L19*-Physiology of the renal system V-Volume regulation Flashcards
(24 cards)
What measurements change when the body loses fluid ?
In most cases like bleeding or sweating, both total extracellular volume and the circulating volume decrease together.
The body doesnt track total extracellular fluid directly, but instead focuses on what ?
The volume of blood is actively circulating and supplying organs.
What is Juxtaglomerular apparatus ? and explain their structure and its function.
JGA is the complex of late distal tubule in association with renal afferent arteriole (both of the same nephron)
- There are granular cells in the afferent(comes in) in the arteriole.
- Thickening of the wall of early distal tubule (or distal TAL), the macula densa(altered or modified cells).
What is the aim of renin-angiotensin-aldosterone system ?
To increase the effective circulating volume.
What 2 things trigger the release of aldosterone ? What does Aldosterone do in general ?
-2 main physiological trigger for aldosterone release are ATII and hyperkalaemia.
- regulator of the ATII action on kidney, maintain the [K+], volume regulation
Describe the steps of the renin-angiotensin system if there is low circulating volume in the body.
Low circulating volume
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low Na+ in distal tubule - key measure of the kidney to measure c.volume
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Macula densa cells detect the low [Na] using NKCC2 cotransporter to detect
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M.d.cells sends chemical signals to Juxtaglomerular cells(granule cells)-are packed with granules.
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sends granules into the circulaiton
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these granules(which are packed with this enzyme) release the enzyme Renin into the circulation
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This Renin can trigger a cascade of signalling changes that affect the whole body.
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Renin acts on a precursor called angiotensinogen(This precursor is produced by liver,adiposites and it is present in the circulation all the time, just ready for Renin to be released).
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Renin then converts/cleaves this Angiotensinogen into angiotensin I.
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Shortet peptide angiotensin I is converted by a second enzyme called angiotensin converting enzyme(in lungs) into Angiotensin II. (this is the main functional hormone with lots of different effects around the body).
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1). causes the release of aldosterone from the adrenal cortex(outer region of the adrenal gland)
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Aldosterone causes increased Na+ reabsorption by distal tubule & collecting duct.
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Body Na+ and volume increases
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Return blood flow to the kidney so increases GFR.
2). Angiotensin II causes the vasoconstriction of efferent arteriole.
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Pressure inside the glomerulus increases
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Return blood flow to the kidney so increases GFR.
3). Angiotensin II also acts on the proximal tubule cells to increase the reabsorption of Na+.
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Pulls back more Na+ and water back into the body, hence increase in the volume in the body
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Return blood flow to the kidney so increases GFR.
People with hypertension(high blood pressure) are given hypertensive drugs. and these drugs work by targeting the inhibition of Renin-Angiotensin system. Give different examples of this inhibition mechanism ?
- ACE inhibitors (captopril, enalopril) > by stopping the production of angiotensin II > stop the Na+ retention > stop volume retention > reduce blood pressure.
- AT1 receptors antagonists ( candesartan, irbesartan ). - antagonists for angiotensin receptors > lower blood pressure
- Aldosterone receptors antagonists - mild diuretic - given to heart failure patients - spironolactone.
- Renin inhibition (aliskiren) - inhibit the Renin enzyme at the start of the cascade to prevent further steps in the cascade.
What is the receptor for Angiotensin II is called and what does it do as a GPCR ?
-main receptor mediating the action of angiotensin II is AT1 receptor, which is found in the periphery and on the smooth muscle cells in blood vessels.
- AT1 receptor is a GPC receptor coupled to Gq protein > increase in IP3 /DAG signalling > increased Ca2+ release from intracellular stores > into the smooth muscle cells and the granule cells of the juxtaglomerular apparatus.
- inhibitors of AT1 receptor, the sartans can bind directly to the receptor and block the effect of the system without having side effect of cough.
What are 4 key actions of Angiotensin II to increase circulating volume ?
- Increase Na+/H+ exchange in the proximal tubule, and hence proximal Na+(increase Na retention) and water reabsorption.
- increase in aldosterone release from the adrenal cortex, which decrease distal Na+ absorption.
- Acts on the brain to stimulate antidiuretic hormone (ADH) to release
- Angiotensin acts on the same brain area to causes thirst so people drink to retain more water.
*Angiotensin is mostly acting on the kidneys to help retain Na+.
* efferent vasoconstriction doesn’t contribute to retaining large volume of water, it actually decrease volume. it helps more to regulate GFR.
Define Haemorrhage and its causes in a sequence of events.
1). i. large volume of blood loss or haemorrhage is sufficient to drop your blood pressure.
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decrease vascular volume -decreased amount of blood available in the circulation
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decreased venous pressure back to the heart
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decreased in cardiac filling
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decreased cardiac output
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decreased circulating volume
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decreased tissue and organ perfusion
ii. this decreased in cardiac output means decrease in blood flow to kidney. this will trigger the renin angiotensin system bc of the low Na+ delivery.
2). i. The decreased in blood pressure is detected by the baro receptor reflex which then increases the sympathetic nervous system activity > this increased renin release.
ii. this decrease in blood pressure is also sensed by renal afferent arteriole, causing a fall in wall tension and causes the release of renin.
Explain the schematic diagram of a renal afferent arteriole.
-there are granule cells located just before the glomerulus.
-renal afferent arterioles have a lot of sympathetic nerves innovating them. when these sympathetic nerves are activated, they do a lot of things like :- 👇
_release renin from granule cells.
-lots of redundancy in the system.
Explain 3 actions of activating sympathetic innervation of afferent arteriole.
- Before the electrical activity gets to the granule cells, sympathetic innervation causes the vasoconstriction and narrowing of the afferent blood vessel. This causes a further fall in the pressure sensed by these cells, bc there is more resistance upstream. This amplifies the fall in wall pressure generated by a fall in blood pressure.
- direct stimulation of renin release from the granule cells.
- Afferent arteriole vasoconstriction drops the glomerulus hydrostatic pressure to the glomerulus and hence lowers the GFR, ultimately decreasing urine output.
What is the key recognised sympathetic transmitter ?
Noradrenaline
On the vascular smooth muscle cells, vasoconstriction of the afferent arteriole is caused by action of what ? and what are they coupled to ?
-caused by action of alpha1-adrenoceptors
-Gq coupled
On the granule cells(the regulation of renin release) are caused by what ? and what are they coupled to ?
-caused by action of beta1-adrenoceptors.
-Gs coupled
-found in both heart and the kidney
Explain the third stimulus to renin release. hint:-with venous pressure
-Fall in blood volume
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the venous pressure falls. Bc venous system is the main source of capacitance(storage) in the circulation.
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causes a fall in the pressure in vasa recta(these are the blood vessels that surround the tubular system in the kidney, which are connected to the venous system)
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hence an increase in the uptake of fluid from the renal interstitial space (from the kidney back to the body-reabsorption)
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greater loss of fluid from the filtrate in the descending limb of Loop of Henle
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this decreases Na+ delivery to the distal tubule which acts as a further stimulus to renin release.
Can you describe any changes to ADH release following(after) haemorrhage ?
Decreased cardiac filling
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activation of baroreceptor reflex
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central actions of ATII all cause an increase in the release of ADH following haemorrhage
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this release leads to an increase in water reabsorption and hence maintenance of circulating volume
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this will however lower osmolality bc this mechanism does NOT retain Na+. Bc initially ADH can cause a fall in [Na+] bc it retains water faster than it retains Na+, sometimes no Na+.
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acute response to haemorrhage will involve hyponatraemia
Describe the interaction between osmoregulation and volume regulation.
-Volume regulation DISTURBS osmoregulation.
-The body accepts decreased osmolality in order to maintain low volume.
Define Osmolarity
concentration of solutes per liter of solution,
osmolarity = focuses on VOLUME
Define Osmolality
measures solutes per kilogram of solvent
Osmolality = focuses on WEIGHT of the solvent
One of the other hormones that contribute to regulating volume is called ANP. What does it stand for ? and how does it regulate volume ?
ANP = Atrial Natriuretic Peptide
-28-amino acid peptide with 17-amino acid ring
-increased venous return > increased atrial filling > increased ANP release.
-ANP travels to the kidney > Acts on ANPa,b receptors(NPR1-2) activating the intrinsic guanylyl cyclase activity(increased cGMP). *****
-there is also a similar peptide produced in the kidney called Urodialtin.
Explain the steps of action of ANP hormone downstream of cGMP into Na+ excretion.
*****Causes a receptor-mediated increase in cGMP levels
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dilates the afferent glomerular arteriole
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increasing GFR
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increases Na+ delivery to the kidney
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decreases Na+/Cl- cotransport activity in the distal tubule
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decreases ENaC and Na+/K+ ATPase activity in the cortical collecting duct
=> net effect => 👆se in renal 5. Na+ excretion in the 6.urine => 5.natri6.uretic
One of the other hormones that contribute to regulating volume is Prostaglandins. and how does it regulate volume ?
- inflammatory mediators
- Both PGE2 and PGI2(prostacyclin) are produced tonically - 2 types of prostaglandins
-Both increase Na+ excretion( ie: are natriuretic)
-If this tonic system is inhibited, this will lead to a fall in prostaglandins and hence Na+ retention.
-In people with normal renal function this effect of NSAIDs may be insignificant, but it becomes more important in renal failure.
One of the other hormones that contribute to regulating volume is Dopamine. and how does it regulate volume ?
-neurotransmitter in the 🧠
-synthesised in the kidney, by the epithelial cells in the proximal tubule, in part from sympathetic nerve terminals.
- Dopamine tonically acts via both D1 receptors(GPCRs coupled to Gs) to 👆se cAMP and 👇se the activity of the Na+/H+ exchanger in the proximal tubule.
👇 leads to….
increased Na+ excretion (ie:natriuretic)
