Week 4 Flashcards
Osmolality revision
All body fluids except the interstitial space of the renal medulla are essentially at 285mOsm.kg-1
-this is due balance of both water and solutes (mostly Na+)
Intake: drinking (1.5L not just pure water), food (0.5L), metabolism (0.4L; the oxidation of food)
Losses: respiration (0.4L), insensible water loss through the skin (insensible perspiration; 0.4l), faeces (0.1L but highly variable), urine 1.5l
So balance is about 2.4L.day-1
Regarding the oxidation of food consider glucose C6H12O6 +6O2-> 6CO2 +6H2O
Sweating can be up to 4l.day-1
Control of ADH release
ADH is the main hormone involved in regulation of osmolality
Mechanism of release
-Osmolality is detected in the anterioventral third ventricle (AV3V) region
-this is where the blood brain barrier is incomplete- so osmolality in this region is closer to osmolality of plasma
-AV3V neurones project to the supraoptic and paraventricular parts of the hypothalamus
- they respond to an increase in osmolality by increasing the release of ADH from the posterior pituitary (neurohypophysis)
ADH (vasopressin) is synthesised in the cell bodies as a prehormone cleaved as it descends to the pituitary and prior to release
ADH is coreleased with its carrier peptide neurophysin (function unknown)
ADH is unstable in the circulation and so only has a half life for 10mins
ADH mechanism of action
After its release it travels to the V2 receptors on the cortical collecting ducts, basolateral membrane
- the V2 receptors are linked to adenylyl cyclase
-this allows for the activation of PKA resulting in protein phosphorylation and the exocytosis of vesicles containing AQP2
-the purpose of this ‘constitutive’ exocytosis is not to release a substance into the lumen but to change the content of the membrane
ADH also binds to V1 receptors:
-V1 receptors are mainly on the smooth muscle cells of veins causing vasoconstriction (or venoconstriction)
- for the V1 receptors the signalling pathway is through PLC (IP3/DAG)
Cellular pathways regulating AQP2 on the apical membrane
ADH binds to V2 receptor on basolateral membrane activates cAMP through adenylyl cyclase pathway
CAMP-> nucleus transcription-> AQP2 synthesis via vesicles containing AQP2 which then insert themselves onto apical membrane
CAMP activates PKA which also causes insertion of AQP2 on apical membrane
Structural organisation of AQP1
AQP1 is a multi subunit oligomer organised as a tetramer of 4 identical polypeptide subunits (channels)
With a large glycan attached to only one
Pore for water found through centre of each subunit
Oxytocin
Hypothesis: oxytocin increases thirst
What we know:
-oxytocin is a key trigger of the milk let down reflex during breast feeding
-oxytocin is also an agonist at V1 and V2 receptors
-breast feeding commonly triggers thirst
But is there a causative link?
Thirst
Inadequate water intake causes an increase in osmolality of the plasma
Osmolality is detected in the anteroventral 3rd ventricle AV3V region (same for the regulation of ADH release)
AV3V neurones project to the median preoptic area of the hypothalamus which increases thirst
So ADH release and thirst seem to happen at the same time
response to decreased Osmolality
The response is activated very frequently as we tend to ‘binge drink’
Decreased Osmolality causes a suppression of ADH release and suppression of thirst
This suggest correctly that there is tonic ADH release
-theres a basal level of ADH
Effect of osmolality on the circulating [ADH] (and ADH secretion)
Under normal physiological conditions (Osmolality of 285mosm/kg) we have a basal rate of ADH release
The existence of basal release we can have bi-directional control of renal function:
-when Osmolality is high ADH secretion increases to cause water retention in kidney
-when osmolality is low, ADH secretion falls and we tend to have a diuresis
NB: this is a very steep relationship, osmolality does not have to shift very much before ADH is switched off
So when people drink large quantities of water-> the Osmolality drops-> ADH secretion suppressed -> diuresis is induced
Because ADH has a short half life rate of ADH production proportional the concentration in the plasma
-this is because any change in rate of production is quickly translated to change in concentration
-so a change in ADH concentration implies a change is ADH production
[ADH] is proportional to the rate of secretion at equilibrium with first order clearance
Response to ADH
Maximal ADH:
- urine production rate is low 300-400 ml/day
-we produce a concentrated urine -> Osmolality= 1400mOsm.kg-1
No ADH:
-urine production rate is high 25L/day
-urine is not very concentrated-> osmolality 60-90 mOsm.kg-1
Drinking sea water
Sea water has a osmolality of 2000 mOsm/kg
If we drink 1kg of sea water we are consuming 1kg of water and 2000mOsm of solute molecules
So to clear the 2000mosm of salt in 1kg of sea water we will require:
-2000mosm/1400mosm.kg-1= 1.4l of water to clear
This implies that drinking sea water will cause dehydration
Neonates can only produce urine with a maximum osmolality of 500 mosm.kg-1 (due to underdeveloped kidneys)
-thats why its very important not to make infant formula feeds too concentrated (high osmolality)-> lead to dehydration
The problem is even worse if the fluid consumed is metabolised to increase number of osmolytes
Aside: while incorrect formula feed preparation was a real problem in the 70s it’s rare now a bigger clinical problem is “ breast feeding associated hypernatraemic dehydration
Salt loading
Max urine osmolality is 1400 mosm.kg-1
Suppose you need to secrete 1400mosm of solute in a day this means that you need at least 1kg of water i.e about 1L of urine this means that solute and water excretion can only be regulated over a finite range
So if you had a high daily solute load of 2800mOsm that would require a minimum urine production of 2l/day
The ability to concentrate urine in other animals
Many animals such as rats can concentrate urine to a higher Osmolality
For example in rats urine concentrations can reach 3000mOsm/kg this implies that rats can drink sea water
Not all dietary osmolytes are equal
The dominant osmolytes in the circulation are Na+ and Cl- but they aren’t the dominant osmolytes ingested
Much larger quantities of carbohydrates, fat and proteins are consumed than the mass of:
-potassium 3.5g
-sodium 2.4g
Excluding fat all of these intakes reach the circulation from the gut in a water soluble form and therefore contributes osmolytes which can affect osmolality
Fates post absorption
The carbohydrates converted to simple sugars are transported into cells so don’t contribute significant to osmolality except in the context of diabetes mellitus C6H12O6 is oxidised to CO2 (rapidly excreted) and water only transiently increase osmolality
Similarly proteins are broken down into amino acids which are rapidly taken up by cells so plasma change in osmolality is small.
The nitrogen can be removed through urea (circulating concentration 2.5-6.7mM) which has a high renal clearance so while flux is high the contribution to Osmolality is low
However sodium stays in extracellular space for long time not taken up by cells in large quantities-> have the greatest effect on osmolality
