Antidiuretic hormone (ADH), also known as vasopressin, is a nonapeptide synthesized mainly by magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus and in small amounts by some extra-hypothalamic tis sues. Its primary function is maintaining hydroelectrolyte balance through regulating renal reabsorption of water. In particular, ADH has an antidiuretic effect by inducing an increase in the hydro-osmotic permeability of the cells lining the distal tube and medullary nephron collector ducts. In the absence of ADH, these cells are impermeable to water, but following the binding of the hormone to their receptors, they express on their apical membrane pores for water consisting of the protein aquaporin 2, which allows the reabsorption of water followed by the urine concentration and the increase in volemia, arterial pressure, and cardiac output. The magnitude of the antidiuretic effect is proportional to plasma ADH concentrations. ADH also maintains electrolyte balance by stimulating renal sodium reabsorption, mediated by ENaC (epithelial sodium channel) luminal channels, further promoting water reabsorption.
ADH at high concentrations also exerts other actions. It induces vascular wall smooth muscle contraction in the skin and gastrointestinal tract, reduces lipolysis in adipose tissue, stimulates glycogenolysis in the liver, and finally, acts synergistically with corticotropin-releasing hormone (CRH) for the secretion of ACTH. All of these effects are mediated by the interaction of ADH with its receptors.
The most critical factor that regulates the secretion of ADH is the “effective” osmotic pressure of liquids whose variations are detected by specialized hypothalamic cells known as osmoreceptors. There is a regulatory threshold below which ADH secretion is reduced, leading to the elimination of a large volume of very dilute urine (water diuresis) and above which, instead, ADH levels increase in direct pro portion to plasma osmolality, up to a reduction in urine flow of 0.35 mL/min. The threshold for ADH release usually corresponds to a plasma osmolality of 280 mOsm/L and sodium levels of 135 mmol/L. The threshold value has interindividual variabilities, being genetically determined, and intraindividual variability, related to physiological factors such as posture, pregnancy, menstrual cycle, and aging.
Although plasma hyperosmolality represents the primary stimulus for ADH release, volemia and blood pressure reductions represent valuable inputs to its secretion. In particular, ADH levels increase in response to a >10–20% reduction in blood pressure and/or volemia. Finally, ADH secretion can be influenced by other variables such as nausea, vomiting, smoking, acute hypoglycemia, and various drugs (diuretics, morphine, carbamazepine, clonidine, etc.). Above all, nausea, even if transitory and not accompanied by vomiting, is a powerful stimulant that can induce a 100–1000-fold increase in circulating levels of ADH.
ADH exerts its effects through interaction with membrane receptors, which can be of three types:
• V1aR: predominantly expressed on vascular smooth muscle and responsible for a calcium-mediated vasoconstriction mechanism
• V2R: expressed mainly on collector duct cells and, to a lesser extent, at the endothelial level
• V1bR or V3R: mainly expressed on corticotropic cells of the adenohypophysis, where it modulates ACTH release via calcium signaling-mediated signal transduction
ADH has a half-life of about 10 minutes and is mainly eliminated renally and partly hepatically.
