Volume regulation Flashcards
What is the effective circulating volume?
The body can’t measure the total extracellular water content easily.
The effective circulating volume is instead regulated.
What is the relationship of actual and effective circulating volume?
Actual extracellular volume and effective circulating volume change together during a haemorrhage, sweating etc.
But in heart failure, the heart is not appropriately circulating blood, the kidney detects this, so water is retained.
What is the juxtaglomerular apparatus?
The complex of late distal tubule in association with the afferent arteriole of the same nephron.
There are juxtaglomerular granular cells in the afferent arteriole, which sense changes in the distal tubule, and can regulate its diameter to change hydrostatic pressure and filtration, and also secrete renin.
What are the cells of the juxtaglomerular apparatus?
The walls of the distal tubule are modified and thickened to form macula densa cells.
The cells around the blood vessels are also altered to be juxtaglomerular cells.
These cells come together to regulate volume.
What is the role of the juxtaglomerular apparatus?
Regulates the renin-angiotensin system, which aims to increase the effective circulating volume.
How is the juxta glomerulus stimulated?
When there is low circulating volume, little Na+ is delivered to the glomerulus.
So there is low Na+ concentration in the distal tubule.
The macula densa cells detect this using NKCC (Na-K-Cl cotransporter)
What do the macula densa cells do?
They signal to the juxtaglomerular cells that are next to them.
The juxtaglomerular cells release granules into circulation, which contain the enzyme renin.
Renin triggers the renin-angiotensin system.
How does renin activate angiotensin?
Renin acts on the precursor angiotensinogen, which is present in circulation and produced by the liver.
Renin cleaves angiotensinogen to form angiotensin I.
Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme (ACE), found in the lungs.
Angiotensin II generally increase GFR and retains Na+.
What is the indirect action of angiotensin II?
Angiotensin II acts on adrenal gland above the kidney to release aldosterone hormone from its cortex (outer region).
Aldosterone acts in the distal tubule and collecting duct to increase Na+ reabsorption.
As Na+ and water are reabsorbed, it increases the blood volume, and increases blood flow to the kidney.
What is the direct action of angiotensin II?
Angiotensin II acts on the efferent arteriole to cause vasoconstriction, this increases the pressure in the glomerulus, and increases GFR.
It also acts on the proximal tubule to increase Na+ reabsorption, and therefore water reabsorption, and so increases blood volume.
Why is the Renin Angiotensin system inhibited?
Used to treat hypertension (high BP).
Anti-hypertensive drugs target the mechanism mediated by ATII.
Forms of inhibition:
ACE inhibitors.
AT1 receptor antagonists
Aldosterone receptor antagonists
Renin inhibition, by aliskiren.
What are ACE inhibitors?
Prevent conversion of angiotensin I to angiotensin II.
This stops Na+ retention, and therefore volume retention, so BP is reduced because there is less fluid exerting pressure on the blood vessel walls.
e.g. captopril, enalapril
What are AT1 receptor antagonists?
Drugs target the ATI receptors, so ATII is not formed.
e.g. candesartan, irbesartan.
What are aldosterone receptor antagonists?
Antagonists block the aldosterone receptor, which stops some of the renin angiotensin system, and lowers BP.
e.g. spironolactone, which is a mild diuretic and used in heart failure when volume is retained.
What is the ATI receptor?
Main receptor for ATII.
A GPCR coupled through Gq.
This increases IP3/DAG signalling, so increases Ca2+ release from intracellular stores.
e.g. AT1 receptors found on smooth muscle cells (of blood vessels) and the granule cells of the juxtaglomerular apparatus, which causes contraction.
What are ATI receptor inhibitors?
‘Sartans’ act directly on the receptor, to block ATII, and the effect of the renin angiotensin system.
Better than ACE inhibitors as do not cause a cough side effect.
ACE are involved in bradykinin, so ACE inhibitors cause excess bradykinin, causing a cough.
Used to treat hypertension.
How does angiotensin II increase circulating volume?
Increase Na+/H+ exchange in the proximal tubule, and hence proximal Na+ and water absorption.
Increase in aldosterone release from the adrenal cortex, which increases distal Na+ absorption.
Cause ADH release, by acting on the brain, and retain water.
Causes thirst, by acting on the hypothalamus.
What is efferent arteriole vasoconstriction?
Efferent arteriole vasoconstriction helps to maintain the GFR, rather than volume.
What is a haemorrhage?
Large amount of bleeding, sufficient to drop blood pressure.
Decreased vascular volume, decreased venous pressure, decreased cardiac filling, decreased cardiac output, decreased circulating volume - decreased tissue and organ perfusion.
What does a haemorrhage do on the kidneys?
Decrease in blood pressure, decreases blood flow to the kidneys, which increases sympathetic activity.
The nerves act on the transmitter on the granule cells to increase renin release.
How does the afferent arteriole respond to a haemorrhage?
The decrease in blood pressure is sensed by the afferent arteriole.
The decrease causes a fall in wall tension and causes the release of renin.
The baroreceptor reflex increases sympathetic nervous system activity.
What is the effect of activating sympathetic innervation of afferent arteriole?
Vasoconstriction upstream of granule cells, which causes a further fall in the pressure, which is sensed by granule cells, and hence amplifies the fall in wall pressure generated by a fall in blood pressure. Generates renin release.
Direct stimulation of renin release from the granule cells.
Afferent arteriole vasoconstriction drops glomerular hydrostatic pressure to the glomerulus and so lowers GFR.
What is the effect of sympathetic transmission in the afferent arteriole?
Sympathetic nerves mainly release neurotransmitter noradrenaline.
Smooth muscle cell vasoconstriction on afferent arteriole, is regulated by a1-adrenoceptors, which are Gq coupled.
On granule cells, (regulate renin release) have b1-adrenoceptors, and are Gs coupled.
B1 receptors are normally associated with the heart, but act in the kidney.
How does venous pressure stimulate renin release?
Blood volume falls, venous pressure falls, which decreases the pressure in the vasa recta, so increases the uptake of fluid from the renal interstitial space.
This means a greater loss of fluid from the filtrate, especially in the descending limb of the Loop of Henle.
This decreases Na+ to the distal tubule, which stimulates renin release.
