Vasopressin

Vasopressin, also known as arginine vasopressin (AVP), antidiuretic hormone (ADH), or argipressin, is a is_associated_with::neurohypophysial hormone found in most is_associated_with::mammals. Its two primary functions are to retain water in the body and to constrict blood vessels. Vasopressin regulates the body's retention of water by acting to increase water reabsorption in the kidney's collecting ducts, the tubules which receive the very dilute urine produced by the functional unit of the kidney, the nephrons. Vasopressin is a is_associated_with::peptide hormone that increases water permeability of the kidney's collecting duct and distal convoluted tubule by inducing translocation of is_associated_with::aquaporin-CD water channels in the plasma membrane of collecting duct cells. It also increases is_associated_with::peripheral vascular resistance, which in turn increases arterial is_associated_with::blood pressure. It plays a key role in is_associated_with::homeostasis, by the regulation of water, is_associated_with::glucose, and is_associated_with::salts in the blood. It is derived from a is_associated_with::preprohormone precursor that is synthesized in the is_associated_with::hypothalamus and stored in vesicles at the is_associated_with::posterior pituitary. Most of it is stored in the posterior pituitary to be released into the bloodstream. However, some AVP may also be released directly into the is_associated_with::brain, and accumulating evidence suggests it plays an important role in is_associated_with::social behavior, sexual motivation and pair bonding, and maternal responses to stress. It has a very short half-life between 16–24 minutes.

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 is_associated_with::kidneys to conserve water, thus concentrating the is_associated_with::urine and reducing urine volume. At high concentrations, it also raises blood pressure by inducing moderate is_associated_with::vasoconstriction. In addition, it has a variety of neurological effects on the brain, having been found, for example, to influence pair-bonding in is_associated_with::voles. The high-density distributions of vasopressin receptor AVPr1a in is_associated_with::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 is_associated_with::pigs and is often used in human therapy.

Kidney
Vasopressin has two main effects by which it contributes to increased urine osmolarity (increased concentration) and decreased water excretion:


 * 1) Increasing the water permeability of distal convoluted tubule and collecting duct cells in the kidney, thus allowing water reabsorption and excretion of more concentrated urine, i.e., antidiuresis. This occurs through insertion of water channels (Aquaporin-2) into the is_associated_with::apical membrane of distal convoluted tubule and collecting duct epithelial cells. Aquaporins allow water to move down their osmotic gradient and out of the nephron, increasing the amount of water re-absorbed from the filtrate (forming urine) back into the bloodstream. is_associated_with::V2 receptors, which are is_associated_with::G protein-coupled receptors on the basolateral plasma membrane of the epithelial cells, couple to the heterotrimeric G-protein Gs, which activates is_associated_with::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 containing AQP channels, 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 is_associated_with::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) Increasing permeability of the inner medullary portion of the collecting duct to is_associated_with::urea by regulating the cell surface expression of is_associated_with::urea transporters, which facilitates its reabsorption into the is_associated_with::medullary interstitium as it travels down the concentration gradient created by removing water from the is_associated_with::connecting tubule, is_associated_with::cortical collecting duct, and is_associated_with::outer medullary collecting duct.
 * 3) Acute increase of is_associated_with::sodium absorption across the ascending is_associated_with::loop of henle. This adds to the is_associated_with::countercurrent multiplication which aids in proper water reabsorption later in the is_associated_with::distal tubule and is_associated_with::collecting duct.

Serum osmolarity/osmolality is also effected by vasopressin due to its role in keeping proper electrolytic balance in the blood stream. Improper balance can lead to dehydration, alkalosis, acidosis or other life-threatening changes. The hormone ADH is partly responsible for this process by controlling the amount of water the body retains from the kidney when filtering the blood stream.

Cardiovascular system
Vasopressin increases peripheral vascular resistance (vasoconstriction) and thus increases arterial is_associated_with::blood pressure. This effect appears small in healthy individuals; however it becomes an important compensatory mechanism for restoring blood pressure in is_associated_with::hypovolemic shock such as that which occurs during hemorrhage.

Central nervous system
Vasopressin released within the brain has many actions:


 * Vasopressin is released into the brain in a is_associated_with::circadian rhythm by neurons of the is_associated_with::suprachiasmatic nucleus.


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


 * It is likely that vasopressin acts in conjunction with is_associated_with::corticotropin-releasing hormone to modulate the release of is_associated_with::corticosteroids from the is_associated_with::adrenal gland in response to stress, particularly during pregnancy and lactation in mammals.


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


 * Recent evidence suggests that vasopressin may have analgesic effects. The analgesia effects of vasopressin were found to be dependent on both stress and sex.

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. 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 toward 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 affects 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.

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.

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


 * Secretion in response to reduced plasma volume is activated by pressure receptors in the is_associated_with::veins, atria, and is_associated_with::carotid sinuses.
 * Secretion in response to increases in plasma osmotic pressure is mediated by is_associated_with::osmoreceptors in the is_associated_with::hypothalamus.
 * Secretion in response to increases in plasma CCK 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 is_associated_with::organum vasculosum of the lamina terminalis and the is_associated_with::subfornical organ.

Many factors influence the secretion of vasopressin:
 * is_associated_with::Ethanol (alcohol) reduces the calcium-dependent secretion of AVP by blocking voltage-gated calcium channels in neurohypophyseal nerve terminals in rats.
 * is_associated_with::Angiotensin II stimulates AVP secretion, in keeping with its general pressor and pro-volumic effects on the body.
 * is_associated_with::Atrial natriuretic peptide inhibits AVP secretion, in part by inhibiting Angiotensin II-induced stimulation of AVP secretion.

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 is_associated_with::posterior pituitary gland (except in cases of AVP-secreting tumours). Vasopressin is produced by is_associated_with::magnocellular neurosecretory neurons in the is_associated_with::Paraventricular nucleus of hypothalamus (PVN) and is_associated_with::Supraoptic nucleus (SON). It then travels down the axon 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. However there are two other sources of AVP with important local effects:
 * AVP is also synthesized by is_associated_with::parvocellular neurosecretory neurons at the PVN, transported and released at the is_associated_with::median eminence, which then travels through the is_associated_with::hypophyseal portal system to the anterior pituitary where it stimulates is_associated_with::corticotropic cells synergistically with CRH to produce ACTH (by itself it is a weak secretagogue).
 * Vasopressin is also released into the brain by several different populations of smaller neurons.

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

Structure and relation to oxytocin


The vasopressins are is_associated_with::peptides consisting of nine is_associated_with::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 is_associated_with::disulfide bond. Lysine vasopressin has a is_associated_with::lysine in place of the arginine.

The structure of is_associated_with::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.

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

Lack of AVP
Decreased AVP release (neurogenic - i.e. due to alcohol intoxication or tumour) or decreased renal sensitivity to AVP (nephrogenic, i.e. by mutation of V2 receptor or AQP) leads to is_associated_with::diabetes insipidus, a condition featuring is_associated_with::hypernatremia (increased blood is_associated_with::sodium concentration), is_associated_with::polyuria (excess urine production), and is_associated_with::polydipsia (thirst).

Excess AVP
High levels of AVP secretion may lead to is_associated_with::hyponatremia. In many cases, the AVP secretion is appropriate (due to severe hypovolemia), and the state is labelled "hypovolemic hyponatremia". In certain disease states (is_associated_with::heart failure, is_associated_with::nephrotic syndrome) the body fluid volume is increased but AVP production is not suppressed for various reasons; this state is labelled "hypervolemic hyponatremia". A proportion of cases of hyponatremia feature neither hyper- nor hypovolemia. In this group (labelled "euvolemic hyponatremia"), AVP secretion is either driven by a lack of is_associated_with::cortisol or is_associated_with::thyroxine (is_associated_with::hypoadrenalism and is_associated_with::hypothyroidism, respectively) or a very low level of urinary solute excretion (is_associated_with::potomania, low-protein diet), or it is entirely inappropriate. This last category is classified as the is_associated_with::syndrome of inappropriate antidiuretic hormone (SIADH).

SIADH in turn can be caused by a number of problems. Some forms of is_associated_with::cancer can cause SIADH, particularly is_associated_with::small cell lung carcinoma but also a number of other tumors. A variety of diseases affecting the brain or the lung (infections, bleeding) can be the driver behind SIADH. A number of drugs has been associated with SIADH, such as certain antidepressants (is_associated_with::serotonin reuptake inhibitors and is_associated_with::tricyclic antidepressants), the anticonvulsant is_associated_with::carbamazepine, is_associated_with::oxytocin (used to induce and stimulate labor), and the chemotherapy drug is_associated_with::vincristine. It has also been associated with fluoroquinolones (including is_associated_with::ciprofloxacin and is_associated_with::moxifloxacin). Finally, it can occur without a clear explanation.

Hyponatremia can be treated pharmaceutically through the use of is_associated_with::vasopressin receptor antagonists.

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

Vasopressin infusions are also used as second line therapy in is_associated_with::septic shock patients not responding to fluid resuscitation or infusions of is_associated_with::catecholamines (e.g., is_associated_with::dopamine or is_associated_with::norepinephrine).

The role of vasopressin analogues in cardiac arrest
Injection of vasopressors for the treatment of is_associated_with::cardiac arrest was first suggested in the literature in 1896 when Austrian scientist Dr. R. Gottlieb described the vasopressor is_associated_with::epinephrine as an "infusion of a solution of suprarenal extract [that] would restore circulation when the blood pressure had been lowered to unrecordable levels by chloral hydrate." Modern interest in vasopressors as a treatment for cardiac arrest stem mostly from canine studies performed in the 1960s by anesthesiologists Dr. John W. Pearson and Dr. Joseph Stafford Redding in which they demonstrated improved outcomes with the use of adjunct intracardiac epinephrine injection during resuscitation attempts after induced cardiac arrest. Also contributing to the idea that vasopressors may be useful treatments in cardiac arrest are studies performed in the early to mid 1990's that found significantly higher levels of endogenous serum vasopressin in adults after successful resuscitation from out-of-hospital cardiac arrest compared to those who did not live. Results of animal models have supported the use of either vasopressin or epinephrine in cardiac arrest resuscitation attempts, showing improved coronary perfusion pressure and overall improvement in short-term survival as well as neurological outcomes.

Vasopressin vs. epinephrine
Although both vasopressors, vasopressin and is_associated_with::epinephrine differ in that vasopressin does not have direct effects on is_associated_with::cardiac contractility as epinephrine does. Thus, vasopressin is theorized to be of increased benefit over epinephrine in cardiac arrest due to its properties of not increasing myocardial and cerebral oxygen demands. This idea has led to the advent of several studies searching for the presence of a clinical difference in benefit of these two treatment choices. Initial small studies demonstrated improved outcomes with vasopressin in comparison to epinephrine. However, subsequent studies have not all been in agreement. Several is_associated_with::randomized controlled trials have been unable to reproduce positive results with vasopressin treatment in both is_associated_with::return of spontaneous circulation (ROSC) and survival to hospital discharge,  including a is_associated_with::systematic review and is_associated_with::meta-analysis completed in 2005 that found no evidence of a significant difference with vasopressin in five studied outcomes.

Vasopressin and epinephrine vs. epinephrine alone
There is no current evidence of significant survival benefit with improved neurological outcomes in patients given combinations of both epinephrine and vasopressin during cardiac arrest. A systematic review from 2008 did, however, find one study that showed a statistically significant improvement in ROSC and survival to hospital discharge with this combination treatment; unfortunately, those patients that survived to hospital discharge had overall poor outcomes and many suffered permanent, severe neurological damage. A more recently published clinical trial out of Singapore has shown similar results, finding combination treatment to only improve the rate of survival to hospital admission, especially in the is_associated_with::subgroup analysis of patients with longer "collapse to emergency department" arrival times of 15 to 45 minutes.

2010 American Heart Association Guidelines
The 2010 is_associated_with::American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care recommend the consideration of vasopressor treatment in the form of epinephrine in adults with cardiac arrest (Class IIb, LOE A recommendation). Due to the absence of evidence that vasopressin administered instead of or in addition to epinephrine has significant positive outcomes, the guidelines do not currently contain vasopressin as a part of the cardiac arrest algorithms. It does, however, allow for one dose of vasopressin to replace either the first or second dose of epinephrine in the treatment of cardiac arrest (Class IIb, LOE A recommendation).

Vasopressin receptor inhibition
A is_associated_with::vasopressin receptor antagonist is an agent that interferes with action at the is_associated_with::vasopressin receptors. They can be used in the treatment of is_associated_with::hyponatremia.