Arginine vasopressin (AVP), also known as argipressin or antidiuretic hormone (ADH), is a hormone found in most mammals, including humans.^[1]

Vasopressin is a peptide hormone. It is derived from a preprohormone precursor that is synthesized in the hypothalamus, from which it is liberated during transport to the posterior pituitary. Most of it is stored in the posterior part of the pituitary gland to be released into the blood stream; some of it is also released directly into the brain.

Physiology

Function

One of its most important roles is to regulate the body's retention of water, being released when the body is dehydrated; it causes the kidneys to conserve water (but not salt), concentrating the urine, and reducing urine volume. It also raises blood pressure by inducing moderate vasoconstriction. In addition, it has a variety of neurological effects on the brain, having been found, for example, to influence pair-bonding in voles.

A very similar substance, lysine vasopressin (LVP) or lypressin, has the same function in pigs and is often used in human therapy.

Kidney

AVP increases the permeability to water of the distal convoluted tubules and collecting tubules in the nephrons of kidneys and thus allows water reabsorption and excretion of a smaller volume of concentrated urine - antidiuresis. This occurs through insertion of additional water channels (aquaporins) into the apical membrane of the duct epithelial cells. V2 receptors, G protein-coupled receptors coupled to G_s, on the basolateral membrane of the cells lining the distal convoluted tubules and conducting tubules (in the nephron) have an active site for AVP. The G protein, which is in contact with the V2 receptor inside the cell, dephosphorylates GTP (guanine triphosphate) turning it into GDP (guanine diphosphate) plus an inorganic phosphate ion (Pi). The G protein uses the energy obtained from GTP to move to adenylyl cyclase, triggering adenylyl cyclase to turn ATP (adenine triphosphate)into cAMP (cyclic adenosine monophosphate) plus 2 inorganic phosphates. The repressor protein that regulates the gene for protein kinase A has a binding site for cAMP, causing the repressor protein to change its shape and leave the operator region of the gene. This allows for transcription of the gene for protein kinase A. The gene is then translated to produce protein kinase A. Protein kinase A signals ATP to dephosphorylate, providing energy for vescicles (which have aquaporin channel proteins as a part of their membranes) to move to the apical membrane of the cell and fuse with it. The aquaporin channel proteins allow water to pass out of the nephron (at the distal convoluted tubules and the conducting tubules) and into the cell, increasing the amount of water re-absorbed from the filtrate in the nephron.

AVP also increases permeability of the medullary portion of the collecting duct to urea, allowing increased reabsorption of urea into the medullary interstitium, down the concentration gradient created from the removal of water in the cortical collecting duct.

Cardiovascular system

Vasopressin, as the name tells, increases the resistance of the peripheral vessels and thus increases arterial blood pressure. This effect appears small in healthy individuals; however it becomes an important compensatory mechanism for restoring blood pressure in hypovolemic shock such as occurs during hemorrhage.

Vasopressin constricts arterioles leading to increased peripheral vascular resistance. However, under normal physiological conditions, there is no net change in blood pressure due to baroreflex activation.

Central nervous system (CNS)

Vasopressin released within the brain has many actions:

• It has been implicated in memory formation, including delayed reflexes, image, short- and long-term memory, though the mechanism remains unknown, and these findings are controversial. However, the synthetic vasopressin analogue desmopressin has come to interest as a likely nootropic.

• Vasopressin is released into the brain in a circadian rhythm by neurons of the suprachiasmatic nucleus of the hypothalamus.

• Vasopressin released from centrally-projecting hypothalamic neurons is involved in aggression, blood pressure regulation and temperature regulation.

In recent years there has been particular interest in the role of vasopressin in social behavior. It is thought that vasopressin, released into the brain during sexual activity, initiates and sustains patterns of activity that support the pair-bond between the sexual partners; in particular, vasopressin seems to induce the male to become aggressive towards other males.

Evidence for this comes from experimental studies in several species, which indicate that the precise distribution of vasopressin and vasopressin receptors in the brain is associated with species-typical patterns of social behavior. In particular, there are consistent differences between monogamous species and promiscuous species in the distribution of vasopressin receptors, and sometimes in the distribution of vasopressin-containing axons, even when closely-related species are compared. Moreover, studies involving either injecting vasopressin agonists into the brain, or blocking the actions of vasopressin, support the hypothesis that vasopressin is involved in aggression towards other males. There is also evidence that differences in the vasopressin receptor gene between individual members of a species might be predictive of differences in social behavior.

Control

Vasopressin is secreted from the posterior pituitary gland in response to reductions in plasma volume and in response to increases in the plasma osmolality:

• Secretion in response to reduced plasma volume is activated by pressure receptors in the veins, atria, and carotids.
• Secretion in response to increases in plasma osmotic pressure is mediated by osmoreceptors in the hypothalamus.

The neurons that make vasopressin, in the supraoptic nucleus and paraventricular nucleus, are themselves osmoreceptors, but they also receive synaptic input from other osmoreceptors located in regions adjacent to the anterior wall of the third ventricle. These regions include the organum vasculosum of the lamina terminalis and the subfornical organ.

Many factors influence the secretion of vasopressin:

• Ethanol reduces vasopressin secretion. The resulting decrease in water reabsorption by the kidneys leads to a higher urine output.
• Angiotensin II may stimulate the secretion of vasopressin.^[2]

Secretion

The main stimulus for secretion of vasopressin is increased osmolarity of plasma. Reduced volume of extracellular fluid also has this effect, but is a less sensitive mechanism.

The vasopressin that is measured in peripheral blood is almost all derived from secretion from the posterior pituitary gland (except in cases of vasopressin-secreting tumours). However there are two other sources of vasopressin with important local effects:

• Vasopressin is produced in the supraoptic nucleus of the hypothalamus and travels down the axons in neurosecretory granules through the infundibulum. These carry the peptide directly to the posterior pituitary gland, where it is stored in Herring bodies until it is released into the blood.
• Vasopressin is also released into the brain by several different populations of neurons (see below).

Summary Table

Here is a table summarizing some of the actions of AVP at its three receptors, differently expressed in different tissues and exerting different actions:

Structure and relation to oxytocin

The vasopressins are peptides consisting of nine amino acids (nonapeptides). (NB: the value in the table above of 164 amino acids is that obtained before the hormone is activated by cleavage). The amino acid sequence of arginine vasopressin is Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly, with the cysteine residues forming a sulfur bridge. Lysine vasopressin has a lysine in place of the arginine.

The structure of oxytocin is very similar to that of the vasopressins: it is also a nonapeptide with a sulfur bridge and its amino acid sequence differs at only two positions (see table below). The two genes are located on the same chromosome separated by a relatively small distance of less than 15,000 bases in various species. The magnocellular neurons that make vasopressin are adjacent to magnocellular neurons that make oxytocin, and are similar in many respects. The similarity of the two peptides can cause some cross-reactions: oxytocin has a slight antidiuretic function, and high levels of vasopressin can cause uterine contractions.

Here is a table showing the superfamily of vasopressin and oxytocin neuropeptides:

Vertebrate Vasopressin Family
Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2	Argipressin (AVP, ADH)	Most mammals
Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2	Lypressin (LVP)	Pigs, hippos, warthogs, some marsupials
Cys-Phe-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2	Phenypressin	Some marsupials
Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Arg-Gly-NH2	Vasotocin†	Non-mammals
Vertebrate Oxytocin Family
Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2	Oxytocin (OXT)	Most mammals, ratfish
Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Ile-Gly-NH2	Mesotocin	Most marsupials, all birds, reptiles, amphibians, lungfishes
Cys-Tyr-Ile-Gln-Ser-Cys-Pro-Ile-Gly-NH2	Seritocin	Frogs
Cys-Tyr-Ile-Ser-Asn-Cys-Pro-Ile-Gly-NH2	Isotocin	Bony fishes
Cys-Tyr-Ile-Ser-Asn-Cys-Pro-Gln-Gly-NH2	Glumitocin	Skates
Cys-Tyr-Ile-Asn/Gln-Asn-Cys-Pro-Leu/Val-Gly-NH2	Various tocins	Sharks
Invertebrate VP/OT Superfamily
Cys-Leu-Ile-Thr-Asn-Cys-Pro-Arg-Gly-NH2	Diuretic Hormone	Locust
Cys-Phe-Val-Arg-Asn-Cys-Pro-Thr-Gly-NH2	Annetocin	Earthworm
Cys-Phe-Ile-Arg-Asn-Cys-Pro-Lys-Gly-NH2	Lys-Connopressin	Geography & imperial cone snail, pond snail, sea hare, leech
Cys-Ile-Ile-Arg-Asn-Cys-Pro-Arg-Gly-NH2	Arg-Connopressin	Striped cone snail
Cys-Tyr-Phe-Arg-Asn-Cys-Pro-Ile-Gly-NH2	Cephalotocin	Octopus
Cys-Phe-Trp-Thr-Ser-Cys-Pro-Ile-Gly-NH2	Octopressin	Octopus
†Vasotocin is the evolutionary progenitor of all the vertebrate neurohypophysial hormones. Only vasotocin found in hagfish & lampreys (Agnatha appeared 500 million years ago)

Role in disease

Decreased vasopressin release or decreased renal sensitivity to vasopressin leads to diabetes insipidus, a condition featuring hypernatremia (increased blood sodium content), polyuria (excess urine production), and polydipsia (thirst).

High levels of vasopressin secretion (syndrome of inappropriate antidiuretic hormone, SIADH) and resultant hyponatremia (low blood sodium levels) occurs in brain diseases and conditions of the lungs. In the perioperative period, the effects of surgical stress and some commonly used medications (e.g., opiates, syntocinon, anti-emetics) lead to a similar state of excess vasopressin secretion. This may cause mild hyponatremia for several days.

Pharmacology

Vasopressin analogues

Vasopressin agonists are used therapeutically in various conditions, and its long-acting synthetic analogue desmopressin is used in conditions featuring low vasopressin secretion, as well as for control of bleeding (in some forms of von Willebrand disease) and in extreme cases of bedwetting by children. Terlipressin and related analogues are used as vasocontrictors in certain conditions. Use of vasopressin analogues for esophageal varices commenced in 1970.^[9]

Vasopressin infusion has been used as a second line of management in septic shock patients not responding to high dose of inotropes (e.g., dopamine or norepinephrine). It had been shown to be more effective than epinephrine in asystolic cardiac arrest.^[10] While not all studies are in agreement, a 2006 study of out-of hospital cardiac arrests has added to the evidence for the superiority of vasopressin in this situation.^[11]

Vasopressin receptor inhibition

Demeclocycline, a tetracycline antibiotic, is sometimes used to block the action of vasopressin in the kidney in hyponatremia due to inappropriately high secretion of vasopressin (SIADH, see above), when fluid restriction has failed. A new class of medication (conivaptan, tolvaptan, relcovaptan, lixivaptan) acts by inhibiting the action of vasopressin on its receptors (V1 and V2), with conivaptan acting on V1a and V2 and the remainder mainly on V2 receptors. The same class of drugs is also being studied in congestive heart failure.

References

Further Reading

• Brenner & Rector's The Kidney, 7th ed., Saunders, 2004. Full Text with MDConsult subscription

• Caldwell, H.K. and Young, W.S., III. Oxytocin and Vasopressin: Genetics and Behavioral Implications in Lim, R. (ed.) Handbook of Neurochemistry and Molecular Neurobiology, 3rd edition, Springer, New York, pp. 573-607, 2006. 320kb PDF