Antidiuretic Hormone (ADH)

Also known as arginine vasopressin (AVP), ADH is a nine-amino-acid peptide made in the supraophthalmic nucleus (SON) of the hypothalamus. Once made, it is transported by axons to the posterior pituitary, where it is released into the bloodstream.

Secretion of ADH to reabsorb water is regulated by two mechanisms.

1. Osmoreceptors located in the anterolateral hypothalamus measure Posm. These cells play key roles in water and sodium balance. Changes in Posm result in cell swelling or shrinking, thus signaling the release (or prevention of the release) of ADH. At Posm below 280 mosm/kg, these cells are virtually inactive and do not stimulate ADH secretion. However, small changes above this Posm (even of only 1%) will trigger major firing changes in osmoreceptors (Figure 1). At a Posm of 290 mosm/kg, enough ADH would be secreted (5 pg/mL) to cause a maximum retention of water, yielding Urineosm of 1250 mosm/kg. Any [ADH] above 5 pg/mL results in this same maximal antidiuresis (Figure 2). Not all osmotically active substances can stimulate shrinking or swelling of the of osmoreceptors; while sodium ions are able to do this, urea cannot since it can freely cross membranes.
   
   
   
   
   
   In addition to regulating release of ADH, osmoreceptors also regulate thirst with a relationship similar to that shown for ADH in Figures 1 and 2.
   
   
2. Baroreceptors, located in the carotid sinus and aortic arch, measure blood pressure. Unlike osmoreceptors, baroreceptors must be suppressed in order to stimulate the release of ADH; this suppression, in turn, comes about after a fall in blood pressure. Sensory fibers from cranial nerve IX (glossopharyngeal) and X (vagus) carry this signal from the sinus and arch to the ADH-releasing neurons of the hypothalamus.
   
   
   
   Another difference in the baroreceptors is that larger changes in the dependent value (in this case circulating blood volume) are needed to release ADH. Ten to fifteen percent of the blood volume must be lost to result in ADH secretion (Figure 3). Figure 3 also shows that this threshold value depends largely on the original blood volume. But the decreased sensitivity put aside, these receptors have the potential of releasing much more ADH; this is particularly relevant since ADH acts as a vasoconstrictor at high concentrations (therefore, these receptors help maintain blood pressure by increasing peripheral vascular resistance). They can also override osmoreceptor signals.
   
   
   
   Baroreceptors can also stimulate thirst.

NOTE: ADH release is also influenced by [Angiotensin II] and drugs. Nicotine, ether, morphine, and barbiturates increase ADH release while alcohol inhibits it.

The table below summarizes the major characteristics of osmoreceptors and baroreceptors.

Actions of ADH

1. Water reabsorption: This action is mediated by ADH interactions with V2 receptors on the basolateral membrane of collecting-duct principal cells. Coupled to adenylyl cyclase by a G protien, these receptors lead to the eventual activation of cAMP-dependent protein kinase A, which increases water-channel insertion into the apical membrane. The V2-receptor interactions also increase the collecting duct permeability to urea. As a result, with ADH present, urea and sodium ion contribute equally to the osmolality of the medullary interstitium.
   
   Regardless of the mechanism, it is important to realize that ADH only controls “pure” or osmotically-free water, not solutes.
   
   
2. Vasoconstriction: This action is achieved at high [ADH] and is mediated by V1 receptors on vascular smooth muscle cells.

FYI:

Three malfunctions of the ADH system result in noticeable disease. All have some form of treatment.

1. Central diabetes insipidus: This disease is seen when the pituitary gland is unable to secrete ADH.
2. Nephrogenic diabetes insipidus: This disease is seen when the collecting ducts are unable to respond to ADH due to a mutation in the V2 receptor.
3. Syndrome of inappropriate ADH secretion (SIADH): This disease is seen when drugs or tumors result in continued secretion of ADH or increased action of ADH on the collecting ducts.

Antidiuretic Hormone Agonists and Antagonists

ADH Agonists

Two peptides, ADH and desmopressin, facilitate water reabsorption from the collecting tubule by cAMP-mediated insertion of water channels there. As a result, both decrease the volume of urine and increase its concentration.

Clinical Uses: The two can be used for central diabetes insipidus but not nephrogenic diabetes insipidus. The latter requires reabsorption of water before it reaches the nonfunctional collecting duct system. Salt restriction, thiazides, and loop diuretics can partially achieve this by reducing blood volume and stimulating PCT reabsorption as a result.

Toxicity: Hyponatremia may result in the presence of ADH or desmopressin. Hypertension can also result with high doses.

ADH antagonists

ADH antagonists demeclocycline and lithium work at some point after the cAMP generation, likely by preventing the insertion of water channels

Clinical Uses: The two can be used against any chemical (like ADH) that acts on the V2 receptor. Tumors or drugs can produce the V2 agonists and can cause significant hyponatremia. SIADH can be treated well with demeclocycline; lithium is used less due to its toxicities.

Toxicity: In younger children, demeclocycline can cause abnormalities in teeth and bone as well as liver and kidney toxicities. Lithium can cause nephrogenic diabetes insipidus, edema, thyroid function decrease, and much more.