Pitressin

ピトレシン

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/05/24 16:13:10」(JST)

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Arginine vasopressin
Space-filling model of arginine vasopressin
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1jk4, 1jk6, 1npo, 2bn2
Identifiers
Symbols	AVP ; ADH; ARVP; AVP-NPII; AVRP; VP
External IDs	OMIM: 192340 MGI: 88121 HomoloGene: 417 GeneCards: AVP Gene
Gene ontology Molecular function • protein kinase activity • signal transducer activity • receptor binding • neuropeptide hormone activity • neurohypophyseal hormone activity • V1A vasopressin receptor binding • V1B vasopressin receptor binding • cysteine-type endopeptidase inhibitor activity involved in apoptotic process Cellular component • extracellular region • extracellular space • cytosol • secretory granule • dendrite Biological process • maternal aggressive behavior • positive regulation of systemic arterial blood pressure • generation of precursor metabolites and energy • protein phosphorylation • water transport • signal transduction • positive regulation of cytosolic calcium ion concentration • cell-cell signaling • negative regulation of female receptivity • grooming behavior • locomotory behavior • positive regulation of cell proliferation • positive regulation of gene expression • positive regulation of glutamate secretion • positive regulation of cell growth • positive regulation of cAMP biosynthetic process • positive regulation of prostaglandin biosynthetic process • positive regulation of cellular pH reduction • positive regulation of peptidyl-serine phosphorylation • response to testosterone • response to nicotine • social behavior • regulation of renal sodium excretion • vasoconstriction • hyperosmotic salinity response • maternal behavior • negative regulation of apoptotic process • penile erection • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process • sodium-independent organic anion transport • response to ethanol • positive regulation of vasoconstriction • multicellular organismal water homeostasis • negative regulation of transmission of nerve impulse • transmembrane transport • ERK1 and ERK2 cascade • protein kinase C signaling • negative regulation of release of cytochrome c from mitochondria Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	551	11998
Ensembl	ENSG00000101200	ENSMUSG00000037727
UniProt	P01185	P35455
RefSeq (mRNA)	NM_000490	NM_009732
RefSeq (protein)	NP_000481	NP_033862
Location (UCSC)	Chr 20: 3.06 – 3.07 Mb	Chr 2: 130.58 – 130.58 Mb
PubMed search	[1]	[2]

Vasopressin, also known as arginine vasopressin (AVP), antidiuretic hormone (ADH), or argipressin, is a neurohypophysial hormone found in most 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 collecting ducts of the nephron, which is the functional component of the kidney. Vasopressin is a peptide hormone that increases water permeability of the kidney's collecting duct and distal convoluted tubule by inducing translocation of aquaporin-CD water channels in the kidney nephron collecting duct plasma membrane. It also increases peripheral vascular resistance, which in turn increases arterial blood pressure. It plays a key role in homeostasis, by 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 may also be released directly into the brain, and accumulating evidence suggests it plays an important role in social behavior, sexual motivation and pair bonding, and maternal responses to stress. It has a very short half-life between 16–24 minutes.

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. At 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 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 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.
   V2 receptors, which are 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. Increasing permeability of the inner medullary portion of the collecting duct to urea by regulating the cell surface expression of urea transporters, which facilitates its reabsorption into the medullary interstitium as it travels down the concentration gradient created by removing water from the connecting tubule, cortical collecting duct, and outer medullary collecting duct.
3. Acute increase of sodium absorption across the ascending loop of henle. This adds to the countercurrent multiplication which aids in proper water reabsorption later in the distal tubule and 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 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

Avp is expressed in the periventricular region of the hypothalamus in the adult mouse. Allen Brain Atlases

Vasopressin released within the brain has many actions:

• Vasopressin is released into the brain in a circadian rhythm by neurons of the 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 corticotropin-releasing hormone to modulate the release of corticosteroids from the adrenal gland in response to stress, particularly during pregnancy and lactation in mammals.

• Selective AVPr1a blockade in the 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 posterior pituitary gland in response to reductions in plasma volume, in response to increases in the plasma osmolality, and in response to cholecystokinin (CCK) secreted by the small intestine:

• Secretion in response to reduced plasma volume is activated by pressure receptors in the veins, atria, and carotid sinuses.
• Secretion in response to increases in plasma osmotic pressure is mediated by osmoreceptors in the 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 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 in rats.
• Angiotensin II stimulates AVP secretion, in keeping with its general pressor and pro-volumic effects on the body.
• 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 posterior pituitary gland (except in cases of AVP-secreting tumours). Vasopressin is produced by magnocellular neurosecretory neurons in the Paraventricular nucleus of hypothalamus (PVN) and 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 parvocellular neurosecretory neurons at the PVN, transported and released at the median eminence, which then travels through the hypophyseal portal system to the anterior pituitary where it stimulates 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:

Type	Second messenger system	Locations	Actions
AVPR1A	Phosphatidylinositol/calcium	Liver, kidney, peripheral vasculature, brain	Vasoconstriction, gluconeogenesis, platelet aggregation, and release of factor VIII and von Willebrand factor; social recognition, 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

Structure and relation to oxytocin

Chemical structure of the argipressin (indicating that this compound is of the vasopressin family with an arginine at the 8th amino acid position.

Chemical structure of 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 disulfide bond. 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.

Below 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-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
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.

Role in disease

Lack of AVP

Decreased AVP 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).

Excess AVP

High levels of AVP secretion may lead to hyponatremia. In many cases, the AVP secretion is appropriate (due to severe hypovolemia), and the state is labelled "hypovolemic hyponatremia". In certain disease states (heart failure, 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 cortisol or thyroxine (hypoadrenalism and hypothyroidism, respectively) or a very low level of urinary solute excretion (potomania, low-protein diet), or it is entirely inappropriate. This last category is classified as the syndrome of inappropriate antidiuretic hormone (SIADH).

SIADH in turn can be caused by a number of problems. Some forms of cancer can cause SIADH, particularly 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 (serotonin reuptake inhibitors and tricyclic antidepressants), the anticonvulsant carbamazepine, oxytocin (used to induce and stimulate labor), and the chemotherapy drug vincristine. It has also been associated with fluoroquinolones (including ciprofloxacin and moxifloxacin). Finally, it can occur without a clear explanation.

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

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

The role of vasopressin analogues in cardiac arrest

Injection of vasopressors for the treatment of cardiac arrest was first suggested in the literature in 1896 when Austrian scientist Dr. R. Gottlieb described the vasopressor 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 epinephrine differ in that vasopressin does not have direct effects on 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 randomized controlled trials have been unable to reproduce positive results with vasopressin treatment in both return of spontaneous circulation (ROSC) and survival to hospital discharge, including a systematic review and 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 subgroup analysis of patients with longer "collapse to emergency department" arrival times of 15 to 45 minutes.

2010 American Heart Association Guidelines

The 2010 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

Main article: vasopressin receptor antagonist

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

See also

• Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH)
• Oxytocin
• Sexual motivation and hormones
• Vasopressin receptor
• Vasopressin receptor antagonists
• Copeptin

References

Further reading

• Rector, Floyd C.; Brenner, Barry M. (2004). Brenner & Rector's the kidney (7th ed.). Philadelphia: Saunders. ISBN 0-7216-0164-2. 

External links

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

UpToDate Contents

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• 1. 陰部神経ブロックおよび傍子宮頸管ブロック pudendal and paracervical block
• 2. 中枢性尿崩症の治療 treatment of central diabetes insipidus
• 3. 妊娠中絶の概要 overview of pregnancy termination

English Journal

• Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia.

• Tamma R, Sun L, Cuscito C, Lu P, Corcelli M, Li J, Colaianni G, Moonga SS, Di Benedetto A, Grano M, Colucci S, Yuen T, New MI, Zallone A, Zaidi M.Author information Department of Histology, University of Bari, 70124 Bari, Italy.AbstractAlthough hyponatremia is known to be associated with osteoporosis and a high fracture risk, the mechanism through which bone loss ensues has remained unclear. As hyponatremic patients have elevated circulating arginine-vasopressin (AVP) levels, we examined whether AVP can affect the skeleton directly as yet another component of the pituitary-bone axis. Here, we report that the two Avp receptors, Avpr1α and Avpr2, coupled to Erk activation, are expressed in osteoblasts and osteoclasts. AVP injected into wild-type mice enhanced and reduced, respectively, the formation of bone-resorbing osteoclasts and bone-forming osteoblasts. Conversely, the exposure of osteoblast precursors to Avpr1α or Avpr2 antagonists, namely SR49059 or ADAM, increased osteoblastogenesis, as did the genetic deletion of Avpr1α. In contrast, osteoclast formation and bone resorption were both reduced in Avpr1α(-/-) cultures. This process increased bone formation and reduced resorption resulted in a profound enhancement of bone mass in Avpr1α(-/-) mice and in wild-type mice injected with SR49059. Collectively, the data not only establish a primary role for Avp signaling in bone mass regulation, but also call for further studies on the skeletal actions of Avpr inhibitors used commonly in hyponatremic patients.
• Proceedings of the National Academy of Sciences of the United States of America.Proc Natl Acad Sci U S A.2013 Nov 12;110(46):18644-9. doi: 10.1073/pnas.1318257110. Epub 2013 Oct 28.
• Although hyponatremia is known to be associated with osteoporosis and a high fracture risk, the mechanism through which bone loss ensues has remained unclear. As hyponatremic patients have elevated circulating arginine-vasopressin (AVP) levels, we examined whether AVP can affect the skeleton directl
• PMID 24167258

• Cellular localization of adenine receptors in the rat kidney and their functional significance in the inner medullary collecting duct.

• Kishore BK, Zhang Y, Gevorgyan H, Kohan DE, Schiedel AC, Müller CE, Peti-Peterdi J.Author information Nephrology Research (151M Veterans Affairs Salt Lake City Health Care System, 500 Foothill Drive, Salt Lake City, UT 84148. BK.Kishore@hsc.utah.edu.AbstractThe Gi-coupled adenine receptor (AdeR) binds adenine with high affinity and potentially reduces cellular cAMP levels. Since cAMP is an important second messenger in the renal transport of water and solutes, we localized AdeR in the rat kidney. Real-time RT-PCR showed higher relative expression of AdeR mRNA in the cortex and outer medulla compared with the inner medulla. Immunoblots using a peptide-derived and affinity-purified rabbit polyclonal antibody specific for an 18-amino acid COOH-terminal sequence of rat AdeR, which we generated, detected two bands between ∼30 and 40 kDa (molecular mass of native protein: 37 kDa) in the cortex, outer medulla, and inner medulla. These bands were ablated by preadsorption of the antibody with the immunizing peptide. Immunofluorescence labeling showed expression of AdeR protein in all regions of the kidney. Immunoperoxidase revealed strong labeling of AdeR protein in the cortical vasculature, including the glomerular arterioles, and less intense labeling in the cells of the collecting duct system. Confocal immunofluorescence imaging colocalized AdeR with aquaporin-2 protein to the apical plasma membrane in the collecting duct. Functionally, adenine (10 μM) significantly decreased (P < 0.01) 1-deamino-8-d-arginine vasopressin (10 nM)-induced cAMP production in ex vivo preparations of inner medullary collecting ducts, which was reversed by PSB-08162 (20 μM, P < 0.01), a selective antagonist of AdeR. Thus, we demonstrated the expression of AdeR in the renal vasculature and collecting ducts and its functional relevance. This study may open a new avenue for the exploration of autocrine/paracrine regulation of renal vascular and tubular functions by the nucleobase adenine in health and disease.
• American journal of physiology. Renal physiology.Am J Physiol Renal Physiol.2013 Nov 1;305(9):F1298-305. doi: 10.1152/ajprenal.00254.2013. Epub 2013 Aug 28.
• The Gi-coupled adenine receptor (AdeR) binds adenine with high affinity and potentially reduces cellular cAMP levels. Since cAMP is an important second messenger in the renal transport of water and solutes, we localized AdeR in the rat kidney. Real-time RT-PCR showed higher relative expression of Ad
• PMID 23986514

• Is the addition of vasopressin to norepinephrine beneficial for the treatment of septic shock?

• Sandifer JP, Jones AE.
• Annals of emergency medicine.Ann Emerg Med.2013 Nov;62(5):534-5. doi: 10.1016/j.annemergmed.2013.01.031. Epub 2013 May 16.
• PMID 23683544

Japanese Journal

• ステロイド投与により下垂体茎腫大が著明に改善したリンパ球性漏斗下垂体神経葉炎の一症例

• 板垣 英二,関 博之,下山 達宏,勝田 秀紀,田中 利明,牛川 憲司,丸山 雅弘,山口 真哉,小澤 幸彦,片平 宏,滝沢 誠,吉元 勝彦,石田 均
• 杏林医学会雑誌 39(1/2), 41-47, 2008
• 症例は33歳女性。7ヶ月前から口渇，多飲，多尿を生じ精査のため入院。多尿（5,000〜8,000ml/日）と低張尿（浸透圧 113mOsm/L）を認め，血漿浸透圧は296mOsm/Lと軽度の高値を示した。尿浸透圧は飲水制限試験で上昇を認めず，ピトレッシン投与で上昇。血漿ADHは5%高張食塩水負荷試験で上昇を認めなかった。一方，下垂体前葉機能は正常に保たれていた。頭部MRIでは均一に造影される下垂体 …
• NAID 130000135258

• Spontaneous Resolution of Diabetes Insipidus After Pituitary Stalk Sectioning During Surgery for Large Craniopharyngioma : Endocrinological Evaluation and Clinical Implications for Surgical Strategy

• NISHIZAWA Shigeru,OHTA Seiji,OKI Yutaka
• Neurologia medico-chirurgica 46(3), 126-135, 2006-03-15
• … Urine osmolarity was high in the morning, and a significant increase in urinary osmolarity was noted after Pitressin injection. …
• NAID 110004656792

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抗利尿ホルモン : 約 57,000 件
バソプレシン : 約 19,000 件
バゾプレシン : 約 9,010 件
バソプレッシン : 約 7,590 件
バゾプレッシン : 約 4,160 件

en

arginine vasopressin : 約 7,090 件
vasopressin : 約 9,170 件
antidiuretic hormone : 約 7,410 件

分類

• 下垂体後葉ホルモン
• 下垂体後葉(神経性下垂体)で後葉ホルモン産生神経細胞の軸索末端から分泌される。
• オキシトシンとバソプレシンはアミノ酸が2残基違うだけである(2007後期生理学授業プリント)

性状

• ペプチド

産生組織

PED. 1328

• 視床下部の視索上核(supraoptic nucleus SON)および室傍核(paraventricular nucleus PVN)にある大細胞性神経細胞(大神経細胞 magnocellular neuron)で産生
• 下垂体茎を経由して下垂体後葉まで軸索内を輸送される。

標的組織

• 腎臓の集合管
• 腎臓の細い上行脚、太い上行脚、接合尿細管にも作用する (SP.816)

生理作用

• 抗利尿

• 集合管に作用し水の再吸収を促進(V2受容体)

• 昇圧作用

• 血管平滑筋の収縮(V1受容体)
• V1受容体は抗利尿作用を示すより大用量で動作(SAN.189)　←　生理的な量では血管収縮による血圧上昇はない。

• 尿素再吸収

• 髄質内層集合管で尿素の再吸収を高める(SP.817)

• ACTH分泌？

作用機序

抗利尿作用	集合管上皮細胞	V2R
血管平滑筋収縮(昇圧作用)	血管内皮	V1R

分泌調節

• 血漿浸透圧↑、循環血漿量↓→分泌↑　( 出血 )
• 血漿浸透圧↓、循環血漿量↑→分泌↓　( 水の大量摂取 )

• 1. 視床下部の浸透圧受容体→視索上核・傍室核
• 2. 内頚動脈・大動脈弓の圧受容器→延髄の血管運動中枢→視索上核・傍室核
• 3. その他
  • 分泌刺激性：悪心、アンジオテンシンII、ニコチン酸
  • 分泌抑制性：心房性Na利尿ペプチド、エタノール

	分泌促進	分泌抑制
血漿浸透圧・循環血液量	出血→血圧低下、循環血液量減少	水負荷→血漿浸透圧低下、循環血液量増加
	水制限→循環血液量減少、血漿浸透圧上昇	等張液負荷→循環血液量増加
	高張食塩水負荷→血漿浸透圧上昇
薬物	プロスタグランジンE2	フェニトイン
	モルフィン	アルコール
	ニコチン	心房性Na利尿ペプチド
	β受容体作動薬	α受容体作動薬
	アンジオテンシンII
	麻酔薬
	低酸素症
	高炭酸ガス血症
	ビンクリスチン
	シクロホスファミド
	クロフィブレート
	カルバマゼピン
	バルビツール酸系薬
	アセチルコリン
	ヒスタミン
	メトクロプラミド
環境など	立位・失神、疼痛、陽圧呼吸、遠心力	寒冷、陰圧呼吸、水中、臥位

ADH分泌促進/作用増強する薬物

QB.D-331

• 抗悪性腫瘍薬：シスプラチン、ビンクリスチン、シクロホスファミド
• 抗精神病薬：ハロペリドール、アミトリプチリン
• 抗痙攣薬：カルバマゼピン
• 血糖降下薬：クロルプロパミド
• 抗高脂血症薬：クロフィブレート

ADHの作用を修飾する物質

• 糖質コルチコイド：水代謝作用(水利尿)：GFR↑させたりADHに拮抗することで細胞内への水移動を抑制する

癌患者とADH

日腎会誌 2012:54(7):1016-1022

Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. NEJM. 2007;356:2064-2072. PMID 17507705

• 異所性ADH産生腫瘍、抗悪性腫瘍薬の副作用、手術侵襲、嘔気・嘔吐、疼痛

分子機構

ここまで、2007後期生理学授業プリント＆想像　でまとめた

• 集合管の上皮の基底側に発現していると思われるV(75%){2};Rを介して、アクアポリン2(AQP2)が発現して尿細管腔側に局在、アクアポリン2から水を細胞内に取り込み、アクアポリン3を介して細胞基底側(血管腔)に水が移動する (2007後期生理学授業プリント, SP.817 図12-63)

• 以下の記述と矛盾する気がする・・・
  • 水輸送体apuaporin1(AQP1)に作用して集合管における水透過性を高める(SP.817)。

---

効能又は効果

ピトレシン注射液２０

• 下垂体性尿崩症、下垂体性又は腎性尿崩症の鑑別診断
• 腸内ガスの除去 (鼓腸、胆のう撮影の前処置、腎盂撮影の前処置)
• 食道静脈瘤出血の緊急処置

薬効薬理

ピトレシン注射液２０

• 1. 抗利尿作用

• 遠位尿細管における水の再吸収を促進することにより、抗利尿作用を発揮する1)。

• 2. 腸管平滑筋に対する作用

• 腸管平滑筋に直接作用してこれを収縮させる

• 3. 止血作用

• 腹部内臓の細動脈を収縮させ、門脈血流を減少させるので、一時的に門脈圧が下降するため、門脈圧亢進による食道出血時に止血作用を発揮する。

副作用

ピトレシン注射液２０

血管収縮による血圧上昇、狭心症、腹痛がありうる。(QB.D-357)

• 重大な副作用：ショック、横紋筋融解症、心不全・心拍動停止、精神錯乱・昏睡、水中毒、中枢神経障害(中心性橋脱髄症)、無償、心室頻拍

禁忌

ピトレシン注射液２０

• 1. 本剤の成分に対しアナフィラキシー又は過敏症の既往歴のある患者
• 2. 冠動脈硬化症 (心筋梗塞症、狭心症等) の患者［心筋虚血を延長させることがある。］
• 3. 急速な細胞外水分の増加が危険となるような病態 (心不全、喘息、妊娠中毒症、片頭痛、てんかん等) のある患者［水中毒を起こすことにより、それらの病態を悪化させるおそれがある。］
• 4. 血中窒素貯留のある慢性腎炎の患者［水分貯留を起こすことにより、血中窒素の排泄が抑制されるおそれがある。］

添付文書

• ピトレシン注射液２０

http://www.info.pmda.go.jp/go/pack/2414402A1035_1_02/2414402A1035_1_02?view=body

臨床検査

基準値

• 0.3-4.2pg/ml (RIA2抗体法) (検査の本)
• 0.3-4.0pg/ml (RIA2抗体法) (LAB.695)

「pitressin」

　　[★]

同

Pitressin

関

Vasopressin