Hormonal control of water excretion

Question 1

Regulating osmolality and volume

Answer 1

• Osmolality is regulated by water intave vs excretion (ADH)
• ECFV is regulated by varying Na reabsorption (RAAS)
• These two are usually active at the same time (decreased Posm increases ADH, and decreased ECFV increases RAAS)
• Ex: CHF leads to low perfusion (effective circulating volume) which leads to release of RAAS and ADH (RAAS also stimulates ADH release)
• This causes reabsorption of Na and H2O, leading to concentrated urine (increased Uosm) and a reduced urine volume
• Also leads to expanded ECF and hyponatremia

Question 2

Changes in Posm

Answer 2

• Reflect problems with water intake or ADH regulation
• Too much water leads to hyponatremia-> cerebral edema (cells swell)
• Too little water leads to hypernatremia-> cerebral constriction (cells shrink)
• When plasma ADH is high (fluid restricted) there will be small amounts of concentrated urine
• When plasma ADH is low (fluid excess) there will be large amounts of dilute urine

Question 3

Regulation of ADH release

Answer 3

• Usual stimulus is increased Posm (as little as 3 mOsm), which causes osmoreceptors in hypothalamus to send signals to PVN/SON to tell post pituitary to release ADH
• ADH release is very sensitive to Posm, but can also be due to changes in blood volume (or effective circulating volume)
• When blood volume decreases by 10% the stretch receptors in atria and arterial baroreceptors also trigger ADH release
• This can be stimulated by low effective circulating volume (CHF, cirrhosis) even if there isn’t a real volume depletion
• Important to note that while ADH is more sensitive to Posm, higher levels of ADH are achieved when it is released due to low blood volume
• Other factors can stimulate ADH release: pain, stress, etc

Question 4

Actions of ADH 1

Answer 4

• Often ADH and RAAS are regulated in concert to restore lost salt and volume (hemorrhage, sweating, fasting)
• ADH stimulates thirst so you drink water, which is critical in order to rectify the osmolality/volume status
• ADH binds to 2 different receptors in the kidneys
• V2 receptor has high affinity for ADH thus will bind at low ADH levels
• This receptor increase cAMP which increases H2O and urea permeability in the CD and Na transport in TAL and DCT

Question 5

Actions of ADH 2

Answer 5

• The gradients of urea and Na in the ISF lead to retention of water to concentrate the urine and dilute the plasma
• V1 receptors have low affinity and thus only bind ADH when its levels are high
• They are located in arterioles and cause vasoconstriction, since the only times when ADH are high enough to activate them are during blood loss, dehydration, and thus hypotension

Question 6

Stimulation of V1 vs V2 receptors

Answer 6

• Only high levels of ADH will cause V1 and V2 activation
• This usually happens when there is large change in blood volume, w/o a change in osmolality (hemorrhage, cholera)
• ADH then causes retention of water via V2 and prevents fall of BP via V1
• Small changes of osmolality will not cause ADH release to the degree that is required to activate V1

Question 7

Epithelial effect of ADH from V2 1

Answer 7

• In TAL and DCT ADH increases Na reabsorption thru NKCC (TAL) and NCC (DCT), as well as increasing K channels and basolateral Cl channels
• ADH activates COX for PG synthesis to counteract and buffer the ADH response
• Activates AC to generate cAMP for protein kinases
• In the CD epithelia there is an increase in AQP2 channels in the apical membrane
• This is b/c the activation of protein kinase which phosphorylate AQP2 in their recycling vesicles, and this phosphorylation allows the channels to interact w/ tropomyosin to destabilize the actin barrier than normally prevents their insertion

Question 8

Epithelial effect of ADH from V2 2

Answer 8

• Therefore AQP2 is unregulated in the apical membrane and water reabsorption capacity is increased
• Water leaves the basolateral membrane via AQP3/4 which are constitutively expressed
• Note: AQP1 (in PT) is not expressed in CD and thus not regulated by ADH
• ADH also increases the activity of type 1 urea transporters (UT1) in the IMCD cells by phosphorylating UT1, which allows for more urea transport/recycling increasing the ISF gradient for more water reabsorption and urinary concentration

Question 9

VSMC effect of ADH from V1

Answer 9

• When ADH levels are high (blood loss, volume depletion), the V1 receptors in VSMCs stimulate a rise in IC Ca and lead to vasoconstriction
• This prevents a fall in BP and preserves perfusion pressure

Question 10

Stimulating thirst

Answer 10

• Increases in Posm is a strong stimulus for water intake
• Profound volume contraction can provoke thirst (ATII acting on SFO- no BBB in this region)
• Increased BP can inhibit thirst
• Gastric Na loading can stimulate thirst before and increase in Posm
• ADH released correlated with (but may not cause) thirst