Endocrine Physiology lecture 4

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Endocrine Physiologylecture 4

• Dale Buchanan Hales, PhD
• Department of Physiology Biophysics

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Antidiuretic hormone and the mineralcorticoids
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Synthesis of ADH

• It is synthesized as pre-prohormone and processed
  into a nonapeptide (nine amino acids).
• Six of the amino acids form a ring structure,
  joined by disulfide bonds.
• It is very similar in structure to oxytocin,
  differing only in amino acid 3 and 8.
• ADH synthesized in the cell bodies of
  hypothalamic neurons in the supraoptic nucleus
• ADH is stored in the neurohypophysis (posterior
  pituitary)forms the most readily released ADH
  pool

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Hypothalamus and posterior pituitary
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Structure of ADH
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Synthesis of ADH

• Mechanical disruption or the neurohypohyseal
  tract by trauma, tumor, or surgery temporarily
  causes ADH deficiency.
• ADH will be restored after regeneration of the
  axons (about 2 weeks).
• But if disruption happens at a high enough level,
  the cell bodies die in the hypothalamus resulting
  in permanent ADH deficiency

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Antidiuretic Hormone ADH

• ADH is also known as arginine vasopressin (AVP
  ADH) because of its vasopressive activity, but
  its major effect is on the kidney in preventing
  water loss.

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ADH conserve body water and regulate tonicity of
body fluids

• Regulated by osmotic and volume stimuli
• Water deprivation increases osmolality of plasma
  which activates hypothalmic osmoreceptors to
  stimulate ADH release

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ADH increases renal tubular absorption of water
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Primary action of ADH antidiuresis

• ADH binds to V2 receptors on the peritubular
  (serosal) surface of cells of the distal
  convoluted tubules and medullary collecting
  ducts.
• Via adenylate cyclase/cAMP induces production and
  insertion of AQUAPORIN into the luminal membrane
  and enhances permeability of cell to water.
• Increased membrane permeability to water permits
  back diffusion of solute-free water, resulting in
  increased urine osmolality (concentrates urine).

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ADH conserve body water and regulate tonicity of
body fluids

• Regulated by osmotic and volume stimuli
• Water deprivation increases osmolality of plasma
  which activates hypothalmic osmoreceptors to
  stimulate ADH release

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Secretion of ADH

• The biological action of ADH is to conserve body
  water and regulate tonicity of body fluids.
• It is primarily regulated by osmotic and volume
  stimuli.
• Water deprivation increases osmolality of plasma
  which activates hypothalmic osmoreceptors to
  stimulate ADH release.

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Secretion of ADH

• Conversely, water ingestion suppresses
  osmoreceptor firing and consequently shuts off
  ADH release.
• ADH is initially suppressed by reflex neural
  stimulation shortly after water is swallowed.
• Plasma ADH then declines further after water is
  absorbed and osmolality falls

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Pathway by which ADH secretion is lowered and
water excretion raised when excess water is
ingested
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Secretion of ADH osmolality control

• If plasma osmolality is directly increased by
  administration of solutes, only those solutes
  that do not freely or rapidly penetrate cell
  membranes, such as sodium, cause ADH release.
• Conversely, substances that enter cells rapidly,
  such as urea, do not change osmotic equilibrium
  and thus do not stimulate ADH release.
• ADH secretion is exquisitely sensitive to changes
  in osmolality.
• Changes of 1-2 result in increased ADH
  secretion.

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ADH and plasma osmolality
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Secretion of ADHhemodynamic control

• ADH is stimulated by a decrease in blood volume,
  cardiac output, or blood pressure.
• Hemorrhage is a potent stimulus of ADH release.
• Activities, which reduce blood pressure, increase
  ADH secretion.
• Conversely, activities or agents that increase
  blood pressure, suppresses ADH secretion.

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ADH and blood pressure
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Pathway by which ADH secretion and tubular
permeability to water is increased when plasma
volume decreases
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Secretion of ADH

• Hypovolemia is perceived by pressure receptors
  -- carotid and aortic baroreceptors, and stretch
  receptors in left atrium and pulmonary veins.
• Normally, pressure receptors tonically inhibit
  ADH release.
• Decrease in blood pressure induces ADH secretion
  by reducing input from pressure receptors.
• The reduced neural input to baroreceptors
  relieves the source of tonic inhibition on
  hypothalamic cells that secrete ADH.
• Sensitivity to baroreceptors is less than
  osmoreceptors senses 5 to 10 change in volume

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Hypothalamus, posterior pituitary and ADH
secretion connection with baroreceptors
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Secretion of ADH

• Hypovolemia also stimulates the generation of
  renin and angiotensin directly within the brain.
• This local angiotensin II enhances ADH release in
  addition to stimulating thirst.
• Volume regulation is also reinforced by atrial
  naturetic peptide (ANP).
• When circulating volume is increased, ANP is
  released by cardiac myocytes, this ANP along with
  the ANP produced locally in the brain, acts to
  inhibit ADH release.

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Secretion of ADH

• The two major stimuli of ADH secretion interact.
  
• Changes in volume reinforce osmolar changes.
• Hypovolemia sensitizes the ADH response to
  hyperosmolarity.

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Plasma Osmolality vs. ADH
The set point of the system is defined as the
plasma osmolality value at which ADH secretion
begins to increase. Above this point slope is
steep reflecting sensitivity of system. Set
point varies from 280 to 290 mOsm/kg H2O
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Blood volume vs. ADH
When blood volume or arterial pressure decreases,
inhibitory input from baroreceptors is over
ridden and ADH secretion is stimulated.
Normally, signals from baroreceptors tonically
inhibit ADH secretion.
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Interaction between osmolar and blood
volume/pressure stimuli
With a decrease in blood volume, set point shifts
to lower osmolality and slope is steeper. During
circulatory collapse kidney continues to conserve
water despite reduction in osmolality. With
increase in blood volume, set point shifts to
higher point and sensitivity is decreased.
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Actions of ADH

• The major action of ADH is on renal cells that
  are responsible for reabsorbing free (osmotically
  unencumbered) water from the glomerular filtrate.
  
• ADH responsive cells line the distal convoluted
  tubules and collecting ducts of the renal
  medulla.
• ADH increases the permeability of these cells to
  water.
• The increase in membrane permeability to water
  permits back diffusion of water along an osmotic
  gradient.
• ADH significantly reduces free-water clearance by
  the kidney

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Actions of ADH

• ADH action in the kidney is mediated by its
  binding to V2 receptors, coupled to adenylate
  cyclase and cAMP production.
• cAMP activates protein kinase A which prompts the
  insertion of water channels into the apical
  membrane of the cell.
• When ADH is removed, the water channels withdraw
  from the membrane and the apical surface of the
  cell becomes impermeable to water once again. .

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Actions of ADH

• This mechanism of shuttling water channels into
  and out of the apical membrane provides a very
  rapid means to control water permeability
• The basolateral membrane of the ductal cells are
  freely permeable to water, so any water that
  enters via the apical membrane exits the cell
  across the basolateral membrane, resulting in the
  net absorption of water from the tubule lumen
  into the peritubular blood.

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Actions of ADH

• Water deprivation stimulates ADH secretion,
  decreases free-water clearance, and enhances
  water conservation.
• ADH and water form a negative feedback loop.

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Inputs reflexly controlling thirst.
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Actions of ADH

• ADH deficiency is caused by destruction or
  dysfunction of the supraoptic and parventricular
  nuclei of the hypothalamus. Inability to produce
  concentrated urine is a hallmark of ADH
  deficiency and is referred to as diabetes
  insipidus.
• ADH also acts on the anterior pituitary to
  stimulate the secretion of ACTH.

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Aldosterone and the mineralocorticoids

• The mineralocorticoid, aldosterone is vital to
  maintaining sodium and potassium balance and
  extracellular fluid volume.
• Aldosterone is an adrenal corticosteroid,
  synthesized and secreted by the adrenal cortex.

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Cross section through the adrenal gland cortex
and medulla
salt
sugar
sex
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Aldosterone

• The adrenal cortex is composed of three major
  zones, differentiated by the histological
  appearance and type of corticosteroid they
  produce.
• The outermost is the zona glomerulosa, is very
  thin and consists of small cells with elongated
  mitochondria.

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Adrenal zones

• The middle zona fasiculata is the widest zone and
  consists of columnar cells that are highly
  vacuolated with numerous lipid droplets.
• These lipid droplets are composed of cholesterol
  esters the substrate for adrenal steroid hormone
  biosynthesis.

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Adrenal zones

• The innermost zona reticularis contains fewer
  lipid droplets than fasiculata cells, but have
  similar mitochondria.
• ACTH has trophic effects on the zona fasiculata
  and reticularis.

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Aldosterone synthesis

• Aldosterone is synthesized and secreted by the
  zona glomerulosa .
• The synthesis of aldosterone from cholesterol to
  corticosterone is identical to the synthesis of
  glucocorticoids in the zona fasiculata.
• The C18 methyl group of corticosterone is
  hydroxylated and converted to an aldehyde
  yielding aldosterone.

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Aldosterone synthesis

• ACTH also stimulates aldosterone synthesis.
• However the ACTH stimulation is more transient
  than the other stimuli and is diminished within
  several days.
• ACTH provides a tonic control of aldosterone
  synthesis.
• In the absence of ACTH, sodium depletion still
  activates renin-angiotensin system to stimulate
  aldosterone synthesis.
• Aldosterone levels fluctuate diurnallyhighest
  concentration being at 8 AM, lowest at 11 PM, in
  parallel to cortisol rhythms.

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Aldosterone synthesis in the adrenal zona
glomerulosa
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Aldosterone function

• The principal function of aldosterone is to
  sustain extracellular fluid volume by conserving
  body sodium.
• Aldosterone is largely secreted in response to
  signals that arise from the kidney when a
  reduction in circulating fluid volume is sensed.
  
• When body sodium is depleted, the fall in
  extracellular fluid and plasma volume decreases
  renal arterial blood flow and pressure.

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Aldosterone action

• Aldosterone binds to the mineralocorticoid
  receptor in target cells and affects
  transcriptional changes typical of steroid
  hormone action.
• The kidney is the major site of mineralocorticoid
  activity.

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Aldosterone action

• Increased blood pressure results from excess
  aldosterone.
• Hypertension is an indirect consequence of sodium
  retention and expansion of extracellular fluid
  volume.

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Regulation of aldosterone secretion Activation
of renin-angiotensin system in response to
hypovolemia is predominant stimulus for
aldosterone synthesis.
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Components of renin-angiotensin-aldosterone system
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Aldosterone and renin-AII

• The juxtaglomerular cells of the kidney respond
  to hypovolemia by secreting renin. Renin acts on
  angiotensinogen (which is secreted by the liver)
  to form angiotensin I which is further cleaved by
  angiotensin converting enzyme (which is secreted
  by the lungs) to angiotensin II.

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Aldosterone

• Angiotensin II acts on the zona glomerulosa to
  stimulate aldosterone synthesis.
• Angiotensin II acts via increased intracellular
  cAMP to stimulate aldosterone synthesis.

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Aldosterone

• ANP reinforces the effects of the
  renin-angiotensin system on aldosterone
  secretion.
• In response to volume expansion, artrial myocytes
  secrete ANP which binds to receptors in the zona
  glomerulosa to inhibit aldosterone synthesis.
• ANP acts via increased intracellular cGMP which
  opposes cAMP and inhibits aldosterone synthesis.
  
• ANP also reduces aldosterone indirectly by
  inhibiting renin release.

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Action of aldosterone on the renal tubule.
Sodium reabsorption from tubular urine into the
tubular cells is stimulated. At the same time,
potassium secretion from the tubular cell into
urine is increased. Na/K-ATPase, and Na
channels work together to increase volume and
pressure, and decrease K.
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Aldosterone mechanism

• The aldosterone-induced proteins serum and
  glucocorticoid-inducible kinase (Sgk),
  corticosteroid hormone-induced factor (CHIF), and
  Kirsten Ras (Ki-Ras) increase the activity and/or
  no. of these transport proteins during the early
  phase of action

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Aldosterone action

• Aldosterone stimulates the active reabsorption of
  sodium from the tubular urine back into the
  nearby capillaries in the distal tubule.
• Water is passively reabsorbed with sodium which
  maintains sodium concentrations at a constant
  level.
• Hence extracellular fluid volume expands in a
  virtually isotonic fashion

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Pathway by which aldosterone secretion and
tubular sodium reabsorption is increased when
plasma volume is decreased
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Aldosterone clears potassium

• Aldosterone facilitates the clearance of
  potassium from the extracellular fluid, and
  potassium stimulates aldosterone synthesisthus
  providing a feedback control mechanism to control
  potassium levels.
• Conversely, potassium depletion lowers
  aldosterone secretion.
• Potassium stimulates aldosterone synthesis by
  depolarizing zona glomerulosa cell membranes to
  stimulate aldosterone synthesis.

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Aldosterone action

• Aldosterone stimulates the active secretion of
  potassium from the tubular cell into the urine.
• Most potassium that is excreted daily results
  from distal tubular secretion.
• Hence aldosterone is critical for disposal of
  daily dietary potassium load at normal plasma
  potassium concentrations.

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Pathway by which an increased potassium intake
induces greater potassium excretion mediated by
aldosterone
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Summary of aldosterone system
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Aldosterone time course of action
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Aldosterone genomic vs. non-genomic
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Aldosterone Action
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Cortisol is at 1000 fold higher concentrations
than aldosterone
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Aldosterone action

• Cortisol binds well to the mineralocorticoid
  receptor and plasma cortisol levels are orders of
  magnitude higher than aldosterone.
• Target tissues for aldosterone are protected from
  glucocorticoid excess via the action of
  11b-hydroxysteroid dehydrogenase, the enzyme that
  converts cortisol to cortisone, a biological
  inactive metabolite.
• Aldosterone is not a substrate for 11b-HSD and
  thus only it can bind to its receptor.

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Integrated control of water and sodium homeostasis

• All of the renal, adrenal, cardiac, vascular,
  brain and endocrine influences on body fluid
  homeostasis converge on kidney as final site of
  regulation
• AII and aldosterone are anti-natiuretic
• Increase Na, result in water retention, increase
  plasma volume and perfusion pressure
• Counter regulator effects of ANP
• Stimulate urinary Na and water excretion
• Inhibit antidiuretic effects of ADH

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Integrated control of water and sodium homeostasis

• Imbalances in any one of these hormones affects
  volume status and plasma osmolar state

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Hyperaldosteronism

• Hyperaldosteronism is known to be caused by
  primary overproduction of aldosterone in
  conditions such as Conns syndrome.
• Conditions of low cardiac output are also known
  to stimulate synthesis of aldosterone.
• Both conditions result in sustained hypertension.
  

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Hyperaldosteronism

• Previously, the hypertension associated with
  hyperaldoseteronism was thought to be mediated
  exclusively through the mineralocorticoid
  receptor located in classical epithelial target
  tissues and result from renal sodium retention.
• We now know that cardiac hypertension associated
  with hyperaldosteronism is far more complex.

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Hyperaldosteronism

• The treatment of patients with severe congestive
  heart failure with spironolactone
  (mineralocorticoid antagonist) produced
  significant reduction in mortality and morbidity,
  despite the very modest diuretic effect of the
  drug.
• The demonstration of local synthesis of
  aldosterone by cardiac and vascular cells
• The demonstration of high affinity, low capacity
  binding proteins for mineralocorticoids in
  cardiac myocytes and vascular endothelial cells.

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Hyperaldosteronism

• The demonstration that 11-beta-hydroxysteroid
  dehydrogenase is expressed in cardiac myocytes.
• The identification of classic mineralocorticoid
  receptor in paraventricular nuclei and amygdala
  in the brain, regions known to be associated with
  salt intake.