Neurohypophysial hormones

neurohypophysial hormones-oxytocin and vasopressin

1. NEUROHYPOPHYSIAL HORMONES
OXYTOCIN
STRUCTURE:
Oxytocin has the chemical formula C43H66N12O12S2. Oxytocin is a peptide hormone.It is a
relatively short polypeptide, being composed of only nine amino acids (a nonapeptide). The
sequence is cysteine - tyrosine -isoleucine - glutamine - asparagine - cysteine - proline -
leucine - glycine (CYIQNCPLG). The cysteine residues form a sulfur bridge. Oxytocin has a
molecular mass of 1007 daltons. One international unit (IU) of oxytocin is the equivalent of
about two micrograms of pure peptide.

Vasopressin: The structure of oxytocin is very similar to that of vasopressin, an antidiuretic hormone that
is also a nonapeptide: cysteine - tyrosine - phenylalanine - glutamine - asparagine - cysteine - proline -
arginine - glycine).These neurohypophysial hormones are closely related structurally but they serve quite
different physiological roles.Oxytocin controls milk release from the mammary gland and contraction of the
uterus,whereas AVP is concerned with water balance. Vassopressin, whose residues also form a sulfur
bridge, has a sequence that differs from oxytocin by two amino acids,a Phenylalanine and an Arginine at the
3 and 8 position.
Oxytocin and vasopressin are the only known hormones released by the human posterior pituitary gland to
act at a distance. However, oxytocin neurons make other peptides, including corticotropin-releasing hormone
(CRH) and dynorphin, for example, that act locally. The magnocellular neurons that make oxytocin are
adjacent to magnocellular neurons that make vasopressin, and are similar in many respects.

2. Oxytocin was the first hormone for which the structure was identified and which was synthesized in the
laboratory (Blakemore and Jennett 2001). Oxytocin and vasopressin were isolated and synthesized by
Vincent du Vigneaud in 1953, work for which he received the Nobel Prize in Chemistry in 1955.

PHYSIOLOGICAL ROLE: Oxytocin is involved in the control of milk release and in uterine
contraction during labor.Vasopressin, or antidiuretic hormone as its name implies,is important in the
homeostatic control of the extracellular fluid volume.the antidiuretic response is of survival value to
individuals of both sexes.OT ,on the other hand,apparently functions only during specific times in the
reproductive cycle of the adult female.
Oxytocin controls milk release and uterine contractions: Oxytocin is a hormone that
plays only a transitory role,possibly specific to the female,andthen,in some cases,only if she becomes
pregnant and delivers a child at term.
Milk release(let down):OT functions in the control of milk release after parturition.Sensory
nerve endings,which are localized to the areolae and nipples of the breast,are stimulated by suckling
and afferent neural pathways conduct these stimuli to the neurohypophysis.
At parturition,dilation of the cervix(vaginal stretching) may also be a stimulus to OT secretion.
There is increased uterine activity during mating, and milk ejection during coitus in the human female
and other animals has been reported.
The major target organ of OT is the mammary gland of the pregnanat female.
Uterine contraction: OT has been used for years to induce labor in human females as it contacts
the myometrium(uterotropic action).Although OT in the maternal circulation throughout
pregnanacy,OT concentration in the blood increase only during the final stages of
labor,notbefore.Circulating OT is not essential for the initiation or maintenanceof spontaneous
labor.parturation can begin in the absence of circulating OT and although OT antiserum suppresses
lactation,it fails to affect parturition.
Vascular smooth muscle actions:Neurohypophysial hormones contract or relax vascular
smooth muscle.There may be two different kinds of neurohypophysial hormone receptors,one that
subserves contraction and other that subserves relaxation. OT is highly effective in contracting human
umbilical arteries and veins whereas AVP is relatively inactive.
Romantic attachment:In some studies, high levels of plasma oxytocin have been correlated
with romantic attachment. For example, if a couple is separated for a long period of time, anxiety can
increase due to the lack of physical affection. Oxytocin may aid romantically attached couples by
decreasing their feelings of anxiety when they are separated.

3. Human sexual response:Plasma OT levels increase during sexual arousal(self-stimulation) in
both women and men and are significantly higher during orgasm/ejacuation than during prior
baseline testing.OT is secreted specifically at the time of ejacuation in males.This is preceded by a rise
in AVP secretion during arousal,which returns to baseline values by the time of ejacuation.AVP release
during arousal may be associated with specific suppression of OT until ejacuation.OT may play a role
in the physiology of sexual responses by facilitating contractions of the smooth muscles of the uterus
and vagina in women.Likewise,release of OT during sexual responses in men may be related to
increased contractility of reproductive smooth muscle tissue.Thus, OT may enhanceboth sperm and
egg transport,thereby promoting reproductive success.
Social Behaviour and wound healing: Oxytocin is also thought to modulate inflammation by
decreasing certain cytokines. Thus, the increased release in oxytocin following positive social
interactions has the potential to improve wound healing. A study by Marazziti and colleagues used
heterosexual couples to investigate this possibility. They found increases in plasma oxytocin following
a social interaction were correlated with faster wound healing. They hypothesized this was due to
oxytocin reducing inflammation, thus allowing the wound to heal more quickly. This study provides
preliminary evidence that positive social interactions may directly influence aspects of health.
Oxytocin evokes feelings of contentment, reductions in anxiety, and feelings of calmness and security
when in the company of the mate. This suggests oxytocin may be important for the inhibition of the
brain regions associated with behavioral control, fear, and anxiety, thus allowing orgasm to occur.
Research has also demonstrated that oxytocin can decrease anxiety and protect against stress,
particularly in combination with social support.

Vasopressin(AVP) mediates osmoregulation and blood pressure
responses:Arginine Vasopressin(AVP) has two major physiological actions:It induces the
contraction or relaxation of certain types of smooth muscle and it promotes the movement of water
and Na
+
across epithelial tissues,notably the distal tubule of the mammalian kidney and the skin and
urinary bladder of amphibians.
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

4. through tubular cells and back into blood, leading to a decrease in plasma osmolarity and an increase
osmolarity of urine.
Osmoregulation and 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, stimulate secretion from the neurons that produce antidiuretic hormone.
When plasma osmolarity is below a certain threshold, the osmoreceptors are not activated and
secretion of antidiuretic hormone is suppressed. When osmolarity increases above the threshold, the
ever-alert osmoreceptors recognize this as their 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 stimulated 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.
Mechanism of action:
Oxytocin
i)A rise in Ca
2+
,produced either spontaneously or by an agonist such as OT interacting with its
receptor(R) ,causes Ca
2+
to bind to calmodulin(Ca
2+
/CaM).
ii)This activates myosine light chain kinase(MLCK).This kinase then phosphorylates light
chains on myosine(P-myosine).This allows actin binding and activates myosine Mg-
ATPase,thus contraction can occur with hydrolysis of ATP.

5. P-myosine is dephosphorylated by phosphatases,leading to relaxation.
iii)If MLCK is phosphorylated,for example by Ca
2+
calmodulin-dependent protein kinase II,then
it is much less efficient at phophorylating myosine,and force falls.Reduction of Ca
2+
will also
promote relaxation.



Vasopressin.
Vasopressin acts on three different receptors, vasopressin receptor V1a (which initiates
vasoconstriction, liver gluconeogenesis, platelet aggregation and release of factor VIII),
vasopressin receptor V1b (which mediates corticotrophin secretion from the pituitary) and
vasopressin receptor V2 which controls free water reabsorption in the renal medullar. The
binding of vasopressin to the V2 receptor activates adenylate cyclase which causes the
release of aquaporin 2 channels into the cells lining the renal medullar duct. This allows water
to be reabsorbed down an osmotic gradient so the urine is more concentrated.

6. Pathophysiology:
Diabetes Insipidus: 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.
Syndrome of inappropriate vasopressin secretion: The state of continual AVP release
without relationship to plasma osmolarity or volume is referred to as the syndrome of inappropriate
vasopressin secretion.

7. The syndrome is chatracterized by an inability to excrete a maximally dilute urine,which results in
retention of water,an expansion of extracellular fluid volume,and a resultant dilutional hyponatremia.
The most common cause of excessive AVP secretion is malignancy;AVP is secreted from a small cell
carcinoma of the lung.Although plasma and urinary levels of AVP may be markedly elevated,the
amount of hormone in the blood or urine may be similar to that of normal individuals.