Sodium and Potassium Balance

Question 1

What is osmolarity?

Answer 1

Measure of the solute (particle) concentration in a solution (osmoles/L)

Depends on the number of dissolved particles

Question 2

So what is 1 Osmole?

Answer 2

1 Osmole = 1 mole of dissolved particles per litre (e.g. 1 mol of NaCl = 2 mol of particles in solution)

The greater the number of dissolved particles, the greater the osmolarity

Question 3

How is osmolality different?

Answer 3

Osmolarity = number of particles of solute per liter of solution

Osmolality = number of particles of solute per kilogram of solvent

Question 4

What is normal plasma osmolarity?

Answer 4

285-295 mosmol/L

Question 5

What is the most prevalent solute in the plasma?

What else makes up plasma?

Answer 5

Sodium - 140 mmol/L (most important and dictates ECF volume)

Chloride - 105 mmol/L
Bicarbonate - 24 mmol/L
Potassium - 4 mmol/L
Glucose - 3-8 mmol/L
Calcium - 2 mmol/L
Protein - 1 mmol/L

Question 6

What happens when you increase sodium dietary intake?

Answer 6

Increase total body sodium
Increased osmolarity (but this can’t happen due to semi-permeability of membranes)
So leads to increased water intake and retention
Increased ECF volume - until plateau reached
Increased blood volume and pressure

Then if you reduce sodium in your diet - you lose the water as you lose sodium from the system

Question 7

What happens when you decrease sodium dietary intake?

Answer 7

Decrease total body sodium
Decreased osmolarity (but this can’t happen due to semi-permeability of membranes)
So leads to decreased water intake and retention
Decreased ECF volume - until plateau reached
Decreased blood volume and pressure

Question 8

What happens under normal conditions of euvolemia?

Answer 8

Euvolemia has normal sodium levels = inhibition of Na+ intake

Question 9

What controls sodium intake?

Answer 9

Lateral parabrachial nucleus - a set of cells that respond to serotonin and glutamate as transmitters to suppress basal sodium intake

Question 10

What happens at the lateral parabrachial nucleus during Na+ deprivation VS euvolemia?

Answer 10

Na+ deprivation = increased appetite for Na+ driven by GABA and opioids

Euvolemia = inhibit Na+ intake

Question 11

What is salt when present in low quantities in food?

What is salt when present in high quantities in food?

Answer 11

Appetitive = low sodium content in food

Aversive = high sodium content in food

Question 12

Where is sodium reabsorbed in the nephron?

So how much sodium is actually excreted?

Answer 12

60-70% reabsorbed in PCT

As the tubular fluid travels down the descending limb of the loop of Henle, no sodium is reabsorbed

However, in the thick ascending limb a further 25% is reabsorbed

A further 5 % is reabsorbed in the DCT

A further 3% in the collecting duct

So less than 1% of the sodium that enters the tubular fluid is excreted

Question 13

How would you increase the amount of sodium excreted?

Answer 13

Increase GFR (glomerular filtration rate)
Increase sodium excretion

Question 14

What affects GFR?

Is it desirable that changes in GFR are proportional to sodium lost?

Answer 14

Renal plasma flow
Mean arterial pressure
Proportional up to a threshold then plateaus

Not really

Question 15

How does sodium affect GFR?

Answer 15

The DCT is in contact with cells around the glomerulus - so the DCT contains macula densa cells, which are in contact with the extraglomerular mesangial cells (found between the glomerulus and DCT), which are in contact with the juxtaglomerular cells (on the glomerulus)

High tubular sodium

Macula densa cells are found on the DCT and respond to high sodium levels by increasing sodium/chloride uptake via triple transporter

Causes Macula Densa cells to release adenosine

Detected by extraglomerular mesangial cells - which interacts with the juxtuglomerular cells to release renin

This causes smooth muscle cells of the glomerulus to contract = reduced blood flow

Reduces perfusion pressure and so GFR

Question 16

Why is the macula densa production of renin in response to high sodium less important?

Answer 16

Over a short period of time = short term regulation system

So does not affect overall renin production long term

Question 17

What is the best way to retain sodium and water?

Answer 17

Filter less

Reduction of pressure gradient at Bowman’s capsule

Question 18

What factors allow for less filtration?

Answer 18

Sympathetic activity:

Contracts SMC of afferent arteriole

Stimulates sodium uptake of cells of PCT

Stimulates JGA (juxtaglomerular apparatus) to produce renin

Renin cleaves angiotensinogen to form angiotensin I, ACE cleaves angiotensin I to Angiotensin II

Angiotensin II promotes vasconstriction and reabsorption of sodium in PCT

Angiotensin II stimulates adrenal glands to produce aldosterone

Aldosterone promotes reabsorption in collecting duct

Question 19

What factors allow for greater filtration?

Answer 19

ANP (atrial naturietic peptide) - acts as a vasodilator

Reduces reabsorption of sodium throughout nephron - PCT, DCT and CD

Question 20

What is aldosterone and where is it synthesised?

When is it released and why?

Answer 20

Aldosterone = steroid hormone

Synthesised and released from the adrenal cortex (zona glomerulosa)

Released in response to angiotensin II and a decrease in BP (detected via baroreceptors)

Question 21

What does angiotensin II do to stimulate aldosterone production?

Answer 21

Promotes synthesis of aldosterone synthase (enzyme)

Aldosterone synthase causes the last 2 ezymatic steps in the production of aldosterone from cholesterol

Question 22

What is the role of aldosterone in the kidney?

Answer 22

Stimulates:
Increased Sodium reabsorption
(controls reabsorption of 35g Na/day)
Increased Potassium secretion
Increased hydrogen ion secretion

Question 23

What does aldosterone excess lead to?

Answer 23

Hypokalaemic alkalosis

Question 24

How does aldosterone work?

Answer 24

Steroid hormone - lipid soluble so will pass through the cell membrane

Once inside the cell, binds to mineralocorticoid receptor inside cytoplasm bound to protein HSP 90

HSP 90 is consequently removed and the receptor is dimerised (no longer a monomer, instead is a dimer)

Allows it to translocate to the nucleus - i.e. moves into nucleus

It binds to DNA, where it stimulates transcription of mRNA genes that are under its control

Question 25

What proteins are produced in response to aldosterone?

Answer 25

Na/K ATPase Epithelial sodium channel These travel to their respective membranes Regulatory proteins that stimulate the activity of the 2 transporters (Na+/K+ ATPase and epithelial sodium channel) so the channels are active

Question 26

What is hypoaldosteronism?

Answer 26

Reabsorption of sodium in the distal nephron is reduced Increased urinary loss of sodium - leads to increased loss of water in the urine ECF volume falls Increased renin, Ang II and ADH

Question 27

What are signs and symptoms of hypoaldosteronism?

Answer 27

Dizziness Low blood pressure - responsible for the dizziness Salt craving palpitations

Question 28

What is hyperaldosteronism?

Answer 28

Reabsorption of sodium in the distal nephron is increased Reduced urinary loss of sodium = increase in total sodium ECF volume increases (hypertension) Reduced renin, Ang II and ADH Increased ANP and BNP

Question 29

What are symptoms of hyperaldosteronism?

Answer 29

High blood pressure Muscle weakness Thirst - we think we have insufficient water in our system and so drink more water (but this is because of the high total sodium in the body) Polyuria - trying to get rid of all the water being drunk

Question 30

What is Liddle's syndrome?

Answer 30

Looks like hyperaldosteronism but with normal / low aldosterone levels Inherited disease of high BP Mutation in the aldosterone activated sodium channel Channel is always in the ‘on’ state = sodium retention, leading to hypertension

Question 31

How is feedback from increased of decreased ECF detected?

Answer 31

Via baroreceptors (pressure receptors)

Question 32

Where are the low pressure baroreceptors found?

Answer 32

Atria Right ventricle Pulmonary vasculature

Question 33

Where are the high pressure baroreceptors found?

Answer 33

Carotid sinus Aortic arch Juxtaglomerular apparatus

Question 34

What happens in response to low pressure on the low pressure side of the baroreceptors?

Answer 34

Low BP Reduced baroreceptor firing Signal through afferent fibres to the brainstem Leads to sympathetic activity Leads to ADH release

Question 35

What happens in response to high pressure on the low pressure side of the baroreceptors?

Answer 35

High BP Leads to atrial stretch ANP, BNP released

Question 36

What happens in response to low pressure on the high pressure side of the baroreceptors?

Answer 36

Same as low pressure side (with reduced baroreceptor firing = sympathetic acitivy and ADH release) but also Signals to JGA (juxtoglomerular apparatus) cells to suppress renin release

Question 37

What is ANP?

Answer 37

Atrial Natriuretic Peptide Small peptide made in the atria (also make BNP) Released in response to atrial stretch (i.e. high blood pressure)

Question 38

What are the actions of ANP?

Answer 38

Vasodilatation of renal (and other systemic) blood vessels Inhibition of Sodium reabsorption in proximal tubule and in the collecting ducts Inhibits release of renin and aldosterone Reduces blood pressure

Question 39

How does ANP work?

Answer 39

Binds to a receptor that is guanylyn cyclase Guanylyn cyclase causes conversion of GTP to cyclic GMP Leads to activation of protein kinase G Cellular responses in response to that - e.g. vasodilation of the renal and systemic blood vessels, inhibition of sodium in PCT and CD and inhibition of renin + aldosterone production

Question 40

What happens in response to volume expansion of blood?

Answer 40

Reduced sympathetic activity leading to reduced sodium reuptake in the PCT, reduction in renin production (and so aldosterone) Increase in ANP and BNP Promotes sodium excretion

Question 41

What happens when there is contraction of the blood volume?

Answer 41

Increased sympathetic activity leading to increased sodium reuptake in the PCT, increase in renin production (and so aldosterone) Decrease in ANP and BNP, increase ADH production Promotes sodium reabsorption

Question 42

What would be the effect on water secretion of increased sodium levels reaching the collecting duct?

Answer 42

Increase osmolarity of tubular fluid by increasing sodium Reduce gradient across membrane into the medulla (loop of henle) Reduce amount of water that can be reabsorbed So reduced ECF volume

Question 43

How are ACE inhibitors diuretics?

Answer 43

Reduces Angiotensin II production = vasodilation Increases vascular volume = reduction in BP Reduced Na+ reuptake in the PCT = reduced Na+ in the distal nephron Reduces gradient across tubular fluid into interstitium at the loop of Henle = reduced water reabsorption Reduced aldosterone = reduced uptake of sodium in the CD Reduced ECF volume = reduced BP

Question 44

What are some other diuretics and where do they act on the nephron?

Answer 44

``` Osmotic diuretics - PCT Carbonic anhydrase inhbitors - PCT Lymph diuretics - thin limb of loop of Henle Thiazide diuretics - DCT Potassium sparing - CD ```

Question 45

How do carbonic anhydrase inhibitors work?

Answer 45

Reduced Na+ reuptake in the PCT Increased Na+ in the distal nephron = reduced gradient across tubular fluid into interstitium at the loop of Henle = reduced water reabsorption Reduced acidity of urine as CA no longer converted H2CO3 into H2O and CO2

Question 46

How do loop diuretics work? | E.g. Furosemide

Answer 46

Block the triple transporter Inhibitors Reduced Na+ reuptake in the loop of Henle Increased Na+ in the distal nephron Reduced water reabsorption

Question 47

How do thiazide diuretics work?

Answer 47

Block Na/Cl transporter Reduced Na+ reuptake in the DCT Increased Na+ in the distal nephron Reduced water reabsorption Also increases calcium reabsorption (via sodium calcium antiporters)

Question 48

How do potassium sparing diuretics work?

Answer 48

Inhibitors of aldosterone function (e.g. spironolactone) Fewer sodium reuptake channels synthesised = reduced sodium reuptake in the distal nephron

Question 49

What is potassium?

Answer 49

Potassium = main intracellular ion at 150 mmol/L, extracellularly = 3-5 mmol/L

Question 50

What does extracellular postassium effect? What does high extracellular K+ result in? What does low extracellular K+ result in?

Answer 50

Excitable membranes High K+ = depolarises membranes leading to more action potentials, heart arrhythmias Low K+ = heart arrhythmias (asystole)

Question 51

What happens to dietary potassium?

Answer 51

K+ present in almost all foods, esp. unprocessed foods After a meal --> K+ is absorbed Increases plasma K+ conc. Tissue uptake of K+ is stimulated by insulin, aldosterone, and adrenaline

Question 52

How does insulin stimulate uptake of K+ into tissues?

Answer 52

Stimulates Na+/H+ exchanger Increases sodium entering cells To reduce intracellular sodium Na+/K+ ATPase used So Na+/K+ ATPase activity increases = brings in more K+

Question 53

Where in the nephron is potassium reabsorbed and secreted? So how much potassium is excreted via the urine overall?

Answer 53

67% (or 2/3) reabsorbed in the PCT Further 20% reabsorbed in thick ascending limb of loop of Henle - via Na+/K+/Cl- triple transporter Potassium secretion in DCT and CD Up to 50% of K+ secreted in DCT Up to 30% secreted in CD 15-80% of K+ in glomerular filtrate is excreted

Question 54

Why can only 15% of the K+ in the filtrate be excreted?

Answer 54

Due to reabsorption in the DCT (3%) and CD (9%)

Question 55

Why is there a range of what percentage of K+ is reabsorbed?

Answer 55

Depends on plasma concentration

Question 56

What is K+ secretion stimulated by?

Answer 56

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

Question 57

How is potassium secreted by the principal cells in the DCT and CD?

Answer 57

Increase in activity of Na+/K+ ATPase - affects membrane potential to stimulate K+ secretion More potassium inside the cell = more potassium secreted into DCT / CD

Question 58

How does K+ excretion respond to tubular flow?

Answer 58

Distal cells have primary cilia Increase in flow detected by cilia = increase in PDK1 Increases Ca2+ conc in cell Stimulates activity of opening K+ channels K+ moves out of the cell as it is pumped by Na+/K+ ATPase

Question 59

What is hypokalemia?

Answer 59

Low K+ levels (in blood) Hypokalemia one of the most common electrolyte imbalances (seen in up to 20% of hospitalised patients)

Question 60

What can cause hypokalemia? | Inadequate dietary intake (too much processed food)

Answer 60

Diuretics (due to increase tubular flow rates) Surreptitious vomiting Diarrhoea Genetics (Gitelman’s syndrome; mutation in the Na/Cl transporter in the distal nephron)

Question 61

What is hyperkalemia?

Answer 61

High K+ levels (in blood) Common electrolyte imbalance present in 1-10% of hospitalised patients

Question 62

What causes hyperkalemia?

Answer 62

Seen in response to K+ sparing diuretics ACE inhibitors Elderly Severe diabetes Kidney disesase