vasopressin

Arginine vasopressin (neurophysin II, antidiuretic hormone, diabetes insipidus, neurohypophyseal)
Space-filling model of arginine vasopressin
Available structures
1jk4, 1jk6, 1npo, 2bn2
Identifiers
Symbols	AVP; ADH; AVP-NPII; VP
External IDs	OMIM: 192340 MGI: 88121 HomoloGene: 417
Gene ontology Molecular function • neurohypophyseal hormone activity Cellular component • extracellular region • soluble fraction Biological process • generation of precursor metabolites and energy • water transport • signal transduction • cell-cell signaling • diuresis • positive regulation of cAMP biosynthetic process • vasoconstriction
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	551	11998
Ensembl	ENSG00000101200	ENSMUSG00000037727
UniProt	P01185	Q3UUQ5
RefSeq	NM_000490 (mRNA)	NM_009732 (mRNA)
	NP_000481 (protein)	NP_033862 (protein)
Location	Chr 20: 3.01 - 3.01 Mb	Chr 2: 130.27 - 130.27 Mb
PubMed search	[1]	[2]

Arginine vasopressin (AVP), also known as vasopressin, 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 and stored in vesicles at the posterior pituitary. Most of it is stored in the posterior pituitary to be released into the blood stream; however, some of it is also released directly into the brain.

Physiology

Function

One of the most important roles of AVP is to regulate the body's retention of water; it is released when the body is dehydrated and causes the kidneys to conserve water, thus concentrating the urine, and reducing urine volume. In high concentrations, 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

Vasopressin has three effects by which it contributes to increased urine osmolarity (increased concentration), and decreased urine excretion. These are:

1) It 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 (Aquaporin-2s) into the apical membrane of the tubules/collecting duct epithelial cells. The aquaporins allow water to pass out of the nephron (at the distal convoluted tubules and the conducting tubules) and into the cells, increasing the amount of water re-absorbed from the filtrate.

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, move to adenylyl cyclase, triggering adenylyl cyclase to convert ATP into cAMP, plus 2 inorganic phosphates. The cAMP cascade then triggers the insertion of Aquaporin-2 water pores by exocytosis of storage vesicles.

The repressor protein that regulates the gene for protein kinase A (PKA) 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 PKA. PKA then signals ATP to dephosphorylate, providing energy for vesicles (which contain aquaporin channel proteins in their membranes) to fuse with the apical membrane of the cell. Calcium ions may also be required in this process, therefore it may be possible that, PLC (phospholipase C- beta) has an associated role. It should be noted that PLC can be activated by a G-protein coupled receptor.

2) ADH's second effect on the kidney is to increase the permeability of the papillary 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.

3) The third effect that AVP has on the kidney is that it stimulates sodium reabsorption in the thick-ascending loop of Henle by increasing the activity of the Na⁺-K⁺-2Cl^--cotransporter.

Cardiovascular system

Vasopressin increases peripheral vascular resistance 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.

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 Supraoptic nucleus.

• 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.^[2]

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 AVP receptors, and sometimes in the distribution of vasopressin-containing axons, even when closely-related species are compared.^[3] Moreover, studies involving either injecting AVP agonists into the brain, or blocking the actions of AVP, support the hypothesis that vasopressin is involved in aggression towards other males. There is also evidence that differences in the AVP receptor gene between individual members of a species might be predictive of differences in social behavior. One study has suggested that genetic variation in male humans effects pair-bonding behavior. The brain of males uses vasopressin as a reward for forming lasting bonds with a mate, and men with one or two of the genetic alleles are more likely to experience marital discord. The partners of the men with two of the alleles affecting vasopressin reception state disappointing levels of satisfaction, affection, and cohesion. ^[4]

Control

Vasopressin is secreted from the posterior pituitary gland in response to reductions in plasma volume, in response to increases in the plasma osmolality, and in response to cholecystokinin by the small intestine:

• 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.
• Secretion in response to increases in plasma Cholecystokinin is mediated by an unknown pathway.

The neurons that make AVP, in the hypothalamic supraoptic nuclei (SON) and paraventricular nuclei (PVN), 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 (alcohol) acts as an antagonist for AVP in the collecting ducts of the kidneys, which prevents aquaporins from binding to the collecting ducts, and prevents water reabsorption.
• Angiotensin II may stimulate the secretion of AVP.^[5]

Secretion

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

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

• Vasopressin is produced in the PVN and SON and travels down the axons through the infundibulum within neurosecretory granules that are found within Herring bodies, localized swellings of the axons and nerve terminals. These carry the peptide directly to the posterior pituitary gland, where it is stored until released into the blood.
• Vasopressin is also released into the brain by several different populations of smaller neurons (see below).

Receptors

Below 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

Chemical structure of argipressin

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 disulfide 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 most 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 AVP 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, coelacanths
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.[12]

Role in disease

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

High levels of AVP secretion (syndrome of inappropriate antidiuretic hormone, SIADH) and resultant hyponatremia (low blood sodium levels) occurs in brain diseases and conditions of the lungs (Small cell lung carcinoma). 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 vasoconstrictors in certain conditions. Use of vasopressin analogues for esophageal varices commenced in 1970.^[13]

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.^[14] 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 AVP in this situation, but these studies relied on sub-group analysis and better designed prospective studies show no benefit in ACLS.^[15][16]

Vasopressin receptor inhibition

A vasopressin receptor antagonist is an agent that interferes with action at the vasopressin receptors. They can be used in the treatment of hyponatremia.^[17]

References

Further reading

• Rector, Floyd C.; Brenner, Barry M. (2004). Brenner & Rector's the kidney (7th ed.). Philadelphia: Saunders. ISBN 0-7216-0164-2. http://home.mdconsult.com/das/search/openres/56203699-5?searchisbn=460046813. 

v • d • e PDB Gallery 1jk4: DES 1-6 BOVINE NEUROPHYSIN II COMPLEX WITH VASOPRESSIN   1jk6: UNCOMPLEXED DES 1-6 BOVINE NEUROPHYSIN   1npo: BOVINE NEUROPHYSIN II COMPLEX WITH OXYTOCIN   2bn2: CRYSTAL STRUCTURE OF BOVINE NEUROPHYSIN II COMPLEXED WITH THE VASOPRESSIN ANALOGUE PHE-TYR AMIDE