Vasopressin

Arginine vasopressin (AVP), also known as vasopressin, argipressin or antidiuretic hormone (ADH), is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's permeability. It also increases peripheral vascular resistance, which in turn increases arterial blood pressure. It plays a key role in homeostasis, and the regulation of water, glucose, and salts in the blood. 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 bloodstream; however, some AVP is also released directly into the brain, where it plays an important role in social behavior and bonding.

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. The high-density distributions of vasopressin receptor AVPr1a in prairie vole ventral forebrain regions have been shown to facilitate and coordinate reward circuits during partner preference formation, critical for pair bond formation.

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 two effects by which it contributes to increased urine osmolality (increased concentration) and decreased water excretion. These are:

1) Increase in the permeability to water of the cells of distal tubule and collecting duct in the kidney and thus allows water reabsorption and excretion of concentrated urine, i.e., antidiuresis. This occurs through insertion of water channels (Aquaporin-2) into the apical membrane of the distal tubule and collecting duct epithelial cells. The aquaporins allow water to move out of the nephron, increasing the amount of water re-absorbed from the forming urine back into the bloodstream.

V2 receptors, G protein-coupled receptors on the basolateral plasma membrane of the epithelial cells couple to the heterotrimeric G-protein G_s, which activates adenylyl cyclases III and VI to convert ATP into cAMP, plus 2 inorganic phosphates. The rise in cAMP then triggers the insertion of aquaporin-2 water channels by exocytosis of intracellular vesicles, recycling endosomes. Vasopressin also increases the concentration of calcium in the collecting duct cells, by episodic release from intracellular stores. Vasopressin, acting through cAMP, also increases transcription of the aquaporin-2 gene, thus increasing the total number of aquaporin-2 molecules in collecting duct cells.

Cyclic-AMP activates protein kinase A (PKA) by binding to its regulatory subunits and allowing them to detach from the catalytic subunits. Detachment exposes the catalytic site in the enzyme, allowing it to add phosphate groups to proteins (including the aquaporin-2 protein), which alters their functions.

2) Increase in the permeability of the inner 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 connecting tubule, cortical collecting duct, and outer medullary collecting duct.

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 that which occurs during hemorrhage.

Central nervous system

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; 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.

Selective AVPr1a blockade in the ventral pallidum has been shown to prevent partner preference, suggesting that these receptors in this ventral forebrain region are crucial for pair bonding.

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. Vasopressin receptors distributed along the reward circuit pathway, to be specific in the ventral pallidum, are activated when AVP is released during social interactions such as mating, in monogamous prairie voles. The activation of the reward circuitry reinforces this behavior, leading to conditioned partner preference, and thereby initiates the formation of a pair bond.

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 secreted 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) reduces the calcium-dependent secretion of AVP by blocking voltage-gated calcium channels in neurohypophyseal nerve terminals. Angiotensin II stimulates AVP secretion, in keeping with its general pressor and pro-volemic effects on the body. Atrial natriuretic peptide inhibits AVP secretion, in part by inhibiting Angiotensin II-induced stimulation of AVP secretion. circadian tau |- | AVPR1B or AVPR3 || Phosphatidylinositol/calcium || Pituitary gland, brain || Adrenocorticotropic hormone secretion in response to stress; social interpretation of olfactory cues |- | AVPR2 || Adenylate cyclase/cAMP || Basolateral membrane of the cells lining the collecting ducts of the kidneys (especially the cortical and outer medullary collecting ducts) || Insertion of aquaporin-2 (AQP2) channels (water channels). This allows water to be reabsorbed down an osmotic gradient, and so the urine is more concentrated. Release of von Willebrand factor and surface expression of P-selectin through exocytosis of Weibel-Palade bodies from endothelial cells |- | VACM-1 || Phosphatidylinositol/calcium || Vascular endothelium and renal collecting tubules || Increases cytosolic calcium and acts as an inverse agonist of cAMP accumulation |}

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 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:

{| style= cellpadding="2" !colspan="3" | Vertebrate Vasopressin Family |- |style="width:300px" |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 |- !colspan="3" | 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-Pro-Gly-NH2 || Prol-Oxytocin || Some New World monkeys, northern tree shrews |- |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 |- !colspan="3" | 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 |- |colspan="3" rowspan=3 | †Vasotocin is the evolutionary progenitor of all the vertebrate neurohypophysial hormones. |}

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.

Hyponatremia can be treated pharmaceutically through the use of vasopressin receptor antagonists. These include the approved drug Vaprisol and the phase III drug lixivaptan.

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 mild haemophilia A) 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.

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. 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.

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.

References

Further reading

External links

Molecular neurobiology of social bonding: Implications for autism spectrum disorders a lecture by Prof. Larry Young, Jan. 4, 2010.

Category:Neuroscience Category:Neurotransmitters Category:Neuropeptides Category:Nootropics Category:Posterior pituitary hormones Category:Neuroendocrinology Category:Renal physiology