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http://cal.man.ac.uk/student_projects/2000/mnby6kas/ sitemap.htm ANTERIOR PITUITARY HORMONES There are 6 major hormones produced by the anterior pituitary, which can be grouped according to structure. Luteinizing hormone, follicle stimulating hormone and thyroid stimulating hormone These are glycoproteins with 2 subunits - and hey all have amino acids. he subunit is common to all these hormones in one species. The subunit gives specificity of binding to receptors and so site of action. The carbohydrate portion of the -subunit affects specificity and half-life. Growth hormone and prolactin These two hormones belong to a family of polypeptide hormones. They share elements of their structure and differ only by 8 amino acids, GH having 191 amino acids and prolactin having 199. Adrenocorticotrophic hormone This is a polypeptide derived from the pro-opiomelanocortin (POMC) precursor molecule, which also gives rise to products such as melanocyte stimulating hormone, lipotrophic hormone and -endorphin. It has 39 amino acids. Thyroid Stimulating Hormone or Thyrotrophin

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ANTERIOR PITUITARY HORMONES

There are 6 major hormones produced by the anterior pituitary, which can be grouped according to structure.

Luteinizing hormone, follicle stimulating hormone and thyroid stimulating hormoneThese are glycoproteins with 2 subunits - and hey all have amino acids. he subunit is common to all these hormones in one species. The subunit gives specificity of binding to receptors and so site of action. The carbohydrate portion of the -subunit affects specificity and half-life.

Growth hormone and prolactinThese two hormones belong to a family of polypeptide hormones. They share elements of their structure and differ only by 8 amino acids, GH having 191 amino acids and prolactin having 199.

Adrenocorticotrophic hormoneThis is a polypeptide derived from the pro-opiomelanocortin (POMC) precursor molecule, which also gives rise to products such as melanocyte stimulating hormone, lipotrophic hormone and -endorphin. It has 39 amino acids.

Thyroid Stimulating Hormone or Thyrotrophin

TSH is released from the anterior pituitary gland in response to thyroid releasing hormone from the hypothalamus and causes the synthesis and secretion of triiodothyronine (T3) and thyroxine (T4) by the thyroid gland.

This is acheived by stimulation of the thyroid follicular cells by binding of TSH to the receptor on the basal surface of the cell and activation of adenylate cyclase.

This leads to iodide uptake. T3 and T4 exert negative feedback on both the pituitary production of TSH and the hypothalamic production of TRH.

Other factors affecting release of TRH from the hypothalamus incluse blood levels glucose and the body's metabolic rate.

Somatostatin inhibits TSH secretion and oestrogen has been shown, in rats, to reverse the negative feedback affect of T3 and T4 on the TSH response to TRH.

Effects of TSH deficiency: Metabolism Body weight increases

Oxygen consumption decreases

What can go wrong

Problems at the level of the hypothalamo-pituitary axis can cause deficiency of TSH

Heat production decreasesBasal metabolic rate decreases

CNS

Impaired mentalityPoor memory and concentrationDrowsiness

Motor nervous system Activity decreases

Sympathetic nervous system Activity decreases

CardiovascularBradycardiaReduced output and blood pressure

GI tract Activity decreasedConstipation

resulting in secondary hypothyroidism which is normally less severe than that caused by disease of the thyroid gland itself. Congenital problems such as pituitary hypoplasia of aplasia may affect any of the pituitary hormones. There may be a loss of midline structures as in septo-optic dysplasia, which also causes loss of optic nerves.

The effects are due to lack of production of thyroid hormones. Treatment is by administration of oral thyroxine.

Hyperthroidism has the opposite symptoms to hypothyroidism including increased oxygen consumption, increased metabolism, weight loss, heat intolerance, sweating, insomnia and nervousness. The most common form is Graves' disease, an autoimmune condition in which thyroid stimulating immunoglobulins exist that mimic the action of TSH but with no normal feedback control. This results in continual production of thyroid hormones and an enlarged thyroid gland. Treatment is with anti-thyroid drugs or by thryoid gland surgery. It is rare to see overproduction of TSH due to a pituitary adenoma.

Gonadotrophins-luteinizing hormone and follicle stimulating hormone

The hypothalamo-pituitary-gonadal axis is different in males and females.

In females GnRH is secreted from the hypothalamus in a cyclical way leading to a cyclical secretion of LH and FSH from the pituitary, which maintains the menstrual cycle.

LH acts on the ovarian follicle and it induces ovulation and maintains the corpus luteum.

FSH causes development of the ovarian follicle and stimulates secretion of oestradiol and progesterone.

The sex steroids feed back to inhibit release of GnRH and therefore LH and FSH. At sustained high levels however, oestradiol causes a sharp increase in LH secretion linked to ovulation. This is an example of positive feedback.

In males GnRH causes the release of LH and FSH from the anterior pituitary, as in females.

LH acts on the Leydig cells of the testes to produce testosterone.

FSH acts on the Sertoli cells of the testes to maintain spermatogenesis as well as production of sex-hormone binding globulin.

In males and females FSH stimulates the production of inhibin, which has a negative feedback effect on the hypothalamus and pituitary.

What can go wrong

Insufficient GnRH causes a fall in gonadotrophin production, which leads to amenorrhoea, due to lack of ovulation, in women and impotence and infertility in men. This is sometimes seen when nutrient intake is too low, as in anorexia nervosa, or when excessive exercise is undertaken. It may also be due to a prolactin secreting tumour because prolactin has effects on the hypothalamo-pituitary-gonadal axis. The problems caused by lack of GnRH may be treated by administration of GnRH, gonadotrophins such as recombinant FSH, or sex steroids.

Growth hormone

Growth hormone release from the anterior pituitary is under the control of two hypothalamic hormones.

GHRH acts to stimulate release of GH while somatostatin acts to inhibit release of GH.

GH exerts its effects directly and also indirectly through insulin-like growth factors (IGFs) 1 and 2. The effects include promotion of growth of bone, soft tissue and viscera as well as having affects on protein synthesis, lipolysis and

glucose transport and metabolism. IGF1 provides negative feedback to the pituitary and hypothalamus.

Other factors affecting GHRH and somatostatin secretion include sleep, exercise, stress and blood glucose levels. Oestradiol also acts to increase sensitivity of tissues to GH.

What can go wrong

A GH secreting tumour may be present in the pituitary gland leading to excessive height due to extra GH during childhood. Excessive production of GH in adulthood,after the growing ends of the bones have fused, leads to the condition of acromegaly and this can be seen as enlarged feet, hands and jaw caused by thickening of the bones as well as thickening of the soft tissue.

Insulin resistance also develops, due to downregulation of the insulin receptors caused by increased insulin production in response to increase glucose concentrations. This gives the symptoms of diabetes mellitus. Treatment of acromegaly is usually surgery to remove the tumour. The dopamine agonist bromocriptone is sometimes administered and somatostatin analogues may also be used.

Hyposecretion if GH in childhood leads to pituitary dwarfism and a characteristic fat distribution concentrated around the face and abdomen caused by a loss of metabolic function.This may be due to a number of reasons, for example irradiation of the hypothalamo-pituitary area, surgery of the pituitary gland or trauma severing the link between hypothalamus and pituitary gland, which result in lack of hypothalamic or pituitary hormone secretion. The syndrome of hypopituitarism and the importance of GH in adults has only recently been recognised. Symptoms of lack of GH include increased abdominal adiposity, reduced strength and exercise capacity, reduced bone density, elevated cholesterol and impaired psychological well-being. GH deficiency in both adults and children can be treated successfully using recombinant human GH.

Prolactin

PRL acts to initiate and maintain milk secretion by the mammary glands. It works with other hormones such as oxytocin, which actually causes milk ejection, and oestradiol, progesterone, glucocorticoids, GH, thyroxine and insulin, which prepare the mammary gland for milk production.

Other functions are unclear but experimental animals have been shown to produce PRL in response to stress. PRL may also play a part in fertility and maternal behaviour.

PRL secretion is under inhibitory control of dopamine. This means that if the link between the hypothalamus and pituitary is severed PRL secretion increases, unlike all other pituitary hormones, where production would decrease without stimulatory control of the hypothalamus.

TSH has a stimulatory affect on PRL secretion. Oestradiol increases PRL production and levels of PRL rise during pregnancy and remain high during lactation.

What can go wrong

PRL secreting tumours are a very common type of pituitary tumour. The high levels of PRL lead to loss of reproductive function and inappropriate milk production (galactorrhoea) in males and females although male symptoms are often less obvious. Treatment is with the dopamine agonist bromocriptine. Undersecretion of PRL is very rare and does not have any clinical symptoms.

Adrenocorticotrophic hormone

ACTH is released in a pulsatile fashion from the pituitary following a circadian rhythm, peaking in the morning and then declining. It is released under control of hypothalamic CRH.

The release of CRH can be affected by external influences such as stress. CRH action is potentiated by petides such as vasopressin.

ACTH controls the production of glucocorticoids by the adrenal cortex, stimulating the conversion of cholesterol to pregnenolone - a precursor of cortisol. Cortisol feeds back to inhibit both the hypothalamus and pituitary gland.

What can go wrong

Oversecretion of ACTH leads to symptoms known as Cushing syndrome. When this is a result of a feedback abnormality it is Cushing disease and is caused by ACTH and CRH secretion being suppressed at abnormally high levels of circulating cortisol. This results in an ACTH secreting pituitary tumour due to overstimulation of the corticotrophs and excess cortisol secretion secondary to this. Excess cortisol secretion may also be caused by a CRH secreting tumour Symptoms of excess cortisol include central obesity, thinning of the skin, bruising, glucose intolerance, susceptibility to infection, muscle wasting and thin bones. Hyperpigmentation of the skin may occur due to the associoated secretion of -MSH with ACTH. When excess ACTH drives excess cortisol production adrenal androgens are also oversecreted leading to symptoms of androgen excess. Treatment is surgery to remove the tumour. Undersecretion of ACTH leads to problems of

glucocorticoid deficiency, such as hypoglycaemia, and androgen deficiency, such as lack of pubic hair and libido in females. This can be treated by administering hydrocortisone.

HYPOTHALAMO-PITUITARY AXIS STRUCTURE AND DEVELOPMENT

The structure of the hypothalamo-pituitary axis as a unit is of vital importance to its ability to function.It has been shown, by experiments where the pituitary gland is removed to a well-vascularised site distant from the hypothalamus, that the pituitary gland must be near the hypothalamus in order to function.

Anatomy

The hypothalamus consists of nervous tissue lying inferior to the two lobes of the thalamus. The pituitary gland, or hypophysis, is found at the base of the brain below the hypothalamus and the two structures are connected via the infundibulum, or pituitary stalk, which carries both axons and blood vessels.

The pituitary gland is about 1- 1.5 cm in diameter and weighs approximately 0.5g although it tends to weigh approximately 20% more in women and may increase by 10% during pregnancy. It sits in the sella turcica which is a depression of the sphenoid bone at the base of the skull and lies behind the sphenoid sinus.

The top of the sella turcica is covered by a diaphragm, which has a foramen in the centre through which the infundibulum passes.

Superior to the diaphragm is the optic chiasm.

The pituitary gland can be divided into two functionally and embryologically distinct parts. These are the anterior pituitary, or adenohypophysis, and the posterior pituitary, or neurohypophysis.

The anterior pituitary makes up 75% of the total weight of the pituitary. The pars distalis forms the major part of the gland. The pars intermedia is rudimentary in man. The pars tuberalis runs up the pituitary stalk.

The posterior pituitary is made up of neuronal processes and glia as an extension of the hypothalamus and its major part is the pars distalis, which lies behind the anterior pituiary in the sella turcica.

FUNCTIONS OF THE HYPOTHALAMO-PITUITARY AXISThe hypothalamo-pituitary axis is the unit formed by the hypothalamus and pituitary gland, which exerts control over many parts of the endocrine system. This unit functions by means of interaction of the nervous and endocrine systems whereby the nervous system regulates the endocrine system and endocrine activity modulates the activity of the CNS.

The Hypothalamus

The hypothalamus has many functions and is one of the major regulators of homeostasis.

It controls the autonomic nervous system, acts with the limbic system to regulate emotional and behavioural patterns, regulates eating and drinking, controls body temperature and regulates diurnal rhythms. It also controls pituitary gland secretions.

The hypothalamus receives input from the external and internal environment as well as having its own receptors. It receives stimuli from the somatic and visceral sense organs. These inputs travel via the medulla oblongata and reach the hypothalamus through innervation by fibres producing dopamine, adrenaline, noradrenaline, serotonin and acetylcholine as well as fibres releasing neuropeptides such as enkephalins, NPY, neurotensin, dynorphins and endorphins.

The release of hormones from the pituitary is therefore subject to many different stimuli from 'higher centres' acting on the hypothalamus.In response to stimuli such as stress, pain and emotions, the hypothalamus can exert effects on the anterior and posterior pituitary gland in order to respond rapidly to environmental change as well as to feedback from internal systems.

The hypothalamus is the least well understood area of the hypothalamo-pituitary axis and research into certain aspects of its function is ongoing. An example is current work involving the recently discovered peptide hormone, Leptin, which has shed light on the existance of an adipose tissue- brain endocrine axis.

The hypothalmus exerts its effects on the pituitary gland in two different ways:

Posterior pituitary

The hypothalamic paraventricular and supraoptic nuclei produce secretory droplets, which are the first stage in formation of the neuropeptides vasopressin and oxytocin. The paraventricular nuclei produce mostly oxytocin and the supraoptic mostly vasopressin although both hormones may also be produced by the other type of nuclei. These hormones are packaged with the protein neurophysin into granules which then move down the axon and are stored in the posterior pituitary. Following stimulation of the hypothalamus these hormones are then released into the bloodstream. Small amounts of the hormones also enter the portal blood supply.

Anterior pituitary

Control of the anterior pituitary is not via a nervous link. It was discovered in the 1930s that the hypothalamus is linked to the anterior pituitary by a network of microcapillaries - the hypophyseal portal vessels. Control is maintained by release of hypothalamic hormones, some of which stimulate release and others inhibit release

Hypothalamic hormone Effect on anterior pituitary gland

Thyrotropin releasing hormone (TRH) release of TSH and PRL

Gonadotropin releasing hormone (GnRH) release of LH and FSH

Growth hormone releasing hormone (GHRH) release of GH

Somatostatin (SS) inhibition of GH

Corticotrophn releasing hormone (CRH) release of ACTH

Dopamine (DA) inhibition of PRL

These hormones are released by exocytosis from storage granules in the hypothalamic-hypophyseotropic nuclei into the capillaries of the primary plexus. From here the hormones travel in the blood through the hypophyseal portal veins into the anterior pituitary secondary plexus. They then act on anterior pituitary cells giving a rapid response. Anterior pituitary hormones are then released into the secondary plexus and anterior hypophyseal veins into the systemic circulation.

Feedback control

Negative feedback is an important factor in controlling the hypothalamic-pituitary-target organ axis function. Once hypothalamic hormones stimulate the release or inhibition of the pituitary hormone, this may then acts at a target gland, such as the thyroid, causing release of further hormones or causing metabolic effects. The action of hypothalamic hormones may be inhibited by long feedback loops from the target gland hormone or by short feedback loops from the pituitary hormone. There may also be direct feedback from the target gland hormone to the pituitary gland.Input is also received at the hypothalamus from higher brain centres, which can be due to internal or external influences Positive feedback also plays a part in certain systems. For example, in the situation where high levels of oestradiol in the blood cause a surge in LH levels during the menstrual cycle.

POSTERIOR PITUITARY HORMONES

The hormones produced by the posterior pituitary gland are oxytocin and vasopressin, which is also known an arginine vasopressin (AVP) or antidiuretic hormone (ADH). These are both peptides with similar structures and made up of 9 amino acids. Their properties are determined by the residue at position 8.

Oxytocin

Oxytocin secretion occurs in response to nervous stimulation of the hypothalamus. This hormone causes contraction of the smooth muscle of the uterus and also of the myoepithelial cells lining the duct of the mammary gland. Although some oxytocin is found in males, its fuction is unclear.

Release of oxytocin is under positive feedback control. Stimulation of mechanoreceptors in the uterus and vagina during parturition cause a rise in oxytocin levels up to a maximum until the stimulus is no longer present and the action of the hormone is no longer needed. The nipple also sends nervous impulses to the hypothalamus upon suckling, leading to contraction of the

myoepithelial cells and expulsion of milk under positive feedback control. Oestradiol potentiates the uterus to oxytocin and progesterone blocks it. Oxytocin

also acts with AVP to promote sodium excretion.

There are no known disorders of oxytocin secretion.

Vasopressin AVP acts primarily on the kidneys at V2 receptors to aid reabsorption of water by

affecting the water permeability of the collecting duct of the kidney. At high concentrations it also causes constriction of the arterioles through its

action at the V1 receptors leading to an increase in blood pressure. Osmoreceptors in the hypothalamus detect an increase in osmotic pressure in the

blood. As well as producing the sensation of thirst in order to cause increased water intake, the hypothalamus causes the release of AVP, which acts to retain water and reduce plasma osmolality.

AVP is under negative feedback control. A fall in blood volume stimulates release

of AVP. Also, a fall in the arterial partial pressure of oxygen and a rise in partial pressure of carbon dioxide stimulate AVP release. Secretion is also affected by the angiotensin II, adrenaline, cortisol and sex steroids. At the level of the hypothalamus, pain, trauma, nausea and vomiting, and a rise in external temperature increase AVP secretion, and psycological and emotional stimuli also affect release.

What can go wrong

Overproduction of AVP can occur due to brain trauma. It leads to water retention, serum hypo-osmolality, hyponatraemia and high urine osmolality.These effects cause symptoms of headache, apathy, nausea and vomiting, impaired conciousness and can be fatal in extreme cases.

Underproduction of AVP results in the condtion of diabetes insipidus, which is neurogenic in origin (rather than due to failure of the kidneys to respond to AVP) and can result from a pituitary tumour, head traumas or surgery which damages the pituitary gland and hypothalamus.Sometimes it is due to autoimmune destruction of the AVP neurons. Clinical signs are excretion of large volumes of urine leading to dehydration and thirst, as well as increased plasma osmolality. The water deprivation test is often used as a diagnostic aid - patients are unable to concentrate their urine and when deprived of water will continue to pass dilute urine of low osmolality while plasma osmolality rises. Treatment of this condition is with analogues of AVP such as desamino D-arginine administered subcutaneously or by nasal spray.

Antidiuretic Hormone (Vasopressin)

Roughly 60% of the mass of the body is water, and despite wide variation in the amount of water taken in each day, body water content remains incredibly stable. Such precise control of body water and solute concentrations is a function of several hormones acting on both the kidneys and vascular system, but there is no doubt that antidiuretic hormone is a key player in this process.

Antidiuretic hormone, also known commonly as arginine vasopressin, is a nine

amino acid peptide secreted from the posterior pituitary. Within hypothalamic neurons, the hormone is packaged in secretory vesicles with a carrier protein called neurophysin, and both are released upon hormone secretion.

Physiologic Effects of Antidiuretic Hormone

Effects on the Kidney

The single most important effect of antidiuretic hormone is to conserve body water by reducing the loss of water in urine. A diuretic is an agent that increases the rate of urine formation. Injection of small amounts of antidiuretic hormone into a person or animal results in antidiuresis or decreased formation of urine, and the hormone was named for this effect.

Antidiuretic hormone binds to receptors on cells in the collecting ducts of the kidney and promotes reabsorption of water back into the circulation. In the absense of antidiuretic hormone, the collecting ducts are virtually impermiable to water, and it flows out as urine.

Antidiuretic hormone stimulates water reabsorbtion by stimulating insertion of "water channels" or aquaporins into the membranes of kidney tubules. These channels transport solute-free water through tubular cells and back into blood, leading to a decrease in plasma osmolarity and an increase osmolarity of urine.

Effects on the Vascular System

In many species, high concentrations of antidiuretic hormone cause widespread constriction of arterioles, which leads to increased arterial pressure. It was for this effect that the name vasopressin was coined. In healthy humans, antidiuretic hormone has minimal pressor effects.

Control of Antidiuretic Hormone Secretion

The most important variable regulating antidiuretic hormone secretion is plasma

osmolarity, or the concentration of solutes in blood. Osmolarity is sensed in the hypothalamus by neurons known as an osmoreceptors, and those neurons, in turn, simulate secretion from the neurons that produce antidiuretic hormone.

When plasma osmolarity is below a certain brink, the osmoreceptors are not activated and antidiuretic hormone secretion is suppressed. When osmolarity increases above the threshold, the ever-alert osmoreceptors recognize this a the cue to stimulate the neurons that secrete antidiuretic hormone. As seen the

the figure below, antidiuretic hormone concentrations rise steeply and linearly with increasing plasma osmolarity.

Osmotic control of antidiuretic hormone secretion makes perfect sense. Imagine walking across a desert: the sun is beating down and you begin to lose a considerable amount of body water through sweating. Loss of water results in concentration of blood solutes - plasma osmolarity increases. Should you increase urine production in such a situation? Clearly not. Rather, antidiuretic hormone is secreted, allowing

almost all the water that would be lost in urine to be reabsorbed and conserved.

There is an interesting parallel between antidiuretic hormone secretion and thirst. Both phenomena appear to be stimulated by hypothalamic osmoreceptors, although probably not the same ones. The osmotic threshold for antidiuretic hormone secretion is considerably lower than for thirst, as if the hypothalamus is saying "Let's not bother him by invoking thirst unless the situation is bad enough that antidiuretic hormone cannot handle it alone."

Secretion of antidiuretic hormone is also simulated by decreases in blood pressure and volume, conditions sensed by stretch receptors in the heart and large arteries. Changes in blood pressure and volume are not nearly as sensitive a stimulator as increased osmolarity, but are nonetheless potent in severe conditions. For example, Loss of 15 or 20% of blood volume by hemorrhage results in massive secretion of antidiuretic hormone.

Another potent stimulus of antidiuretic hormone is nausea and vomiting, both of which are controlled by regions in the brain with links to the hypothalamus.

Disease States

The most common disease of man and animals related to antidiuretic hormone is diabetes insipidus. This condition can arise from either of two situations:

Hypothalamic ("central") diabetes insipidus results from a deficiency in secretion of antidiuretic hormone from the posterior pituitary. Causes of this disease include head trauma, and infections or tumors involving the hypothalamus.

Nephrogenic diabetes insipidus occurs when the kidney is unable to respond to antidiuretic hormone. Most commonly, this results from some type of renal disease, but mutations in the ADH receptor gene or in the gene encoding aquaporin-2 have also been demonstrated in affected humans.

The major sign of either type of diabetes insipidus is excessive urine production. Some human patients produce as much as 16 liters of urine per day! If adequate water is available for consumption, the disease is rarely life-threatening, but withholding water can be very dangerous. Hypothalamic diabetes insipidus can be treated with exogenous antidiuretic hormone.

Vasopressin

From Wikipedia, the free encyclopedia

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Arginine vasopressin (AVP), also known as argipressin or antidiuretic hormone (ADH), is a human hormone that is mainly released when the body is low on water; it causes the kidneys to conserve water by concentrating the urine and reducing urine volume. It also has various functions in the brain and blood vessels.

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

Vasopressin is a peptide hormone liberated from a preprohormone precursor that is synthesized in the hypothalamus as it is transported 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.

Contents

Space-filling model of arginine vasopressin

arginine vasopressin (antidiuretic

hormone)

Identifiers

Symbol AVP VP, ADH

HUGO 894

Entrez 551

OMIM 192340

RefSeq NM_000490

UniProt P01185

Other data

Locus Chr. 20 p13

[hide] 1 Physiology

o 1.1 Control o 1.2 Sources o 1.3 Peripheral actions o 1.4 Actions within the brain

2 Structure and relation to oxytocin 3 Role in disease 4 Pharmacology

o 4.1 Vasopressin analogues o 4.2 Vasopressin receptor inhibition

5 References 6 Further Reading

7 External links

[edit] Physiology

[edit] 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 and caffeine reduce vasopressin secretion. The resulting decrease in water reabsorption by the kidneys leads to a higher urine output. Coffee is an example of a food product that supresses the body's release of antidiuretic hormones, due to its level of caffeine. This intake of caffeine causes the body to lose more water and may lead to dehydration if consumed excessively.

Angiotensin II stimulates the secretion of vasopressin.[1]

[edit] Sources

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 secreted from parvocellular neurons of the paraventricular nucleus at the median eminence into the short portal vessels of the pituitary stalk. These vessels carry the peptide directly to the anterior pituitary gland, where it is an important releasing factor for ACTH, acting in conjunction with CRH.

Vasopressin is also released into the brain by several different populations of neurons (see below).

[edit] Peripheral actions

Vasopressin acts on three different vasopressin receptors. The receptors are differently expressed in different tissues, and exert different actions:

Type Second messenger system Locations Actions

AVPR1A phosphatidylinositol/calciumliver, kidney, peripheral vasculature, [[brain

vasoconstriction, gluconeogenesis, platelet aggregation, and release of factor VIII and von Willebrand factor; social recognition[2], circadian tau[3]

AVPR1B phosphatidylinositol/calcium pituitary gland, brain

adrenocorticotropic hormone secretion in response to stress[4]; social interpretation to olfactory cues[5]

AVPR2 adenylate cyclase/cAMP

apical 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.

[edit] Actions within the brain

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.

[edit] 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-Ser-Asn-Cys-Pro-Ile-Gly-NH2 Isotocin Bony fishesCys-Tyr-Ile-Asn/Gln-Asn-Cys-Pro-Leu/Val-Gly-NH2 Various tocins Sharks

Invertebrate VP/OT SuperfamilyCys-Leu-Ile-Thr-Asn-Cys-Pro-Arg-Gly-NH2 Diuretic Hormone LocustCys-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 OctopusCys-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)

[edit] 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 hyponatraemia for several days.

[edit] Pharmacology

[edit] 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.[6]

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 epinephrine). It had been shown to be more effective than epinephrine in asystolic cardiac arrest.[7] 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.[8]

[edit] 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 tolvaptan acting on V1a and V2 and the remainder mainly on V1a receptors. The same class of drugs is also being studied in congestive heart failure.

[edit] References

1. ̂ Vander, A.J., Renal Physiology, McGraw-Hill, 1991.

2. ̂ Bielsky IF, Hu SB, Szegda KL, Westphal H, Young LJ. Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice.Neuropsychopharmacology. 2004; 29:483-93. PMID 14647484

3. ̂ Wersinger SR, Caldwell HK, Martinez L, Gold P, Hu SB, Young WS 3rd. Vasopressin 1a receptor knockout mice have a subtle olfactory deficit but normal aggression. Genes Brain Behav. 2006 Nov 3; [Epub ahead of print] PMID 17083331

4. ̂ Lolait SJ, Stewart LQ, Jessop DS, Young WS 3rd, O'Carroll AM. The hypothalamic-pituitary-adrenal axis response to stress in mice lacking functional vasopressin V1b receptors. Endocrinology. 2007;148:849-56. PMID 17122081

5. ̂ Wersinger SR, Kelliher KR, Zufall F, Lolait SJ, O'Carroll AM, Young WS 3rd. Social motivation is reduced in vasopressin 1b receptor null mice despite normal performance in an olfactory discrimination task. Horm Behav. 2004;46:638-45. PMID 15555506

6. ̂ Baum S, Nusbaum M, Tumen HJ. The control of gastrointestinal hemorrhage by selective mesenteric infusion of pitressin. Gastroenterology 1970;58:926.

7. ̂ Wenzel V, Krismer AC, Arntz HR, Sitter H, Stadlbauer KH, Lindner KH; European Resuscitation Council Vasopressor during Cardiopulmonary Resuscitation Study Group. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 2004;350:105-13. PMID 14711909.

8. ̂ Grmec S, Mally S. Vasopressin improves outcome in out-of-hospital cardiopulmonary resuscitation of ventricular fibrillation and pulseless ventricular tachycardia: an observational cohort study. Crit Care. 2006 Feb;10(1):R13. PMID 16420660.

[edit] 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

Thirst and sodium appetite

The sensations caused by dehydration, the continuing loss of fluid through the skin and lungs and in the urine and feces while there is no water intake into the body. Thirst becomes more and more insistent as dehydration worsens. Water and electrolytes are needed to replace losses, and an adequate intake of sodium as well as water is important for maintaining blood volume. Normally, the amounts of water drunk and taken in food

are more than enough to maintain hydration of the body, and the usual mixed diet provides all the electrolytes required.

Deficit-induced drinking occurs when a deficit of fluid in one or both of the major fluid compartments of the body serves as a signal to increase drinking. Cellular dehydration, detected by osmoreceptors, causes thirst and vasopressin release. Hypovolemia (low blood volume), detected by volume receptors in the heart and large veins and the arterial baroreceptors, causes immediate thirst, a delayed increase in sodium appetite, activation of the renin-angiotensin system, and increased mineralocorticoid and vasopressin secretion. Increases or decreases in amounts drunk in disease may result from normal or abnormal functioning of mechanisms of thirst or sodium appetite.

Cellular dehydration

Observations using a variety of osmotic challenges have established that hyperosmotic solutions of solutes that are excluded from cells cause more drinking than equiosmolar amounts of solutes that penetrate cells. Thus, the osmotic shift of water out of the cells caused by the excluded solutes provides the critical stimulus to drinking. Continuing water loss in the absence of intake is perhaps a more significant cause of cellular dehydration than administration of an osmotic load, but the same mechanisms apply. See also Osmosis.

Sharing in the overall cellular dehydration are osmoreceptors which initiate the responses of thirst and renal conservation of water. Osmoreceptors are mainly located in the hypothalamus. The nervous tissue in the hypothalamus surrounding the anterior third cerebral ventricle and, in particular, the vascular organ of the lamina terminalis also respond to osmotic stimuli. Osmoreceptors initiating thirst work in conjunction with osmoreceptors initiating antidiuretic hormone (ADH) release to restore the cellular water to its prehydration level. In addition to reducing urine loss, ADH may lower the threshold to the onset of drinking in response to cellular dehydration and other thirst stimuli. The cellular dehydration system is very sensitive, responding to changes in effective osmolality of 1–2%.

Hypovolemia

The cells of the body are bathed by sodium-rich extracellular fluid that corresponds to the aquatic environment of the unicellular organism. Loss of sodium from the extracellular fluid is inevitably accompanied by loss of water, resulting in hypovolemia with thirst followed by a delayed increase in sodium appetite. If not corrected, continuing severe sodium loss eventually leads to circulatory collapse.

Stretch receptors in the walls of blood vessels entering and leaving the heart and in the heart itself are thought to initiate hypovolemic drinking. Volume receptors in the venoatrial junctions and receptors that register atrial and ventricular pressure respond to the underfilling of the circulation with a reduction in inhibitory nerve impulses to the thirst centers, which results in increased drinking. Angiotensin II and other hormones

(such as aldosterone and ADH) are also involved in this response. Arterial baroreceptors function in much the same way as the volume receptors on the low-pressure side of the circulation, exerting continuous inhibitory tone on thirst neurons. A fall in blood pressure causes increased drinking, whereas an acute rise in blood pressure inhibits drinking. The anterior third cerebral ventricle region, which is implicated in angiotensin-induced drinking, plays a crucial role in hypovolemic drinking, body fluid homeostasis, and blood pressure control.

Renin-angiotensin systems

It is believed that drinking caused by hypovolemic stimuli partly depends on the kidneys. The renal thirst factor is the proteolytic enzyme renin, which is secreted into the circulation by the kidney in response to hypovolemia. Renin cleaves an inactive decapeptide, angiotensin I, from angiotensinogen, an α2-globulin that is synthesized in the liver and released into the circulation. Angiotensin I is converted to the physiologically active octapeptide angiotensin II during the passage of blood through the lungs. Angiotensin II is an exceptionally powerful stimulus of drinking behavior in many animals when administered systemically or into the brain. Increased activation of the renin-angiotensin system may sometimes account for pathologically increased thirst in humans. Angiotensin II also produces (1) a rise in arterial blood pressure, release of norepinephrine from sympathetic nerve endings, and secretion of adrenomedullary hormones; and (2) water and sodium retention by causing release of ADH from the posterior pituitary and stimulation of renal tubular transport of sodium through direct action on the kidney and indirectly through increased aldosterone secretion from the adrenal cortex. See also Aldosterone; Kidney.

Neuropharmacology

Many substances released by neurons, and in some cases by neuroglial cells, affect drinking behavior when injected into the brain and may interact with the brain and modify angiotensin-induced drinking. Substances may stimulate or inhibit drinking, or both, depending on the species and the conditions of the experiment. Acetylcholine is a particularly powerful stimulus to drinking in rats, and no inhibitory effects on drinking have been described. Histamine also seems to be mainly stimulatory. However, a lengthening list of neuroactive substances, including norepinephrine, serotonin, nitric oxide, opioids, bombesin-like peptides, tachykinins, and neuropeptide Y, may either stimulate or inhibit drinking with varying degrees of effectiveness, depending on the species or the site of injection in the brain. Natriuretic peptides, prostaglandins, and gamma-amino butyric acid seem to be exclusively inhibitory. See also Acetylcholine; Neurobiology; Synaptic transmission.

Many hormones also affect water or sodium intake. Relaxin stimulates water intake, and ADH (or vasopressin) lowers the threshold to thirst in some species. Vasopressin injected into the third cerebral ventricle may stimulate water intake, suggesting a possible role for vasopressinergic neurons. Increased sodium appetite in pregnancy and lactation depends partly on the conjoint action of progesterone, estrogen, adrenocorticotrophic hormone

(ACTH), cortisol, corticosterone, prolactin, and oxytocin. Aldosterone and other mineralocorticoids, the stress hormones of the hypothalamo-pituitary-adrenocortical axis, corticotrophin, ACTH, and the glucocorticoids also stimulate sodium intake. See also Neurohypophysis hormone.

The effect of many of these substances on drinking behavior shows both species and anatomical diversity. The multiplicity of effects of many of these substances makes it impossible to generalize on their role in natural thirst, but none of these substances seems to be as consistent and as universal a stimulus of increased thirst and sodium appetite as angiotensin.