Endocrine Physiology
lecture 4
Dale Buchanan Hales, PhD
Department of Physiology & Biophysics
Antidiuretic hormone and the
mineralcorticoids
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
Hypothalamus and posterior
pituitary
Structure of ADH
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
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.
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
ADH increases renal tubular
absorption of water
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).
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
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.
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
Pathway by which
ADH secretion is
lowered and water
excretion raised
when excess water is
ingested
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.
ADH and
plasma
osmolality
Secretion of ADH—hemodynamic
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.
ADH and
blood
pressure
Pathway by which ADH
secretion and tubular
permeability to water is
increased when plasma
volume decreases
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
Hypothalamus, posterior pituitary and ADH
secretion– connection with baroreceptors
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.
Secretion of ADH
• The two major stimuli of ADH secretion
interact.
• Changes in volume reinforce osmolar
changes.
• Hypovolemia sensitizes the ADH response
to hyperosmolarity.
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
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.
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.
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
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. .
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.
Actions of ADH
• Water deprivation stimulates ADH
secretion, decreases free-water clearance,
and enhances water conservation.
• ADH and water form a negative feedback
loop.
Inputs reflexly controlling thirst.
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.
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.
Cross section through the adrenal
gland– cortex and medulla
salt
sugar
sex
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.
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.
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.
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.
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 diurnally—highest
concentration being at 8 AM, lowest at 11 PM, in
parallel to cortisol rhythms.
Aldosterone
synthesis in
the adrenal
zona
glomerulosa
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.
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.
Aldosterone action
• Increased blood pressure results from
excess aldosterone.
• Hypertension is an indirect consequence of
sodium retention and expansion of
extracellular fluid volume.
Regulation of
aldosterone
secretion:
Activation of reninangiotensin system
in response to
hypovolemia is
predominant
stimulus for
aldosterone
synthesis.
Components of
reninangiotensinaldosterone
system
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.
Aldosterone
• Angiotensin II acts on the zona
glomerulosa to stimulate aldosterone
synthesis.
• Angiotensin II acts via increased
intracellular cAMP to stimulate aldosterone
synthesis.
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.
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+.
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
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
Pathway by which
aldosterone secretion
and tubular sodium
reabsorption is
increased when plasma
volume is decreased
Aldosterone clears potassium
• Aldosterone facilitates the clearance of potassium
from the extracellular fluid, and potassium
stimulates aldosterone synthesis—thus 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.
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.
Pathway by which
an increased
potassium intake
induces greater
potassium excretion
mediated by
aldosterone
Summary of
aldosterone
system
Aldosterone time course of action
Aldosterone genomic vs. non-genomic
Aldosterone Action
Cortisol is at 1000 fold higher
concentrations than aldosterone
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 11bhydroxysteroid 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.
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
Integrated control of water and
sodium homeostasis
• Imbalances in any one of these hormones
affects volume status and plasma osmolar
state
Hyperaldosteronism
• Hyperaldosteronism is known to be caused
by primary overproduction of aldosterone in
conditions such as Conn’s syndrome.
• Conditions of low cardiac output are also
known to stimulate synthesis of aldosterone.
• Both conditions result in sustained
hypertension.
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.
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.
Hyperaldosteronism
• The demonstration that 11-betahydroxysteroid 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.