Diseases Of The Posterior Pituitary Gland (Neurohypophysis)

Front 1

Disease: Syndrome of Inappropriate Antidiuretic Hormone Hypersecretion (SIADH)

Back 1

Rare form of hyperfunction of the PP, producing excessive level of vasopressin (VP) that is inappropriate for plasma osmolarity in individual

Front 2

What causes an individual to develop Syndrome of Inappropriate Antidiuretic Hormone Hypersecretion (SIADH)?

Back 2

most likely not actually a pituitary problem - often caused by ectopic (in an abnormal place or position) source of VP (e.g. lung cancer)

can occur after AP pituitary surgery (Initial diabetes insipidus (low VP) is followed by SIADH (high VP) which shouldbe managed with reduced fluid intake to prevent hyponatremia

Front 3

Syndrome of Inappropriate Antidiuretic Hormone Hypersecretion (SIADH)

Effects on kidney, urine, and plasma?

Back 3

Water reabsorption by kidney is increased and leads to a reduced renal volume and more concentrated urine

consequence is hyponatremia (decrease in plasma sodium concentration)

Front 4

Diabetes Insipidus (DI)

Back 4

failure of the posterior pituitary to produce vasopressin (VP, ADH)

presents as a polyuria (excess urine) and polydipsia (consequential excess drinking), so it's important to rule out diabetes mellitus

Front 5

What can cause diabetes insipidus?

Back 5

- Post-pituitary surgery that has caused some form of damage to the posteriorlobe

-Metastases and posterior lobe failure

-Fractures of the skull

-End-organ kidney failure

-Transient after transphenoidal pituitary surgery

Front 6

How is diabetes insipidus diagnosed?

Back 6

fluid/water deprivation test with hourly measurements of urine volume and osmolarity

(Monitor for dehydration due to large water volume loss)

Front 7

What is the treatment for DI?

Back 7

Use of a VP analogue (that contains a D- rather than an L- form of arginine in themolecule) to provide a longer half life than VP

Front 8

Oxytocin deficiency

Back 8

only a problem in breast feeding patients and these individuals can be given oxytocin analogues

Front 9

Oxytocin excess

Back 9

Excess production of oxytocin (e.g. ectopic tumor) is rarely seen as it won’t produce symptoms

Front 10

Nonapeptides are transported to their target tissues by which 3 mechanisms?

Back 10

1. Release of hormones into the blood occurs either via the general circulation fromthe PP or into the hypothalamic-hypophysial portal system (and AP)

2. Release at nerve endings across synapses within the CNS where the nonapeptidescan act as neurotransmitters

3. Release from dendrites terminating at the 3rd ventricle which can carry the hormones into the CSF for transport to central receptors

Front 11

In the blood, how are neurohormones transported? What is their half life?

Back 11

In the blood neurohormones are transported to target tissues “unbound” witha half life of around 5 min

Front 12

What type of receptors are VP receptors? How many forms do they exist in?

Back 12

All VP receptors are 7-pass transmembrane G-protein coupled receptors

Exist in at least 3 forms, known as V1a, V1b (also called V3), and V2

Front 13

V1a, V1b (V3) and V2 are found on which chromosomes? What is the percentage of sequence homology between the three?

Back 13

V1a (on chr 12), V1b/V3 (on chr 1) and V2 (on chr X) have 45% sequence homology

Front 14

What is true of the binding between Vasopressin, VTR, Oxytocin, and OTR?

Back 14

Vasopressin can bind OTR but oxytocin cannot bind VTR

Front 15

Vasopressin and oxytocin are ______, differing by only two amino acids in the ring and side branches.

Back 15

nonapeptides

Front 16

The genes for vasopressin and oxytocin are located on chromosome ___.

Back 16

chromosome 20

Front 17

vasopressin and oxytocin are first produced as pre-hormones which are then processed in the _____.

Back 17

ER

Front 18

Pro-vasopressin becomes _______ + _______ + ______.

Back 18

vasopressin + neurophysiology II + copeptin (GP)

Front 19

Vasopressin target tissues:

V1a receptors are present on which target tissues?

Back 19

vascular smooth muscle, hepatocytes, cardiomyocytes, platelets, adrenal cortex, kidneys, CNS (hippocampus, cortex, thalamus, cerebellum)

Front 20

Vasopressin target tissues:

Vlb/V3 receptors are found on which target tissues?

Back 20

AP corticotrophin, heart, lungs, thymus, mammary glands and CNS (hippocampus, cortex, thalamus, cerebellum)

Front 21

Vasopressin target tissues:

V2 receptors are found on which target tissues?

Back 21

Renal cortical and medullary collecting ducts and Loops of Henle, vascular endothelial cells

Front 22

V1a/b receptor signaling pathways:

______ is a co-transcriptional element that activates a transcription factor, ____ (at active sites). Transcription of different genes occurs via the ________--______-____ complex.

Back 22

CREB-BP, CREB (cAMP response element-binding protein)

CREB--CREB-BP complex

Front 23

V2 receptor and its signaling pathway:

A key molecule influenced by vasopressin through the V2 receptor is ______.

Back 23

aquaporin

Front 24

What is the role of aquaporin (influenced by vasopressin through the V2 receptor pathway)?

Back 24

acts as a transmembrane protein to transport water molecules via an osmotic gradient

Front 25

What is the role of the vasopressin-dependent aquaporin (AQP2)?

Back 25

facilitates movement of water from tubular fluid into cells

Front 26

How is the movement (via aggraphores) and synthesis of AQP2 vasopressin-dependent?

Back 26

- AQP2 sequestered in aggraphores is transported to the apical membrane viamicrotubules and microfilaments influenced by VP

- After insertion and use, the receptor protein is inactivated/returned to themembrane for reuse, a process that is fine tuned by VP

Front 27

Describe the basic intracellular mechanism between VP and AQP in the collecting duct.

Back 27

1. Vasopressin (VP) binds to its V2 receptor

2. This activates the associated G-protein

3. G protein activates adenyl cyclase (AC) enzyme

4. AC induces formation of cAMP

5. cAMP activates (phosphorylates) protein kinase A (PKA)

Front 28

Review: what are the three mechanisms by which Vasopressin can act? (via which type of neurons? acting as what type of molecule? target?)

Back 28

1. via parvocellular neurons, acting as a neurotransmitter, to CNS

2. via parvocellular neurons, acting as neurohormone, to (walls of plexus in) median eminence

3. via magnocellular neurones (terminate in NP), acting as neurohormone, to general circulation

Front 29

Physiological actions of VP in CNS?

Back 29

behavioral and other effects

Front 30

Physiological actions of VP secreted to median eminence?

Back 30

Corticotrophin (ACTH) release (AP)

Front 31

Physiological actions of VP secreted into general circulation?

Back 31

1. renal water reabsorption

2. vasoconstriction

3. vasodilation

4. Factor VIII and von Willebrand factor

5. Hepatic glycogenolysis

Front 32

Physiology related to where the VP receptors are. V1a receptors are linked to which principle actions of VP?

Back 32

vasoconstriction, CNS effects, hepatic glycogenolysis, platelet aggregation

Front 33

Physiology related to where the VP receptors are. V1b (V3) receptors are linked to which principle actions of VP?

Back 33

corticotrophin release, CNS effects

Front 34

Physiology related to where the VP receptors are. V2 receptors are linked to which principle actions of VP?

Back 34

renal water absorption, factor VIII and von Willebrand synthesis (VP used to stimulate VIII in hemophilia), vasodilation

Front 35

Both V1a and V1b (V3) receptors are linked to which principle action(s) of VP?

Back 35

CNS effects

Front 36

What are the peripheral actions of VP?

Back 36

-as an antidiuretic (principally water reabsorption in collecting duct)

-maintenance of renal countercurrent multiplier system

-as a vasoconstrictor

-as a vasodilator

Front 37

Describe the peripheral action of VP acting as an antidiuretic.

Back 37

- Migration of aggraphores and insertion AQP2 into AM for waterreabsorption

- Activation of CREB and AQP2 gene expression

- Degradation /recycling of V2 receptor via β arrestin activation

- Recycling of AQP2

- Synthesis of AQP3 to facilitate water leaving via BLM

Front 38

Describe the peripheral actions of VP and maintenance of the renal countercurrent multipliersystem.

Back 38

Maintenance of high medullary interstitial concentrations of solute needed forwater reabsorption and urine concentration

Front 39

If vasopressin is administered and _______ is blocked with an antagonist,vasoconstriction can be blocked.

Back 39

V1R

Front 40

If vasopressin is administered and V1R activity is blocked with an antagonist,vasoconstriction can be blocked. Kidney-independent (i.e. directly on vasculature) vasodilation occurs,decreasing peripheral _______ and resulting in a ______ in BP.

This is due to_____-mediated effect involving local release of vasodilator ______, which acts onadjacent smooth muscle to cause relaxation and dilation.

Back 40

resistance, decrease

V2R-mediated, NO

(Summary: vasopressin administered, V1R activity blocked in, V2R mediates release of vasodilator NO, vasodilation occurs, decrease in BP)

Front 41

Describe the adenohypophysial action of VP

Back 41

VP (often in conjunction with CRH) released into the hypothalamo-AP portal system is directed to the V1b (V3) receptors in the corticotrophs where it isstimulatory

- Corticotrophin (ACTH) release potentiates effects of CRH

- ACTH also stimulates cortisol production; cortisol has an indirect negativefeedback on CRH

Front 42

In long term stress, VP drives production of ______ and is associatedwith increased levels of circulating _______ and enhanced negative feedback on______ release

Back 42

ACTH, cortisol, CRH

Front 43

What is the central action of VP?

Back 43

Vasopressin is released from dendrites abutting walls of 3rd ventricle and acts as a neurohormone

Front 44

How does VP in CSF compare to CP in plasma?

Back 44

VP in CSF is higher than in plasma

Front 45

In CSF, VP is transported to parts of the brain where its action is mediated by what type of receptors?

Back 45

V1aR or V1bR

Front 46

What type of effects does VP have when it acts as a neurohormone and takes central action?

Back 46

Behavioral effects

Front 47

Male prairie vole monogamy and aggression, and females with newlitters, is correlated with _____ in brain

Back 47

V1aR

Front 48

In humans, autism is associated with decreased social functioning and apolymorphism in the ___ receptor gene

Back 48

VP

Front 49

_______ VP action is associated with drinking, learning andmemory functions (via VP in CSF or through neuron projections)

Back 49

Central

Front 50

What is the most important factor of the control of VP secretion?

Back 50

degree of hydration, via osmoreceptors (normal physiology), baroreceptors (less sensitive; operates when blood volume is markedly decreased e.g. hemorrhage), or in response to stressors

Front 51

VP acts via ______ when there's no change in osmolarity.

Back 51

baraoreceptors

Front 52

When there's an increase in plasma osmolality, VP neurons increase in firing rate and act via _____.

Back 52

osmoreceptors

Front 53

Osmoreceptors are present in osmosensitive (stretch-responsive) cells in _______, and vasopressinergic neurons in _______.

Back 53

circulation, hypothalamus

Front 54

Osmoreceptors lie outside the ____________ in subfornical organ (SFO) and organum vasculosum (OVLT) and can directly contact diffusible solutes (e.g Na+ in blood)

Regulates thirst (influences drinking) through _____, which also regulates VP secretion.

Back 54

blood brain barrier, AII,

Front 55

Vasopressinergic neurons fire more regularly when osmolarity of surrounding medium is (increased/decreased).

Back 55

Increased

Front 56

What do osmoreceptors detect?

Back 56

osmoreceptors detect increases in plasma osmolarity associated with VP increase

Front 57

Where are baroreceptors present?

Back 57

in high pressure (arteries) and low pressure (veins) parts of circulation

Front 58

Where are baroreceptors present in high pressure parts of circulation (arteries)?

Back 58

walls of carotid sinus and vagus nerves

Front 59

Where are baroreceptors present in low pressure parts of circulation (veins)? What do they respond to?

Back 59

located in right atrium, vena cava and hepatic veins and respond to changes in venous blood volume

Front 60

What type of baroreceptor responses lead to brain stem and then on cardiovascular center and to vasopressinergic neurons in hypothalamus?

Back 60

both high pressure and low pressure responses

Front 61

When stimulated (e.g. increase in BP or volume) baroreceptors inhibit both ____ and ____ release (baroreceptor reflex) while also increasing PSN activity.

Back 61

SNS, VP

Front 62

How is the baroreceptor reflect regulated?

Back 62

sympathetic and parasympathetic regulation

Front 63

How can the stimulation of baroreceptors, due to an increase in mean arterial pressure, lead to a decrease in BP? (Baroreceptor reflex)

Back 63

stimulation of baroreceptors --> VP decrease --> decrease in water reabsorption via collecting ducts --> decrease in vasoconstriction and blood pressure

Front 64

Posterior pituitary production of Oxytocin (OT)

Receptors and mechanisms of action?

Back 64

GPCR via PLC activation

Locus is on Chr 3 producing a 389 AA sequence

Front 65

Posterior pituitary production of Oxytocin (OT)

Physiological effects?

Back 65

- Peripheral and central effects including social and maternal behaviors

- OT produced by magnocellular neurons of male (stimulation of ejaculation and increase A by Leydig cells) and female (pregnancy and lactation) equally

-uterine contraction, milk ejection reflect, OT central effects

Front 66

Posterior pituitary production of Oxytocin (OT)

Effects on uterine contraction

Back 66

- Prior to labor onset, uterus is dominated by progesterone and OTR is unexpressed

- Distension of uterus (mechanoreceptors in wall) leads to estrogen increase and OTR are synthesized

- Stretch sends impulses up afferent nerves in inferior hypogastric plexus to hypothalamus and OT is released

- OT is also synthesized locally in the uterus as well as ovary, testis, heart and pancreas

Front 67

Posterior pituitary production of Oxytocin (OT)

Effects on the Milk Ejection Reflex

Back 67

- Post-partum suckling by baby leads to OT release from PP

- Influenced by estrogens, progesterone, iodothyronines and prolactin, myoepithelial cells in mammary ducts express OTR and contract

- Milk is ejected from nipple to baby’s mouth

- Milk ejection reflex is controlled by positive feedback

Front 68

Posterior pituitary production of Oxytocin (OT)

Oxytocin (OT) Central effects- released by dendrites into the third ventricle

(where in the brain can OTR be found? What is OT associated with in females?)

Back 68

- OTR can be found in various parts of the brain

- In females, OT is associated with:

▫ various behavioral effects in mothers e.g maternal bonding andprotectiveness

▫ OT-dependent appeasing and less aggressiveness

▫ attenuation of responses such as fear (decreases glucocorticoid production) and positive stimulation of trust and generosity