Sodium and potassium balance

Question 1

Define osmolarity

Answer 1

The measure of a solute (particle) concentration in a solution (osmoles/litre)
1 osmole= 1 mole of dissolved particles per litre
(1 mole of NaCl=2 moles of particles in solution)

Question 2

What is osmolarity dictated by?

Answer 2

The number (NOT THE SIZE) of dissolved particles- the greater the number, the greater the osmolarity)

Question 3

How does our osmolarity remain constant?

Answer 3

By water moving around through semi-permeable membranes

If there’s increased salt concentration in an area, osmolarity of that area will go up, so there’s increased water moving into that area to increase the volume to bring osmolarity back down to normal

If there’s decreased salt concentration in an area, osmolarity of that area will decrease, so there’s water moving out of that area to decrease the volume and bring osmolarity back up to norma;

Question 4

What is normal plasma osmolarity?

Answer 4

285-295mOsm/L

Question 5

What particles make up normal plasma osmolarity in the body?

Answer 5

Na+ 140mmol/L
Cl- 105mmol/L
HCO3- 24mmol/L
K+ 4mmol/L
Glucose 3-8mmol/L
Ca2+ 2mmol/L
Protein 1mmol/L

Question 6

How does an increased dietary sodium intake affect weight and blood pressure?

Answer 6

Increased dietary sodium–> increase in total body sodium–> increased osmolarity (but our body won’t allow this to happen)–> increased water intake and retention–>increased ECF volume–> increased blood volume and blood pressure and total body weight

Question 7

How does an decreased dietary sodium intake affect weight and blood pressure?

Answer 7

Decrease in dietary sodium–> decrease in total body sodium–> decreased osmolarity (but our body does not allow this to happen)–>decreased water intake and retention → decreased ECF volume → decreased blood volume and pressure and decreased body weight

Question 8

What part of the brain centrally controls regulation of sodium intake?

Answer 8

Lateral parabrachial nucleus at the junction of the midbrain and pons

Question 9

What happens at the lateral parabrachial nucleus under normal conditions of euvolemia (normal sodium levels)?

Answer 9

We are suppressing our desire to intake sodium
A set of cells in the parabrachial nucleus that respond to serotonin glutamate suppress basal Na+ intake

Question 10

What happens at the lateral parabrachial nucleus under conditions of Na+ deprivation?

Answer 10

There is an increased appetite for Na+
This is driven by GABA and opioids

Question 11

What is the peripheral mechanism for regulating sodium intake?

Answer 11

• Taste
• If you have food with no salt it tastes unpleasant
• When salt is present in low concs in food it makes it appetising so we want to eat it
• As Na+ conc increases, it becomes more aversive for us so we don’t want to eat it

Question 12

How much (in %) sodium is reabsorbed in different parts of the nephron and how much is excreted?

Answer 12

67% in the PCT (which causes 67% of water to be reabsorbed too)
25% in the thick ascending limb of the loop of Henle
5% in the DCT
3% in the collecting duct
<1% is excreted

Question 13

What happens to sodium excretion if we increase GFR?

Answer 13

Increases

Question 14

How is GFR linked to renal plasma flow rate and blood pressure?

Answer 14

Renal plasma flow rate is proportional to mean arterial pressure

Approx. 20% of renal plasma enters tubular system and therefore GFR= RPF*0.2 and GFR is also proportional to mean arterial pressure

Question 15

What happens at a certain threshold of high blood pressure to GFR and RPF? When and why?

Answer 15

RPF and GFR both plateau at high blood pressures e.g. when exercising, we don’t want to excrete more sodium than is needed

Question 16

Describe the nephron’s system to limit sodium loss through kidney excretion

Answer 16

If there’s high sodium in filtrate, there’s higher than normal sodium passing through the distal convoluted tubule
The DCT is in close association with glomerulus and JGA has macula densa cells which can detect increase in sodium concentration
This leads to increased Na+Cl- uptake via triple transporters
Macula densa cells release adenosine which is detected by extraglomerular mesangial cells which interact with smooth muscle cells in afferent arteriole
This reduces flow of blood into glomerulus, thus reducing perfusion pressure and thus GFR
This adenosine release also leads to reduction in renin production (however this is for a short period of time so doesn’t affect overall renin production over long time period)

Question 17

What are the various systems in the nephron to increase Na+ reabsorption/retention?

Answer 17

Sympathetic activity
Angiotensin II
Low sodium in DCT will stimulate renin production from JGA and thus angiotensin II

Question 18

How does sympathetic activity affect sodium retention?

Answer 18

Contracts smooth muscle cells of afferent arteriole
Increases Na+ uptake of PCT cells
Stimulates renin production at JGA cells which leads to Ang II production

Question 19

How does Ang II affect sodium retention?

Answer 19

Vasoconstriction
Increased Na+ uptake of PCT cells
Stimulates adrenal gland to produce aldosterone which stimulates Na+ uptake in the distal part of DCT and collecting duct

Question 20

What is the function of atrial natriuretic peptide?

Answer 20

Decreases Na+ reabsorption by:

Vasodilation
Decreasing Na+ reabsorption at PCT, DCT and collecting duct
Suppressing renin production at JGA

Question 21

How does the body react when we have low sodium levels?

Answer 21

1) Low sodium means lower blood pressure and low fluid volume

2) This increases beta1-sympathetic activity which stimulates afferent arteriole SMC to contract and reduce glomerular filtration pressure

3) Stimulates renin production which cleaves angiotensinogen into Ang I which is cleaved by ACE into Ang II

4) Ang II stimulates zona glomerulosa of adrenal gland to release aldosterone which increases Na+ reabsorption

5) Ang II also promotes vasoconstriction and Na+ reabsorption

6) This all reabsorbs more Na+ and reduces water output

Question 22

How does the body react when we have high sodium levels?

Answer 22

1) High sodium means higher fluid volume meaning higher blood pressure

2) This suppresses beta1-sympathetic activity and causes production of ANP

3) This reduces renin which reduces Ang I which reduces Ang II which reduces aldosterone

4) This promotes vasodilation and decreases Na+ and water reabsorption

Question 23

What factors stimulate aldosterone synthesis?

Answer 23

Angiotensin II- Ang II stimulates the production of aldosterone synthase which causes the last 2 enzymatic steps in the production of aldosterone from cholesterol

Also released when there’s a decrease in blood pressure via baroreceptors

Question 24

What does aldosterone do in the kidney?

Answer 24

• Stimulates Na+ reabsorption (35g per day)
  
  • Increased K+ secretion
  • Increased H+ secretion

Question 25

What can happen if there's aldosterone excess?

Answer 25

Hypokalaemic alkalosis

Question 26

How does aldosterone work at a cellular level in collecting duct cells?

Answer 26

1) It’s a steroid hormone which are lipid soluble so passes through cell membrane 2) It binds to a mineralocorticoid receptor sitting in cytoplasm bound to a protein called HSP90 3) Once aldosterone is bound, HSP90 gets removed and the mineralocorticoid receptor dimerises 4) It now translocates into nucleus where it binds to DNA and stimulates production of mRNA for genes for epithelial Na+ channel (ENaC) and Na+ K+ ATPase which go to their respective membranes (apical and basolateral respectively) 5) It also increases transcription of regulatory proteins that stimulate activity of those 2 transporters- so you get both more sodium channels and more active sodium channels

Question 27

What happens in hypoaldosteronism?

Answer 27

Reabsorption of sodium in the distal nephron is reduced Increased urinary loss of sodium Reduced ECF volume as water moves out with sodium

Question 28

What does the body do to try and compensate in hypoaldosteronism?

Answer 28

Increases renin, angiotensin II and ADH (other sodium absorption mechanisms) to try and increase reabsorption

Question 29

What symptoms does hypoaldosteronism cause?

Answer 29

Low blood pressure Dizziness- caused by low bp Salt craving Palpitations-due to change in membrane potential

Question 30

What happens in hyperaldosteronism?

Answer 30

- Increased reabsorption of sodium in distal nephron is increased → reduced urinary loss of sodium → increase in total body sodium → ECF volume increases as we’re absorbing lots of water (hypertension) - This reduces renin, Ang II and ADH production and increases ANP and BNP

Question 31

Symptoms of hyperaldosteronism

Answer 31

High bp Polyuria- since we have more water we try to get rid of more Thirst- since our body thinks there’s insufficient water in system Muscle weakness

Question 32

What is Liddle's syndrome and what causes it?

Answer 32

An inherited disease of high blood pressure Caused by a mutation in the aldosterone activated sodium channel so it's always on This leads to increased sodium reabsorption and therefore hypertension

Question 33

What other condition does Liddle's syndrome resemble? How does it differ from it?

Answer 33

Like hyperaldosteronism but with normal or low aldosterone levels

Question 34

Where do we have low pressure baroreceptors?

Answer 34

Heart- atria, right ventricle Vascular system- pulmonary vasculature

Question 35

What is the response to low pressure from the low pressure baroreceptors?

Answer 35

low pressure-->low baroreceptor firing--> signal through afferent fibres to the brainstem-->sympathetic activity and ADH secretion for water retention

Question 36

What is the response to high pressure from the low pressure baroreceptors?

Answer 36

High pressure--> atrial stretch-->ANP and BNP released for greater water loss

Question 37

Where is ANP and BNP made?

Answer 37

Both in atria

Question 38

Describe the mechanism of ANP working after it’s released (on a molecular level)

Answer 38

1)Released in response to atrial stretch 2)Binds to a receptor which is guanylyl cyclase 3)This converts GTP to cyclic GMP (cGMP) 4)This activates protein kinase G 5)This leads to cellular responses

Question 39

What are the cellular responses of ANP?

Answer 39

- Vasodilation of renal (and other systemic) blood vessels - Inhibition of Na+ reabsorption in proximal tubule and in collecting duct - Inhibits release of renin and aldosterone

Question 40

What high pressure baroreceptors do we have?

Answer 40

Carotid sinus, aortic arch, JGA (all in vascular system)

Question 41

How do high pressure baroreceptors respond to low pressure?

Answer 41

Low pressure--> low baroreceptor firing--> signal through afferent fibres to brainstem--> increased sympathetic activity and ADH secretion for water retention reduced baroreceptor firing also → JGA cells → renin released

Question 42

How does the body react in response to volume expansion?

Answer 42

Reduction in sympathetic activity which leads to reduced Na+ reabsorption in PCT Reduced renin production which leads to reduced Ang II and aldosterone production which reduces Na+ reabsorption and promotes excretion Increased ANP and BNP which affects GFR and Na+ reabsorption leading to increased sodium excretion

Question 43

How does the body react in response to volume contraction?

Answer 43

Increased sympathetic activity leading to increased Na+ reabsorption in PCT Increased renin production which leads to increased angiotensin II and aldosterone synthesis, which increases sodium and consequently water reabsorption in collecting duct Reduced ANP and BNP More AVP production in brain to promote water reabsorption by inserting aquaporins in collecting duct cells

Question 44

What is the effect of increased sodium levels on water secretion in nephron?

Answer 44

- Water is reabsorbed in nephron because medulla has gradient of osmolarity throughout it which we match with the osmolarity in the tubular fluid - If there’s increased Na+ in tubular fluid, there’s a reduced gradient from tubular fluid to medulla because tubular fluid osmolarity is higher now so water won’t move into medulla so won’t be reabsorbed - So the more solute arriving in later part of nephron, the less water we can absorb

Question 45

What is the effect of reducing Na+ reabsorption on Na+ levels, ECF volume and BP?

Answer 45

- Reducing Na+ reabsorption reduces total Na+ levels, ECF volume and BP - This is because Na+ levels determine ECF volume and reducing ECF volume reduces BP

Question 46

What types of diuretics are there

Answer 46

ACE inhibitors Osmotic diuretics Carbonic anhydrase inhibitors Loop diuretics Thiazide diuretics K+ sparing diuretics

Question 47

What do ACE inhibitors primarily do?

Answer 47

Reduced Ang II production

Question 48

What are the three types of effects of ACEi

Answer 48

Vascular effects Direct renal effects Adrenal effects

Question 49

What are the vascular effects of ACE inhibitors?

Answer 49

Reduced angiotensin II leads to vasodilation, which then leads to increased vascular volume and reduced blood pressure

Question 50

What direct renal effects do ACEi have?

Answer 50

Decreased Na+ reabsorption in the PCT Increased Na+ in the distal nephron means there's a reduced water potential gradient from tubular fluid into interstitium and therefore less water is reabsorbed This leads to lower blood pressure

Question 51

What adrenal effects does reduced Ang II production have?

Answer 51

- Reduced aldosterone - This leads to reduced Na+ uptake in cortical collecting duct - This also increases Na+ in distal nephron (the region of nephron with the highest osmolarity) which reduces water reabsorption because of reduction in osmotic gradient across tubular wall - Less water reabsorption means lower blood pressure

Question 52

How do osmotic diuretics work?

Answer 52

Put something that cannot be reabsorbed into the PCT Since it cannot be reabsorbed it remains in PCT and lowers the osmolarity there This means less water will get reabsorbed from PCT (which is usually where most water is reabsorbed so we will see the greatest effect here)

Question 53

Where do carbonic anhydrase inhibitors work and how do they function?

Answer 53

In PCT, which is where these enzymes are most active. This drug 1) Block carbonic anhydrase which can’t convert bicarbonate into H2CO3 then H2O and CO2 2) so CO2 can’t go into cell to then be added to H2O to make H2CO3 using another carbonic anhydrase (which wouldn’t work either) 3) so no H2CO3 is split into H+ and HCO3- so H+ can’t be used to move Na+ into cell using Na+/H+ exchanger so net sodium uptake goes down and reduction in urinary acidity so overall carbonic anhydrase inhibitors reduce Na+ reuptake in PCT, increase Na+ in distal nephron and reduce water reabsorption

Question 54

Where do loop diuretics work?

Answer 54

Thick ascending limb of loop of Henle

Question 55

Example of a loop diuretic?

Answer 55

Furosemide

Question 56

How do loop diuretics work?

Answer 56

- Block the Na+/2Cl-/K+ triple transporter - This reduces Na+ reuptake in LOH - Increased Na+ in distal nephron - This decreases osmotic gradient across tubular wall into interstitium so reduced water reabsorption

Question 57

Where do thiazide diuretics work?

Answer 57

DCT

Question 58

What is the main function of thiazide diuretics?

Answer 58

Block NaCl transporter in DCT Increase Na+ in DCT Leads to increased Na+ in distal nephron, reduced osmotic gradient from tubular fluid into interstitium and reduced water reabsorption from distal nephron

Question 59

Secondary effect of thiazide diuretics?

Answer 59

They increase Ca2+ reabsorption Na+/K+ ATPase isn't affected by these drugs so Na+ is pumped from cell into blood But the NaCl transporter in the DCT is blocked so Na+ can’t move into cell from tubular fluid There’s a decrease of Na+ therefore in the cell so Na+ moves from blood into cell via Na+/Ca2+ antiporter so Ca2+ builds up in blood

Question 60

Where do K+ sparing diuretics work?

Answer 60

Collecting duct

Question 61

Give an example of a K+ sparing diuretic

Answer 61

Spironolactone

Question 62

How do K+sparing diuretics work?

Answer 62

Inhibit aldosterone function by binding to mineralocorticoid receptors - Aldosterone usually increases production of Na+ channel and Na+/K+ ATPase to increase Na+ reuptake and also increases K+ secretion and H+ excretion so an excess of aldosterone can lead to hypokalaemic alkalosis - So if this is blocked, activity of this uptake system reduces so Na+ reuptake in distal nephron reduces

Question 63

How are K+ diuretics K+ sparing?

Answer 63

Na+/K+ ATPase pumps K+ out of blood and cell from where it moves into lumen If we block this K+ remains in blood (it is spared)

Question 64

How much K+ is present intracellularly vs extracellularly?

Answer 64

It's the main intracellular ion (150mmol/L) Extracellular K+ is much lower at 3-5 mmol/L

Question 65

Where does the main effect of extracellular K+ occur?

Answer 65

On excitable membranes of nerve and muscle

Question 66

What does high extracellular K+ do?

Answer 66

Depolarises membranes leading to action potential generation and heart arrhythmia

Question 67

What does low extracellular K+ do?

Answer 67

Makes depolarisation more difficult- also leading to heart arrhythmias and asystole (flatline with no ventricular depolarisation)

Question 68

What happens K+ wise when we eat a meal?

Answer 68

- Eating a meal leads to K+ absorption (most foods contain some potassium)- especially unprocessed foods which have a lot of K+ - This increases plasma K+ conc - This needs to be reduced which happens via tissue uptake

Question 69

What stimulates tissue uptake of K+?

Answer 69

Insulin Aldosterone Adrenaline

Question 70

How does insulin stimulate tissue uptake of K+?

Answer 70

Indirectly Insulin stimulates Na+/H+ exchanger which increases Na+ coming into tissue cells This increases intracellular Na+ concentration which needs to be reduced This is done through Na+/K+ ATPase which moves Na+ back into blood out of cell and K+ into cell

Question 71

How is K+ excreted and reabsorbed through nephron in %s?

Answer 71

Like sodium and water about 67% of filtered potassium is reabsorbed in the PCT with a further 20% reabsorbed in the loop of Henle irrespective of plasma potassium. However, in the latter parts of the nephron the handling of potassium depends on a range of factors including plasma potassium such that the amount of potassium excreted is between 1 and 80% of the initial load. In conditions of potassium depletion further potassium reabsorption occurs in the DCT and CT with 3% in the DCT and 9% in the CT. In normal or high potassium levels potassium is secreted.

Question 72

What stimulates K+ secretion into tubular fluid?

Answer 72

Higher plasma K+ Increased plasma pH Increased aldosterone Increased tubular flow rate

Question 73

How does high plasma K+ lead to increased K+ secretion?

Answer 73

- Increased activity of Na+/K+ exchanger meaning more K+ moves into cell - More K+ in the cell then means more K+ leaving the cell in tubular fluid - There is also an effect on membrane potential which helps stimulate K+ secretion

Question 74

How does increased tubular flow rate lead to increased K+ secretion?

Answer 74

Distal cells have primary cilia When there's increased tubular flow, primary cilia can stimulate PDK1 This leads to increased Ca++ in cell, which increases openness of K+ channels allowing K+ to leave cell into tubular fluid after being pumped into cell from blood via Na+/K+ ATPase

Question 75

How does K+ secretion in K+ depleted states differ from normal conditions?

Answer 75

Same as in normal conditions but instead of secretion at DCT and collecting duct, K+ is reabsorbed as well instead similar to the earlier parts of nephron - 3% reabsorbed in DCT and 9% reabsorbed in collecting duct

Question 76

How common is hypokalemia?

Answer 76

One of the most common electrolyte imbalances (seen in up to 20% of hospital patients)

Question 77

What causes hypokalaemia?

Answer 77

- Inadequate dietary intake (too much processed food) - Diuretics which increases tubular flow rates - Surreptitious vomiting- reduced K+ intake - Diarrhoea- reduced K+ intake

Question 78

What genetic conditions can lead to hypokalaemia?

Answer 78

Gitelman’s syndrome (mutation in NaCl transporter in distal nephron) leads to increased K+ loss

Question 79

How common is hyperkalemia?

Answer 79

Common electrolyte imbalance seen in 1-10% of hospitalised patients

Question 80

What causes hyperkalemia?

Answer 80

- K+ sparing diuretics - ACE inhibitors - Being old - Severe diabetes - Kidney disease