ADH, also known as vasopressin, plays a crucial role in maintaining the normal osmolality of extracellular ﬂuid, which depends primarily on the extracellular sodium concentration. ADH exerts its effect by altering the osmolality of excreted urine, which can range from 50 to 1200 mOsm/kg H2O.
When plasma osmolality increases, ADH release causes extensive water reabsorption in the distal nephron. As a result, the urine becomes highly concentrated, and the plasma consequently becomes more dilute. In contrast, when plasma osmolality decreases, inhibition of ADH release prevents water reabsorption in the distal nephron, leading to dilution of urine and concentration of plasma.
MECHANISMS OF RELEASE
ADH is produced in the supraoptic and paraventricular nuclei of the hypothalamus. It is then conveyed along axons to the posterior pituitary for storage and release. ADH release occurs primarily in response to activation of osmoreceptors in the anterior hypothalamus. These receptors, located outside of the blood-brain barrier, are extremely sensitive to changes in plasma osmolality. Their activation has been hypothesized to occur when there is a loss of intracellular ﬂuid secondary to increased extracellular osmotic pressure. In support of this hypothesis, the osmoreceptors are not equally sensitive to all solutes. Sodium, for example, reliably activates osmoreceptors at high concentrations because, as a predominantly extracellular ion, it establishes a transmembrane osmotic gradient. In contrast, urea and glucose generally do not activate osmoreceptors even at high concentrations because they freely enter cells, thus failing to establish an osmotic gradient. When patients experience extreme insulin depletion, however, osmoreceptors may become sensitive to high concentrations of glucose, presumably because of its increased restriction to the extracellular space.
ADH is also released in response to intravascular volume depletion. In this setting, the primary objective is to retain intravascular volume, rather than to adjust plasma osmolarity. Such release is mediated by baroreceptors in the atria, aorta, and carotid sinus, which send afferent signals to the brain along the vagus and glossopharyngeal nerves. This sensing mechanism is not nearly as sensitive as the osmolality-sensing apparatus, however, and does not become active until 5% to 10% of plasma volume has been lost.
Finally, ADH is also released in response to increased levels of angiotensin II (AII), a hormone released during renal hypoperfusion (see Plate 3-18).
ADH exerts multiple effects on the kidneys and cardiovascular system, which include the following:
· In collecting ducts, ADH binds to V2 receptors on the basolateral membrane of principal cells, initiating a signaling cascade that leads to apical insertion of aquaporin channels. The collecting duct becomes permeable to water, which is reabsorbed because of the high osmotic pressure generated by the solute concentrated in the medullary interstitium. Over the long term, ADH also increases transcription of aquaporin channels. Nephrogenic diabetes insipidus is a well-characterized condition in which there is dysfunction of ADH-mediated aquaporin insertion (see Plate 3-27).
· ADH increases the reabsorption of sodium and urea, which increases the solute concentration in the medullary interstitium. As a result, there is a larger gradient for water reabsorption. In the thick ascending limb, ADH up-regulates apical NKCC2 Na+/K+/2Cl- cotransporters and ROM-K channels. Over the long term, ADH also increases transcription of NKCC2 cotransporters. In the collecting duct, ADH up-regulates apical ENaC channels and inner medullary urea transporters. As water is reabsorbed in the cortical and outer medullary collecting duct, urea becomes increasingly concentrated in the tubular lumen. Once urea reaches the IMCD, it is reabsorbed along its chemical gradient into the interstitium.
· ADH exerts a pressor effect on vasa recta capillaries, which minimizes the drift of solute away from the medullary interstitium.
· ADH increases peripheral vascular resistance via the V1a receptor, an important effect in volume depletion states. As a result, ADH is a useful pressor hormone in vasodilatory states, such as septic shock. In addition, ADH may be given during cardiac resuscitation.