Transcript 5104_a4

Physiology
of
vasopressin
secretion:
THE
antidiuretic
hormone
(ADH)
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.
Dehydration increases plasma osmolality and is a
powerful stimulus to trigger vasopressin release
Hypothalamus
OSMORECEPTORS
VP
DEHYDRATION
WATER CONSERVATION
Peripheral Vasopressin Receptors
V1 (vascular smooth muscle) cause vasoconstriction;
V2 (kidney collecting tubules) causing antidiuresis
Primary action of ADH: antidiuresis
• In the kidney, ADH binds to V2 type receptors on
the peritubular (serosal) surface of cells of the
distal convoluted tubules and medullary
collecting ducts.
• Acting through adenylate cyclase/cAMP, ADH
induces production and insertion of
AQUAPORIN 2 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).
Kidney Distal Tubule Cell
Aquaporin-2
H2O
H2O
H2O
Adenylyl cyclase
Gs protein
Vasopressin
V2 vasopressin
receptor
Basolateral
membrane
Phosphorylates
Aquaporin-2
subunits in
vesicles bound to
microtubular
subunits
cAMP
H2O
ADP
ATP
PKA
(active)
cAMP
cAMP
PKA cAMP
(inactive) cAMP
ATP
Cytoplasm
H2O
H2O
H2O
H2O
Apical
membrane
Protein Kinase A Pathway
Nephrogenic Diabetes Insipidus:
defective receptor causes ADH resistance
Figure 4. ADH biochemical action in the distal renal tubule via activation of PKA
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.
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
ADH and
plasma
osmolality
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.
Hypothalamus, posterior pituitary and ADH
secretion– connection with baroreceptors
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.
So what happens if you:
-secrete too much ADH?
Syndrome of inappropriate ADH secretion
• Features: inappropriately low plasma
osmolality vs urine osmolality; low serum
sodium, excessive kidney sodium
excretion.
• Causes: (multiple) e.g Carcinomas, CNS
injury, postoperative…
• Rx: restrict water intake, correct Na levels
So what happens if you:
-Cannot make ADH?
-Unable to secrete ADH?
-Have non-functional receptors?
You have a condition known as
Diabetes Insipidus
• Polydipsia
• Polyuria
Lack of vasopressin or VP receptor
dysfunction results in a condition known
as Diabetes Insipidus (DI)
[also known as water diabetes, often mistaken for
diabetes mellitus or sugar diabetes].
Causes:
Neurogenic (central, hypothalamic, pituitary)
Nephrogenic (vasopressin resistant)
Gestagenic (gestational, during pregnancy)
Dipsogenic (excessive water intake)
Physiological and behavioural mechanisms
mediate responses to a “hydromineral” challenge
to homeostasis
Osmodetectors are located in the gastrointestinal tract, and in the brain. In the
brain, the pioneering studies of Verney and colleagues (~1945) identified the area
along the base of the third ventricle as critical for sensing and responding (release
of ADH) with antidiuresis to a hyperosmotic challenge.
Currently, the focus of osmoreception is on neurons located in the hypothalamic
supraoptic nucleus (SON) and neurons in the organum vasculosum lamina
terminalis (OVLT) situated at the base of the wall of the anterior third ventricle.
Beyond Verney: current vision of the
central osmoreceptor complex
Osmoreceptors do not act alone!
Components of a central neural circuitry likely to be engaged
by a hyperosmotic challenge e.g. dehydration
Electrophysiology of osmoreceptive neurons
in-vivo and in-vitro models
In-vivo electrophysiology: firing patterns +
transient inhibition to baroreceptor activation
are unique to vasopressin-secreting neurons
Magnocellular neurons respond to the challenge: profile of
their activity at the cellular level
In vivo extracellular recordings from putative vasopressin- and oxytocin-secreting neurons reveal
increased firing by a hypertonic challenge (ip 1% NaCl) and decreased firing by a hypotonic challenge
(ip distilled H2O) (from Hussy et al, 2000)
In-vitro electrophysiolgy: intracellular
recordings in brain slices /dissociated cells
Coronal section of rat hypothalamus:
profile of the supraoptic, paraventricular and
suprachiasmatic nuclei in the same slice
SON neurons are intrinsically osmosensitive:
A) in vitro patch clamp recording displays cell firing changes to osmotic stimuli;
B) schema to reflect how excitability is regulated by mechanosensitive stretchinactivated cationoc channels; C) Osmosensitivity of the cationic conductance
Glia contribute to osmoresponsivity:
Schema portrays how taurine released from astrocytic processes in the vicinity of
SON neurons provide a complementary contribution to regulating SON excitability
and firing in different osmotic conditions (from Hussy et al., 2000)
Osmoreception in magnocellular neurons (SON,
OVLT) may involve 4 distinct mechanisms
• ↑ osmolality promotes astrocytes to
release taurine which acts via glycine
receptors to enhance inhibitory
chloride influx.
• ↕ changes in cell volume modulate
stretch-inactivated channels
• excitatory sensory inputs may carry
information from other osmoreceptors
• ↑ osmotic challenges may result in
genomic changes e.g. insertion of
non-inactivating sodium channels that
may amplify induced voltage changes
produced by other mechanisms (Voisin &
Bourque, 2002)
Prolonged hyperosmotic challenges change sodium channel
expression in SON neurons (Tanaka et al., PNAS, 1999)
•
a,b) In-situ hybridization to detect
mRNA encoding for αII (upper) and
Na6 (lower) channels. 7 days of salt
loading (2% NaCl) dramatically
increases mRNA vs controls,
confirmed in optical density
measurement.
•
c,d) Fast (upper) and slow (lower)
tetrodotoxin-sensitive Na+ currents
evoked in isolated SON neurons by
voltage steps or slow voltage ramps
reveal enhanced currents, confirmed
in fast and slow current densities
measured from several neurons vs
controls.