Osmolality and water regulation Flashcards by Nicholas Hewett

Draw the RAAS system

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What causes the liver to release angiotensinogen

GC
Thyroid hormones
Oestrogen
Angiotensin 2
Inflammation

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Renin trigggered by

Macula densa
Hypotension
B1

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Angiotensin 2 actions

Thirst
Aldosterone and ADH
Drives Na/Cl absorption
Increased SNS repsonsiveness
Direct vasoconstriction in peripheral vessels
Mesangial cell contraction
Efferent and afferent arteriole constriction

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Where is aldosterone released from

zona glomerulosa of the adrenal galnd

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What stimulates aldosterone secretion

Hihg potassium
AT2
ACTH

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How does aldosterone act 3

◦ Increasing sodium reabsorption and potassium secretion in the principal cells of the collecting duct
‣ Increased Na/K exchange basolaterally (induces protein synthesis)
‣ Increased Na facilitated diffusion and K+ facilitated diffusion channels into the apical/luminal membrane
◦ Has effects at all exocrine glands (sweat/salivary) and gut to increase Na reabsorption
◦ K+/H+ exchange in intercalated cells (hydrogen ion secretion)

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What is the main determinant of total Na reabsorption

Aldosterone

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ADH comes from

Posterior pituitary

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ADH release is controlled by

◦ Baroreceptors - fall in plasma volume is detected by cardiac atrial receptors which reduce their afferent firming related to the hypothalamus promoting ADH release (a 5-10% loss of blood volume is required for this to occur) —> it shifts the normal set point for ADH release so lower osmolarity is tolerated as water contributes more to blood volume
◦ Osmoreceptors - hypothalamus senses changed osmotic pressure (a rise promotes ADH secretion) - sensing 2-3% change with 280 mosm/kg as their baseline

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What does ADH cause 4

◦ Increases water permeability of the collecting duct luminal membrane promoting medullary water reabsorption
‣ Inserts protein channels (via cAMP mechanism) into the luminal membrane
◦ Increases urea reabsorption in the inner medullary collecting ducts maintaining contribution of urea to high medullary osmolality
◦ Increases potassium excretion by the cortical collecting duct and sodium reabsorption
◦ At high concentrations = vasoconstrictor reducing renal blood flow and GFR

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ANP or ANF is secreted from where

Stretched atria and great veins

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What is the action of ANP 3

◦ Increases GFR by dilating afferent arteriole but constricting the efferent arteriole (higher filtration pressure and coefficient)
◦ Inhibits renin and aldosterone e release —> increased sodium and water rexcretion
◦ Directly inhibits sodium reabsorption in the collecting ducts

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Renin half life

80 minutes

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Renin is found where

◦ stored by the granular cells of the juxtaglomerular apparatus, which lies close to the glomerulus and distal tubule

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What gives negative feedback to renin release

AT2

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What is the rate limiting step to RAAS

renin

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Half life of angiotensin 2

2 minutes
Cleaved by angiotensinases - tissue peptidases

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What hormones odes the kidney not produce but have actions in the kidney

ADH
Aldosterone
ANP
PTH
Calcitonin

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Triggers for sympathetic nervous system activation

hypotension, hypovolemia, descending central stimuli (emotion), hypoglycaemia

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Sensors that activate the sympathetic nervous system

various baroreceptors in the carotid sinus, aorta and atria and descending input from cortex

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What is the efferent supply to the SNS

sympathetic nervous system (medulla, spinal cord, sympathetic ganglia) - descneding from the rostral ventrolateral medulla via intermediolateral column of the spinal cord
◦ Adrenal glands are innervated by the greater splanchnic nerve - T5-T9
‣ Pre-ganglionic fibres project to the medulla - cholinergic fibres - T7-9

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What is the nerve supplying the adrenal chramffin cells?

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What is the trigger for the RAAS system to be activated?

SNS activation due to stress, hypotension
Renal hypoperfusion
Salt depletion via juxtamedullary feedback

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What is the origin of renin? Location and precurser molecule

37kDa enzyme synthesied in juxtaglomerular cells of the renal cortex
◦ Prorenin precurser is cleaved
◦ Renin remains in storage vesicles of JG cells
◦ Release and serum concentration the rate limiting step

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Renin is synthesised in stimulation or released from storage upon stimulation?

37kDa enzyme synthesied in juxtaglomerular cells of the renal cortex
◦ Prorenin precurser is cleaved
◦ Renin remains in storage vesicles of JG cells
◦ Release and serum concentration the rate limiting step

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What is the rate limiting step to renin production

37kDa enzyme synthesied in juxtaglomerular cells of the renal cortex
◦ Prorenin precurser is cleaved
◦ Renin remains in storage vesicles of JG cells
◦ Release and serum concentration the rate limiting step

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Where does angiotensinogen come from? What happens once it is metabolised?

◦ Large protein
◦ Majority cleaved to create angiotensin 1
◦ byproduct appears useless

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What is angiotensin 1? What action does it have? What is it metabolised by?

Angiotensin 1 - inert decapeptide
◦ Minimal physiological activity - stimulates catecholamine release when in high concentration
◦ Metabolised by ACE

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ACE enzyme is where? What does it do?

◦ Angiotensin 1 breakdown to angiotensin 2
◦ Bradykinin metabolism
◦ In lung tissue or on endothelia in general

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What type fo molecule is angiotensin 2

Octapeptide

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Describe the half life of angiotensin 2? Where is it metabolised?

◦ Short lived molecule degraded rapidly by endothelial angiotensinases with a half life of 30 seconds

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How does systemic hypotension activate the RAAS system?

Baroreceptor response to low BP stimulate sympathetic nervous system –> beta 1 receptor stimulation on JG cells –> renin release (both ciruclating and direct stimulation)
◦ Then, via increasing intracellular cAMP, protein kinase A mediates the degranulation of renin-containing cells. In fact, anything that ends up increasing cAMP (prostaglandin I2 and E2, milrinone, theophylline) will also produce this effect

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How does renal hypoperfusion translate to RAAS system activation?

Renal perfusion pressure related - unclear mechanism/potentially JG cells - MAP of 85 the threshold for renin release

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What is the pressure threshold for renin release

Renal perfusion pressure related - unclear mechanism/potentially JG cells - MAP of 85 the threshold for renin release

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Describe how salt depletion leads to renin release

Decreased salt intake produces the release of renin
* The macula densa is implicated with juxtaglomerular cells releasing renin

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What are the 6 actions of angiotensin 2

◦ Actions
‣ Potent vasoconstrictor - binds to Gq PCR facilitating IP3 mediated increase in IC calcium and vasoconstriction
* 2x as potent as noradrenaline
‣ Increased sensitivity to catecholamines
‣ Stimulating the release of vasopressin
‣ Stimulating the release of aldosterone
‣ Increased Na+/H+ exchange in the proximal tubules, thus sodium retention and acid excretion
‣ Increased sensation of thirst
◦ Summary actions
‣ Increase BV via water and sodium retention
‣ Increased acid excretion
‣ Increase blood pressure via increased PVR

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What downregulates renin release and the RAAS system?

ANP secretion (promotes natriuresis rather than sodium retention)
endothelin (increases blood pressure)
angiotensin II (negative feedback mechanism)
Increased blood flow to the juxtaglomerular cells

Aldosterone is released due to?

◦ Angiotensin 2 mediated - angiotensin 1 receptor on the surface of zona glomerulosa cells (GPCR)
‣ hypovolemia
‣ sodium depletion
◦ hyperkalemia - if potassium concentration changes membrane potential changes and modified calcium channels open mediating synthesis
◦ Direct effect of ACTH

Where is aldosterone released from?

zona glomerulosa cells of the adrenal cortex - steriod hormone (outer area)

Aldosterone release after stimulation is a fast or slow response system?

◦ It is secreted as soon as it is manufactured (no storage) - regulation occurs at its biosynthesis and aldosterone response takes time

Where does aldosterone bind to its receptor?

Intracellular

Time course of aldosterone effect

1 day

Where does aldosterone act?

Numerous targets, but mainly vessel smooth muscle and renal tubule
◦ Mineralocorticoid recepeotr on the cells of the dital tubules increasing expression of luminal sodium channel promoting reabsorption of sodium and excretion of potassium. Does something similar in the colon

What is the effect of aldosterone?

◦ Extracellular fluid expansion - salt and water retention
◦ Potassium excretion
◦ Vasoconstriction - central and peripheral vasopressor effect in addition to BV increase causing BP rise
◦ Cardiac remodelling

What is the stimulus for ADH release?

◦ hypovolemia
◦ Hypotension
◦ Hyperosmolarity
◦ Angiotensin 2
◦ Stress
◦ Drugs - barbituates

Where is ADH release sensed?

baroreceptors and hypothalamic osmoreceptors (OVLT)

Baroreceptors provide their afferent feedback to where?

NTS –> hypothalamus

How is osmolality sensed?

◦ Hypothalamic hyperosmolality sensors - vasopressin secreting magnocellular neurons are themselves osmosensitive by responsiveness blunted by being behind the BBB hence the need for these organs that stick out into the blood stream
‣ Subfornical organ and organum vasculosum of the lamina terminalis (OVLT)
‣ Mechanism of sensing - stretch sensitive barorecepeotrs except mechanosensitive at a cellular level. As osmolality increases or decreases unprotected cells shrink and swell and this is detected by transient receptor potential vanilloid (TRPV) cation channel proteins - non selective cation channel
‣ The sensors are somewhat selective depending on the agent
* Predominantly extracellular osmolar agents have a greater stimulating effect (raised urea or glucose has a reduced response)

What secretes ADH in the hypothalamus?

◦ Magnocellular neurons of the hypothalamus (supraoptic nucleus and paraventricular nucleus) manufactured here and packaged into granules transported by axonal flow into the posterior pituitary where granules opened and secreted into pituitary portal system connecting the anterior and posterior pituitary
◦ Volume effects are more strong than osmolar

Where are the osmolality receptors

‣ Subfornical organ and organum vasculosum of the lamina terminalis (OVLT)

ADH is what type of hormone?

Nonapeptide

What is the half life of ADH

15 minutes

Where is ADH metabolised

Liver and kidney

What are the actions of ADH

Thirst
Vasoconstriction
Water retention

Describe the MOA of a V1 receptor for ADH

‣ V1 = GPCR –> binding activates phospholipase Beta producing IP3 –> IC calcium rise
‣ Interestingly if given to someone not in shock their BP barely rises even with exceptional doses

Where are V1 receptors found for ADH?

V1 receptors throughout most of the systemic circulation, sparing the pulmonary arteries
‣ Density favours splanchnic arteries

What is the emcahnism of effect of ADH in shock?

Relative vasopressin deficiency - receptors all unoccupied whereas all the other vasopressors are saturating their receptors
* Potentiates the effect of noradrenaline
* Inactivates K(ATP) channels in vascular smooth muscle - extensively activated by sepsis contributing to vasoplegia but quiescent in health
* Vasopressin reduces synthesis of inducible nitric oxide synthase stimulated by bacterial agents and cytokines

Describe the mechanism of action fo V2 receptors for ADH

Vasopressin binds to V2 recepeotrs at the cortical and medullary collecting duct basolateral membrane –> adenylyl cyclase –> cAMP –> luminal insertion of aquaporin2 channels –> concentrating urine by allowing water to move out of the duct lumen - works with sodium retention via aldosterone

What triggers natriuretic peptide secretion

Cardiac chamber distension

Where do ANP and BNP come from?

◦ ANP and BNP are both found in atria primarily - in atrial granules and released in response to stretch
‣ BNP is however released in response to ventricular stretch - ANP is not
‣ ANP is preformed, BNP os synthesised as needed
‣ BNP circulates for longer
◦ They have very similar structures

What is the difference between ANP and BNP?

Where do ANP and BNP act? What type of receptors?

Renal tubule, renal afferent arteriole, multiple others
◦ Recepeotrs in renal tubule, vascular smooth msucle, adrenal glands, heart and brain
◦ Membrane spanning recepeotrs attached to intracellular guanylyl cyclase producing cGMP as a secondary messenger –> protein kinase G and phosphodiesterase mediate downstream effects

What is the effect of ANP?

Increased renal blood flow, increased urinary water and sodium excretion
◦ ANP inhibits sodium channel function and Na/K ATPase activity in cortical collecting ducts
◦ ANP also directly inhibits renin release
◦ ANP interferes with vasopressin binding to V2 recepeotrs
◦ ANP vasodilates the AFFERENT arterioles of the kidney

Where are corticosteriods synthesied?

Released in response to stress of various forms, including haemodynamic stress
◦ Produced in the adrenocortical zona fasciculata

How does hydrocortisone help in shock? 3

Act on the myocardium and peripheral circulation to increase catecholamine sensitivity + interfere with nitric oxide mediated vasodilation
Cross-reacti with mineralocorticoid receptors to increase water and sodium retention

What 5 roles does thyroid hormone have in shock?

Peripheral vascular vasodilation, which results in a reflex increase in cardiac output
Increased vascular reactivity to catecholamines
Increased vascular reactivity to angiotensin-II
Increased blood volume, probably for multiple reasons (eg. because RAAS)
Increased synthesis of renin and angiotensinogen

What is normal osmolality?

The normal value is about 285 mOsm/kg

Describe how osmolality is sensed?

Located in the organum vasculosum lamina terminalis (OVLT) and the subfornical organ
These are circumventricular organs and lack a blood-brain barrier
Fenestrated capillaries here expose the osmosensors to the tonicity of the blood
These are mechanoreceptors which detect their own swelling and shrinking in response to changes in tonicity
Increased tonicity results in cell shrinkage and an increase in the rate of firing

What are the circumventricular organs?

Located in the organum vasculosum lamina terminalis (OVLT) and the subfornical organ
These are circumventricular organs and lack a blood-brain barrier
Fenestrated capillaries here expose the osmosensors to the tonicity of the blood
These are mechanoreceptors which detect their own swelling and shrinking in response to changes in tonicity
Increased tonicity results in cell shrinkage and an increase in the rate of firing

What is the central controller for osmolality?

Specifically, the hypothalamic supraoptic nucleus and periventricular nucleus
There, the vasopressin-producing magnocellular neuron cell bodies reside

What is the nromal level of ADH

Vasopressin secretion is minimal below an osmolality of 285 mOsm/kg,
At normal euvolemia, usually the plasma level is 3 pmol/L

What is vasopressin secretion like at 285 mosm/kg

Vasopressin secretion is minimal below an osmolality of 285 mOsm/kg,
At normal euvolemia, usually the plasma level is 3 pmol/L

How does vasopressin respond to increased tonicity? How does this compare to its response to hypotension?

It increases markedly (twentyfold) when extracellular tonicity increases
It increases massively (a thousand fold) in the presence of hypotension

What is the maximum urine concentration

Maximally concentrated urine is about 1200-1400 mOsm/kg

What is minimally concentrated urien

Maximally dilute urine is about 40-50 mOsm/kg

At what concentration and systemic osmolality is maximal urinary concentration acheived

Maximal response occurs at a vasopressin concentration of about 5 pmol/L, corresponding to an extracellular fluid osmolality of around 290 mOsm/kg

What central response to ADH occurs? What is the mechanism of this?

Thurst is the physiological urge to drink (hypothalamic origin)
Hypothalamic neurons project to the anterior cingulate gyrus and mediate thirst sensation as well as behavioural changes leading to a dopaminergic reward-driven pursuit of water
Thirst stimulated by hypertonicity, hypovolaemia, hypotension and angiotensin 2
This increases water intake

How is thirst stimulated and processed?

Thurst is the physiological urge to drink (hypothalamic origin)
Hypothalamic neurons project to the anterior cingulate gyrus and mediate thirst sensation as well as behavioural changes leading to a dopaminergic reward-driven pursuit of water
Thirst stimulated by hypertonicity, hypovolaemia, hypotension and angiotensin 2
This increases water intake

What 3 hormones are involved in total body water regulation indirectly other than ADH? How do they achieve this?

Renin-angiotensin system
◦ Angiotensin II increases Na+/H+ exchange in the proximal tubules, thus sodium retention, and thus water retention
◦ It also stimulates the release of vasopressin and increases the sensation of thirst
Aldosterone
◦ Release is stimulated by angiotensin II
◦ Aldosterone interacts with a mineralocorticoid receptor in the cells of the distal tubule and increases the expression of a luminal sodium channel (eNAC) which then promotes the reabsorption of sodium, and therefore of water
Natruretic peptides
◦ Decreased ANP and BNP secretion resulting from decreased atrial stretch increases the retention of sodium and water

Using a stimulus, sensor, afferent, efferent, effector and effect model explain regulation of tonciity

Regulation of extracellular fluid tonicity, that can also result in changes to extracellular fluid volume as a byproduct:
◦ Stimulus: increase in tonicity of ~ 1%
◦ Sensor: the subfornical organ and organum vasculosum lamina terminalis, small circumventricular organs that do not have a blood-brain barrier and are therefore sensitive to changes in tonicity (not osmolality- they seem to deprioritise ineffective osmoles)
◦ Afferent: fibres from nucleus of the solitary tract and from abovementioned osmoreceptors
◦ Efferent: vasopressin secretion from the posterior pituitary and binding to renal V2 receptors
◦ Effectors: cortical collecting duct cells
◦ Effect: Increased aquaporin expression and increased water permeability of the cortical collecting duct cells, with the result being increased water reabsorption

What are the potential sensors of extracellular volume?

‣ carotid and aortic baroreceptors (blood pressure)
‣ renal medulla (renal perfusion)
‣ macula densa (renal sodium delivery)
‣ zona glomerulosa of the adrenal glands (sodium concentration, which is affected by extracellular fluid volume changes indirectly, as the result of water retention by vasopressin, the release of which is stimulated by hypotension)
‣ Atrial and ventricular mechanoreceptors

What are the afferents of efferents of regulating extracellular volume?

◦ Afferents:
‣ Blood pressure: glossopharyngeal and vagus nerves
‣ Renal perfusion: intrinsic renal sensors (which remain to be identified)
‣ Sodium: sensors in the macula densa and zoina glomerulosa
◦ Efferents:
‣ Renin
‣ Angiotensin-II
‣ Aldosterone
‣ Natriuretic peptides
‣ Vasopressin

What % of extracellular fluid osmolality is contributed by sodium?

86%

What is the first and second Gibbs Donnan relationship that governs the movement of fluid between intracellular and extracellular fluid compartments

◦ Gibbs Donnan equilibrium - cells contain significant colloids with proteins and inorganic phosphates which are not diffusable setting up a Gibbs Donnan effect across the membrane attracting fluid –> if unregulated cellular swelling would be marked.
‣ Over longer timeframes (days), the intracellular osmolality can also be adjusted by intracellular generation of idiogenic osmoles as intracellular fluid osmolality and electrolyte concentration is vital to excitable membrane function
◦ Second Gibbs Donnan relationship –> The main mechanism that determines the balance of volume between the intracellular and extracellular compartments is the equilibrium of osmolality between these compartments
‣ The most important osmotic agent which contributes to this equilibrium is extracellular sodium, mainly because it is under tight homeostatic control - low membrane permeability AND active extrusion by sodium pump
* It also constitutes with its attendant anions 86% of osmolality fo extracellulr fluid and attracts extra anions extracelluarly

What is the water permeability of most cell membranes?

◦ Lipid bilayer membranes have limited water permeability, about 1μm/s
‣ This reflects the partial solubility of water in lipids
‣ Total water movement between intracellular and extracellular fluid compartments is still relatively rapid, as the total membrane surface is very thin, there’s a huge quantity of water (concentration high) and has a vast surface area (Fick’s law )

What cells are totally impermeable to water?

◦ Membrane permeability to water differs between cells, because of the presence of embedded proteins and lipids which change the membrane properties (eg. aquaporins, or lipid rafts)
‣ The only cells totally impermeable are
* Bladder epithelium
* Ascending limb LOH - to allow hypotonic fluid to enter distal tubule
* Cortical and medullary collecting ducts in absence of ADH to produce hypotonic urine

What is the maximal permeability of a cell to water? Where does this occur

◦ The range of permeabilities can span from almost zero (no permeability whatsoever, eg. bladder urothelium) to 600 µm/s (collecting duct in the absence of vasopressin)

What is the sensitivity of osmoreceptors like?

These are extremely sensitive and can detect a change of less than 3 mOsm/kg (1%)
◦ Swelling of cell = slowing of firing
◦ Shrinkage of cell = more firing

How are vasopressin and thirst related?

x* Osmosensor neurons, particularly those of the subfornical organ, project to the anterior cingulate gyrus which is responsible for the conscious perception of thirst, and which then leads to water-seeking and drinking behaviour
* These same neurons also project to the vasopressin-producing neurons of the hypothalamus
* Increased extracellular tonicity stimulates both, and the subjective sensation of thirst increases in its intensity in parallel to the rate of vasopressin secretion.
* This generates an association between vasopressin levels and thirst, but they are not causally connected, and a vasopressin infusion will not make your patient thirsty.

What is normal ADH level? What is the range of concentrations within normal physiological limits of osmolality? What effects does this correealte with

Normal vasopressin levels are 3-4 pg/ml
At extracellular osmolality of about 290 mOsm/kg (vasopressin levels of 4-5 pg/ml), renal concentration of urine is maximal (1200 mOsm/kg)
◦ The vasopressin level continues rising however well beyond this - has non renal effects
Below extracellular osmolality of about 285 mOsm/kg, vasopressin levels become undetectable and maximally dilute urine is produced (40-50 mOsm/kg)
Linear increase in vasopressin with osmolality

What relationship does vasopressin have with osmolaliuty

Normal vasopressin levels are 3-4 pg/ml
At extracellular osmolality of about 290 mOsm/kg (vasopressin levels of 4-5 pg/ml), renal concentration of urine is maximal (1200 mOsm/kg)
◦ The vasopressin level continues rising however well beyond this - has non renal effects
Below extracellular osmolality of about 285 mOsm/kg, vasopressin levels become undetectable and maximally dilute urine is produced (40-50 mOsm/kg)
Linear increase in vasopressin with osmolality

How is ADH related to hypovolaemia?

Hypovolemia and hypotension are highly potent stimuli for vasopressin release
Levels up to 1000 pg/ml can result from shock and haemorrhage - far greater than sepsis
Baroreceptor stimulation overrides osmoregulation; water retention will still occur even if the extracellular fluid is hypotonic
◦ Threshold for stimulation according to Brandis is 10% change in intravascular volume
Practically this is seen when
◦ The result is an abundance of vasopressin even though the extracellular tonicity may be desperately low. We see evidence of this in hypovolemic hyponatremia, where the patient is depleted of water as well as salt. As volume is restored, the influence of the baroreceptors on the tonicity response is removed, vasopressin secretion is turned off, and a profound polyuria can suddenly occur, potentially producing a disastrously rapid self-correction of sodium.

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Osmolality and water regulation Flashcards

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