ANTIDIURETIC HORMONE
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.
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| MECHANISM OF ANTIDIURETIC HORMONE IN REGULATING URINE VOLUME AND CONCENTRATION |
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).
EFFECTS
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.
