Blood Pressure and the Kidney Flashcards
Relationship Between Salt Intake (Na+) and Blood Pressure
Why do yanomamo see little increase in BP as they age?
The graph relates where a person may live and their age, to their average systolic BP. We can see that at the bottom we have the Yanomamo Indians from Venezuela, with every other group we see as they age, their BP increases, but the Yanomamo BP is very similar throughout their life.
They do not see this age-related increase in BP, the reason for this is due to their low salt diet, in comparison the western diet has very salty diet.
The Yanomamo eat fruit, nuts etc. so have average BP of 100/60, consuming around 10-20mmol sodium per day.
We can see from this that the higher Na+ intake/excretion leads to a higher blood pressure, there is this link between salt and BP.
Why are Na+ levels linked to BP?
What is the major electrolyte in ECFV?
What does chnage in Na+ balance lead to?
What happens with same volume and increased salt?
What happens if we have increase volume too? how is SV affected?
What is a long term control mechanism of blood pressure?
What is a short term control of bp?
Na+ is the major electrolyte in the extracellular fluid (ECFV), be it in plasma or interstitial volumes. K+ is major electrolyte within cells.
Changes in Na+ balance will lead to changes in osmolality, which will change ADH release, this will then change how much water is reabsorbed or excreted in our urine, therefore changing our ECFV (by increasing aquaporins).
Because we have changed our ECFV, this will mean changes in our blood volume and interstitial volume.
If you have increased salt intake and volume remains the same, osmolality will increase, therefore to decrease it, body will add more water -> Hypertension
If we have changes in blood volume, this will have big effect on our stroke volume due to increased ventricular filling so due to Starling’s law (increased preload) we have an increase in stroke volume.
•An increase in SV, will increase cardiac output, increased cardiac output means increased BP
o BP = CO x TPR
This controlling of Na+ levels and hence blood volume is a LONG-TERM control mechanism of blood pressure (i.e. throughout the day).
This is in contrast with the baroreceptors, which exert a short-term control (min-min, reflex control of postural hypotension for example) of blood pressure via sympathetic system.
Control of Na+ Levels
Changes in Na+ will change ECFV - how will this be sensed?
What will be the effect after the changes have been detected?
neuronal level?
hormonal level (hormones involved and what they do?)
what is the third outcome?
what will all these efferent pathways result in?
Na+ levels are very important in controlling blood volume, hence Na+ is important in controlling BP.
Changes in our intake of Na+ via diet, will result in change in ECFV (via ADH), this will be sensed by afferent pathways (arriving), we also then have efferent outputs.
The change in volume will be sensed by the cardiac volume receptors, the baroreceptors and importantly renal artery pressure (kidneys will sense how much blood volume/BP has changed, this is important as this will affect our level of Na+ reabsorption.
Once we have sensed these changes in blood volume, due to the change in Na+, we will then have efferent pathways to produce an output.
On a neuronal level, the sympathetic system will respond due to the baroreceptors and renal arterial pressure changes.
We will also have hormonal responses, RAAS and ANP.
We will also have haemodynamic changes, this is seen especially with blood flow through the kidney. There will be changes in GFR and in pressure natriuresis.
All these efferent pathways will result in changes in renal Na+ output
- We eliminate Na+ via sweat and faeces (not regulated), as well as through regulated renal excretion.
- The important thing to remember is we control Na+ levels quite meticulously, we conserve Na+, this is because we are a low Na+ diet species. We are not made to intake such high levels of Na+.
Conservation of Na+ -> Renin-angiotensin-aldosterone system (RAAS)
Renin
What is it produced by? where are these located?
Why is renin released? What could be potential reasons for this?
what kind of sensors are these detecting cells? what 3 things will they detect and respond to?
what does renin convert? what is this molecule further converted to and where?
Where does this final molecules bind and what is its effects?
Renin is produced by the juxtaglomerular cells (granular cells), which are specialised vascular smooth muscle cells that lie in the wall of the afferent arteriole (supplying blood to glomerulus).
Renin is released from the juxtaglomerular cells, when there is sympathetic stimulation, [Na+] is low at the macula densa -> often due to a decrease in GFR, due to low ECFV, resulting in slow flow through tubule leading to more time for reabsorption, or by a decrease in renal perfusion (BP).
Juxtaglomerular cells are mechano-sensors and will detect changes in BP and blood volume:
- A decrease in BP and blood volume will decrease renal blood flow through the afferent arteriole. The JGCs will detect this and release renin. They are thinking we are having haemorrhage and there has been a loss in blood volume, so we need to increase Na+ retention to increase blood volume and BP.
- If Na+ levels are LOW at the macula densa, this will tell the JGCs we need to release renin to increase Na+ reabsorption (possibly due to low GFR)
- Finally, is sympathetic stimulation of beta1 receptors, this is important because it is drug targets. So, if you give a beta blocker you are reducing renin release by the kidney.
Renin is an enzyme that converts angiotensinogen to Ang I, Ang I is then converted to Ang II by angiotensin converting enzyme (ACE) which is found on the endothelium of blood vessels especially in the lungs.
Angiotensin II binds to its receptor (AT1-R), a GPCR linked to Gq, which is present on the vascular smooth muscle cells so results in vasoconstriction, increasing TPR and thus BP.
Conservation of Na+ -> Renin-angiotensin-aldosterone system (RAAS)
Aldosterone
What is aldosterone? where is it synthesised? and what causes it to be released? (what else is made in this location?)
Where does aldosterone go and what receptors does it act on?
What changes does binding of aldosterone bring about? why are these changes key?
How does it increase BP?
how can hyperaldosteronism lead to hypokalemia?
The receptor is also found on the adrenal glands and stimulates release of aldosterone from the zona glomerulosa.
Aldosterone is a steroid hormone synthesised by the zona glomerulosa of the adrenal gland, it is released by the action of angiotensin II on AT receptors.
- Remember on outside of adrenal gland is capsule, then the Z. glomerulosa producing the mineralocorticoid aldosterone.
- Then the Z. fasiculata producing the glucocorticoids (primary cortisol) and then the Z. reticularis producing the sex steroids (weak androgens)
Aldosterone goes to the kidney to the DCT and collecting ducts. Aldosterone is a steroid which diffuses through the membrane of cells and acts on nuclear receptors (ligand-activated transcription factors).
The binding of aldosterone to the mineralocorticoid receptor causes changes in transcription -> increase in the luminal ENaC channel (sodium channel) and the Na+/K+ pump on basolateral membrane.
- This is key, because if you increase the no. of ENaC channels, there can be more Na+ coming into the tubular cells.
Increased Na+ coming into the cell would increase conc. of Na+ in the cell, so to get rid of this Na+ and maintain the gradient, we increase the number/activity of Na+/K+ pumps which kicks 3 Na+ out for 2 K+ coming in.
Working together this increases the drive to get Na+ from the lumen of the tubule into the blood plasma.
Water will then follow along with Na+ down its osmotic gradient. So, aldosterone by conserving Na+, conserves water, by doing this it increases blood volume and thus increases BP.
This also effects K+:
Increased activity of Na+/K+ pump means more K+ will be taken from the blood put into the cell and it will then passively be secreted into the lumen down the conc. gradient.
So, with aldosterone we are losing K+ we are getting more K+ excretion (which is why hyperaldosteronism will lead to hypokalemia).
Summary
- Aldosterone conserves Na+ by increasing Na+ reabsorption and water follows along with it by osmosis (increasing blood volume) and by doing so decreases the urine amount of Na+.
- Acts at steroid receptors inside cells Increased expression of ENac and Na/K pump
-Results in:
o Increased Na reabsorption at distal tubular sites
o Results in Increased Renal K excretions
- Excess -> Hypokalemia
Na+ Excretion -> Cardiac Natriuretic Peptides
What cardiac natriuretic peptides are important for this? When are they released?
What effect do they have on the renal system?
vasculature?
Hormones?
What is the 2 main effects on diuresis?
We will want to get rid of Na+ and reduce blood volume if it is too high.
The cardiac natriuretic peptides are important for this, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) which are found in specialised cardiac myocytes.
-> These hormones are released in response to increased/too much filling pressures, too much stretch (i.e. a HIGH ECFV).
ANP is trying to get rid of sodium, its effects include:
• Renal
o Causes natriuresis (increased Na+ excretion)
o Because of this water follows causing diuresis (increased water excretion)
• Vasculature
o ANP causes vasodilatation of vessels through a similar mechanism of NO (via GC and PKG) on vascular smooth muscle cells, to decrease TPR and decrease systemic BP.
• Hormonal
o ANP acts on the kidney to decrease renin release (so reduces Ang II which reduces vascular tone even further)
o ANP reduces aldosterone release
ANP has two effects on diuresis:
- Inhibits renin release thus reducing Ang II and aldosterone, it inhibits aldosterone directly
- Reduces ADH release
These effects accumulate to decrease Na+ reabsorption to decrease water uptake and decreases the permeability of the collecting duct.
All this leads to a DECREASE in blood volume
Key Ideas
RAAS is all about conserving Na+, increasing blood volume and BP, while ANP system opposes this and aims to excrete more Na+, decrease blood volume and decrease BP.
• Therefore, things that are controlled by RAAS are also controlled by ANP.
Na+ Excretion -> Pressure Natriuresis
What does this mean?
why does increased renal arterial pressure have no effect on the GFR?
How does increased BP lead to increased Na excretion? (peritubular increased pressure)
We can also increase renal Na+ excretion by pressure natriuresis. This is increase in renal Na+ excretion due to a rise in renal arterial pressure.
Normal mean arterial pressure is around 100mmHg, so the relative sodium excretion is 1. But we can see that if we increase BP, then we are forcing more Na+ to be excreted and more appearing in the urine.
This does NOT occur due to changes in GFR, because renal arterial pressure does not increase GFR (you are still filtering the same % of filtrate and amount of Na+), this is because of the very powerful renal arterial auto-regulation via vasoconstriction, which decreases flow and increases the pressure drop so the pressure stays normal.
It is instead due to a rise in medullary capillary pressure, we have our afferent arteriole, glomerulus, efferent arteriole and then this leads to our peritubular capillaries.
If we have higher pressure in these peritubular capillaries (flow has been controlled, but pressure still high), this will mean movement of fluid out of plasma into interstitial space due to this pressure pushing it harder.
There will subsequently be a rise in pressure in this interstitial area which reduces reabsorption of Na+ from the tubule.
By increasing BP, we are forcing more Na+ into our urine by preventing it being reabsorbed.
Control of Blood Pressure by the Kidney – Clinical Importance
What are the values for hypertension?
How is it classified?
what are some secondary causes of hypertemsions which involved excess renal reabsorption and abnormalities of hormone secretion? (3)
What is essential hypertension?
Hypertension is present when someone has:
Systolic > 140 and/or Diastolic >90
Hypertension is classified as either secondary or essential (causes).
• Secondary is when there is an identifiable cause (5-10% of cases)
• Essential is when there is an unknown cause (>90% of cases)
Some secondary causes of hypertension involve excess renal reabsorption and abnormalities of hormone secretion:
• Liddle’s syndrome
• Conn’s syndrome
• Renal artery stenosis
Essential hypertension may involve abnormal handling of Na+ balance.
Liddle’s Syndrome
What is it/caused by? what does it affect?
How does this lead to more na+ reabsorption?
chain reaction effect?
What is the consequence of this?
Liddle’s syndrome is a rare genetic form of high blood pressure associated with the epithelial Na+ sodium channel (ENaC).
The genetic change changes the AA sequence of the channel, resulting in the channel being open more often and hence there is increased renal sodium reabsorption. Because the channel is open much more, so there will be greater Na+ driving into the cell and into the blood.
This means there will be greater movement of water into the blood plasma.
This increased blood volume and pressure will be sensed by RAAS system and so it will turn off renin release, Ang II production and aldosterone release.
So, our renin and aldosterone levels are now down but as there is a genetic abnormality we still have this going on and we get continued increase in blood volume and pressure (hypertension), it doesn’t turn down the BP.
Conn’s Syndrome
What is this an example of?
What is it caused by?
What is the effect of this?
how can this lead to alkalosis and hypokalamia?
Conn’s syndrome is an example of primary hyperaldosteronism and caused by overproduction of aldosterone by an adrenal gland tumour (adenoma). This is unregulated by renin, it is doing its own thing releasing consistently.
These high levels will result in increased Na+ reabsorption due to increased ENaC channels, increased Na+/K+ ATPase activity which is driving Na+ into the plasma at a very high rate.
Water will follow even more, so there will be an increase in ECFV and increase in blood pressure.
Due to this high pressure our JGCs detect this and turn down renin secretion but this makes no difference as the tumour is releasing aldosterone regardless of renin/Ang II.
We will also get a lot of K+ being kicked out into the urine by Na+/K+ pump due to this aldosterone
- Also, ENaC driving Na+ into cell changes the electrical gradient across the cell, so that it is favourable for K+ to move from cell into the lumen, aldosterone also increases permeability of apical membrane to K+.
- We also get alkalosis in hyperaldosteronism as aldosterone stimulates the H+/K+ antiport in the intercalated cells, this kicks H+ out of cells into lumen and brings K+ back in, however this K+ reabsorption is much less in proportion to what is being excreted so overall we get a big loss of K+, however the loss of H+ is significant enough to lead to an alkalosis.
Renal Artery Stenosis – Abnormal Narrowing of Vessel
What is this? what is the effect of this? how does this lead to na+ retention?
Renal artery stenosis is narrowing of the renal artery, so due to this narrowing we get an increased pressure DROP across this narrowing.
Causing BP to decrease in the kidney and there is hence decreased flow. This is sensed by the kidney (which is probably worrying of blood loss), so it secretes renin, which leads to production of Ang II.
Ang II will result in vasoconstriction of vessels and increase aldosterone leading to increased Na+ retention and thus water retention.
Together the vasoconstriction and water reabsorption ultimately caused by renin results in high blood pressure
Essential Hypertension – Causes Unknown
What do we know about the cause? (2 major factors)
So why do we think defects in renal Na+ handling is involved?
Essential hypertension is hypertension we really don’t know what the cause is.
- We do know there is a genetic predisposition as some ethnic groups get hypertension more than others.
- We also know that there are environmental factors, the lifestyle people live (e.g. their levels of physical activity) and diet (salt intake, Alcohol, diabetes).
These genetics and environmental factors produce particular intermediate phenotypes which lead on to having high BP.
So why do we think defects in renal Na+ handling is involved?
This is because drugs that decrease the RAAS system are frontline anti-hypertensive treatments e.g. ACE inhibitors, Ang II receptor blockers. These systems are important in controlling Na+ levels.
As well as this we know high Na+ intake is linked to high blood pressure.
