimulation of copeptin by hyperosmolarity (induced by infusion of hypertonic saline) can be proposed in order to distinguish between these different etiologies. The treatment of diabetes insipidus depends on the underlying etiology, and in the case of a central etiology, is based on the administration of desmopressin which improves patient symptoms but does not always result in an optimal quality of life. The cause of this altered quality of life may be oxytocin deficiency, oxytocin being also secreted from the neurohypophysis, though this has not been fully established. The possibility of a new test using stimulation of oxytocin to identify alterations in oxytocin synthesis is of interest and would allow confirmation of a deficiency in those patients presenting with diabetes insipidus linked to neurohypophyseal dysfunction.

Vasopressin or antidiuretic hormone (ADH) or arginine vasopressin (AVP) is a nonapeptide synthesized in the hypothalamus. Science has known it to play essential roles in the control of the body’s osmotic balance, blood pressure regulation, sodium homeostasis, and kidney functioning. Given its vital role in multiple functions, it is no surprise that ADH is of great clinical significance. ADH primarily affects the ability of the kidney to reabsorb water; when present, ADH induces expression of water transport proteins in the late distal tubule and collecting duct to increase water reabsorption. Several disease states arise when the body loses control of ADH secretion or responds to its presence. In states of hypovolemia or hypernatremia, ADH is released from the posterior pituitary gland and binds to the type-2 receptor in principal cells of the collecting duct. Binding to the receptor triggers an intracellular cyclic adenosine monophosphate (cAMP) pathway, which causes phosphorylation of the aquaporin-2 (AQP2). After achieving water homeostasis, the ADH levels decrease, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again.

Vasopressins are evolutionarily conserved peptide hormones. Mammalian vasopressin functions systemically as an antidiuretic and regulator of blood and cardiac flow essential for adapting to terrestrial environments. Moreover, vasopressin acts centrally as a neurohormone involved in social and parental behavior and stress response. Vasopressin synthesis in several cell types, storage in intracellular vesicles, and release in response to physiological stimuli are highly regulated and mediated by three distinct G protein coupled receptors. Other receptors may bind or cross-bind vasopressin. Vasopressin is regulated spatially and temporally through transcriptional and post-transcriptional mechanisms, sex, tissue, and cell-specific receptor expression. Anomalies of vasopressin signaling have been observed in polycystic kidney disease, chronic heart failure, and neuropsychiatric conditions. Growing knowledge of the central biological roles of vasopressin has enabled pharmacological advances to treat these conditions by targeting defective systemic or central pathways utilizing specific agonists and antagonists.

Vasodilatory shock is the final common pathway for all forms of severe shock, with sepsis the most common primary etiology and the leading cause of critical illness-related mortality. The pathophysiology of this condition remains incompletely elucidated. Deficiency of the neuropeptide hormone vasopressin seems to play a significant role. The physiology of vasopressin and its interaction with the pathophysiology of vasodilatory shock are described in this review. A brief review of the major randomized controlled trials assessing the efficacy and safety of vasopressin and its analogs in this complex patient cohort is also provided.

Arginine vasopressin (AVP) is the principal hormone involved in regulating the tonicity of body fluids. Less appreciated is the role that AVP plays in a variety of other physiologic functions including glucose metabolism, cardiovascular homeostasis, bone metabolism, and cognitive behavior. AVP receptor antagonists are now available and currently approved to treat hyponatremia. There is a great deal of interest in exploring the potential benefits that these drugs may play in blocking AVP-mediated effects in other organ systems. The purpose of this report is to provide an update on the expanding role of AVP receptor antagonists and what disease states these drugs may eventually be used for.

The biological effects of arginine vasopressin (AVP) are mediated by three receptor subtypes: the V1a and V1b receptors that activate phospholipases via Gq/11, and the V2 receptor that activates adenylyl cyclase by interacting with Gs. Isolation of the cDNAs encoding the V1a and V1b receptor subtypes explained the tissue variability of V1 antagonist binding, whereas identification of the cDNA and gene encoding the V2 receptor provided the information to identify the mutations responsible for X-linked nephrogenic diabetes insipidus. Mutations that abrogate the production and/or release of AVP from the pituitary have diabetes insipidus as their most dramatic manifestation, indicating that the maintenance of water homeostasis is the most important physiological role of this neuropeptide. Evidence for a significant role of AVP in blood pressure control, although actively sought, has been scant.

The neurohypophysis is the structural foundation of a neuro-humoral system coordinating fluid balance and reproductive function through the action of two peptide hormones: vasopressin and oxytocin. Vasopressin is the principle endocrine regulator of renal water excretion, facilitating adaptive physiological responses to maintain plasma volume and plasma osmolality. Oxytocin is important in parturition and lactation but also has several other peripheral and central effects. Data supports a wider role for both peptides in the neuro-regulation of complex behavior. Clinically, deficits in the production or action of vasopressin manifest as Vasopressin deficiency (formerly known as central diabetes insipidus). An understanding of the physiology and pathophysiology of vasopressin is also critical in approaching the diagnosis and management of hyponatremia, the most common electrolyte disturbance in clinical practice. This chapter explores the anatomy, physiology, and pathophysiology of the neurohypophysis, vasopressin and oxytocin; highlighting developments in the neural basis of osmo-sensing; the mechanism of action of vasopressin and oxytocin; together with a description of the cell and molecular biology underpinning some of the disease processes in which both the structure and functions of the two hormones are involved. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.