CR: PBL 3 (Hypertension and Liddle's Syndrome)

Question 1

Define hypertension

Answer 1

Blood pressure over 140/90

Question 2

What causes hypertension?

Answer 2

90% environmental/unidentifiable cause e.g. age ethnicity, salty foods, obesity, smoking, drinking
10% secondary hypertension caused by an underlying conditions e.g. kidney disease, diabetes, the pill or cocaine

Question 3

How may the autonomic nervous system be implicated in causing hypertension?

Answer 3

Arterial baroreceptors may reset to a higher pressure as well as central resetting of aortic baroreflex –> sympathetic inhibition is suppressed.

Question 4

Which molecules contribute to re-programming the autonomic nervous system response in baroreceptors to cause hypertension?

Answer 4

Suppressed baroreceptor activity (prevent sympathetic inhibition) is caused by angiotensin II, reactive oxygen species and endothelin

Question 5

How may endothelial dysfunction be implicated in causing essential hypertension?

Answer 5

Endothelium secretes nitric oxide and endothelin which usually have balance to maintain vascular tone –> dysfunction sets up vicious cycle that maintains high BP

Question 6

What does endothelin do?

Answer 6

Constricts blood vessels

Question 7

Why is K+ on the lower side of normal in Liddle’s syndrome?

Answer 7

With overactivity of the ENaC channel in the DCT of the kidney, there is greater activity of the Na+/K+ pump on the luminal surface of the epithelia, pumping more K+ back into the DCT cells out of the blood, decreasing the K+ concentration in plasma

Question 8

Why is Na+ higher than normal in Liddle’s syndrome?

Answer 8

ENaC channel in the DCT of the kidney is overactive (as the channel doesn’t degrade due to mutation) so more Na+ is in the plasma

Question 9

Why is HCO3- higher than normal in Liddle’s syndrome?

Answer 9

Increased Na+ influx into the DCT cells and thereafter will create a charge difference, and HCO3- may follow to create electroneutrality once more

Question 10

Why are creatinine and creatinine clearance tested for?

Answer 10

To ensure the healthy functioning of kidneys

Question 11

Why is plasma renin activity low in Liddle’s syndrome?

Answer 11

This molecule works to increase Na+ reabsorption in DCT when levels are low but levels are already high due to mutation of ENaC receptor

Question 12

Why is plasma aldosterone activity low in Liddle’s syndrome?

Answer 12

This molecule works to increase Na+ reabsorption in DCT when levels are low but levels are already high due to mutation of ENaC receptor

Question 13

How may left ventricular hypertrophy be diagnosed on ECG?

Answer 13

Thickened walls lead to greater sized R wave (ventricular depolarisation) as well as delayed repolarisation (ST interval) due to greater amount of muscle

Question 14

How may left ventricular hypertrophy be diagnosed on an echocardiogram?

Answer 14

Sounds waves produce live action images of heart so this can reveal thickened muscle, blood flow in each beat and associated heart abnormalities

Question 15

Why may there be left ventricular hypertrophy in Liddle’s syndrome?

Answer 15

There is a greater blood volume and therefore hypertrophy in order to have sufficient contractility to pump this increased volume around the body

Question 16

What does the renin-angiotensin-aldosterone system (RAAS) do?

Answer 16

Maintains steady level of blood sodium

Question 17

Describe the response of the renin-angiotensin-aldosterone system to low blood sodium

Answer 17

Sensed by low Na+ in DCT tubule fluid –> juxtaglomerular cells release renin –> diffuses into blood –> veins –> liver –> cleaves angiotensinogen –> angiotensin peptides –> lungs –> converted to angiotensin II by ACE –> acts on adrenal cortex –> aldosterone –> increases sodium retention in DCT of kidney –> increases blood volume as water follows

Question 18

Which cells release renin?

Answer 18

Juxtaglomerular cells

Question 19

Where is angiotensin II formed?

Answer 19

Lungs (by ACE)

Question 20

Which molecule cleaves angiotensinogen?

Answer 20

Renin

Question 21

Where does angiotensin II act?

Answer 21

Adrenal cortex

Question 22

Where is aldosterone released?

Answer 22

Adrenal cortex

Question 23

Where is sodium primarily reabsorbed in the kidney?

Answer 23

DCT

Question 24

Where does aldosterone act?

Answer 24

Sodium channels of DCT

Question 25

How is the nervous system involved in regulating blood volume?

Answer 25

Sensory nerve fibres in right atrium (some in LA) act as stretch receptors, if they stretch more they signal volume of blood returning to the heart per minute via vagus (CN X) to brainstem –> inhibits sympathetic output to decrease BP

Question 26

How is the hormonal system involved in regulating blood volume?

Answer 26

Specialised muscle cells in RA and IVC act as stretch receptors and in response to stress (excess stretch) they release ANP which decreases Na+ reabsorption in DCT (opposed aldosterone)

Question 27

When and where is atrial natriuretic peptide released (ANP)?

Answer 27

Specialised muscle cells in RA and IVC (heart) in response to stress (blocks action of aldosterone –> reduces BP)

Question 28

When and where is brain-derived natriuretic peptide released (BNP)?

Answer 28

Specialised muscle cells in RA and IVC (heart) in response to ventricular over-stretching so is only released in heart failure

Question 29

Where is the osmotic pressure of blood measured?

Answer 29

Osmoreceptors in the paraventricular and supraoptic nucleus

Question 30

How is angiotensin II involved in the control of blood pressure?

Answer 30

Angiotensin II also acts directly on arterioles –> constriction

Question 31

What happens if hypo-osmolarity is detected in the brainstem?

Answer 31

Renin release from kidney (direct attachment via sympathetic nervous fibres) to increase Na+ reabsorption and then ADH release is inhibited in pituitary gland to allow more water loss –> increase osmolarity of blood

Question 32

What are the initial treatments for hypertension?

Answer 32

ACE inhibitors and angiotensin receptor antagonists

Question 33

Why don’t ACE inhibitors or angiotensin receptor antagonists reduce hypertension in someone with Liddle’s disease?

Answer 33

Prevents production/blocks angiotensin production to stop aldosterone production and prevent sodium uptake in DCT from increasing blood volume and pressure. However, in Liddle’s disease there are too many sodium (ENaC) receptors due to mutation anyway, so will always have sodium retention causing increased blood volume.

Question 34

Describe how Liddle’s syndrome is inherited

Answer 34

Gene causing syndrome is dominant, so if patient is heterozygous, have 50% chance of passing condition onto child

Question 35

Describe the mechanism of action of amiloride

Answer 35

Blocks ENaC channel so sodium can’t enter DCT epithelia –> charge difference not created –> no driving force for chloride to follow –> NaCl stays in tubule fluid so urine stays dilute (prevents water uptake contributing to hypertension)

Question 36

Describe how ENaC channels usually function on DCT in kidney

Answer 36

Na+ absorption in DCT, which then leaves basolateral side causing a charge gradient –> Cl- follows to form NaCl and when not required any more the cell responds to signals to degrade itself and it does

Question 37

Describe how Liddle’s syndrome changes the function of the ENaC receptor on the DCT of the kidney

Answer 37

SCN

Question 38

What may be a consequence of taking amiloride?

Answer 38

Can lead to too much K+ in the blood as a result of lacking Na+ in DCT as Na+/K+ on basolateral surface will cease but passive diffusion of K+ into lumen will not, and this can lead to hyperkalaemia

Question 39

Describe the structure of the ENaC channel

Answer 39

2 alpha subunits, 1 beta and 1 gamma

Question 40

How can Liddle’s syndrome lead to hypokalaemia?

Answer 40

If there is greater sodium influx into the DCT epithelia, this will cause greater activity of the Na+/K+ pump on the basolateral surface so more K+ will be transported out of the blood and this can lead to hypokalaemia

Question 41

Which substance opposes the action of aldosterone?

Answer 41

ANP (atrial natriuretic peptide)

Question 42

Where is ADH produced?

Answer 42

Pituitary gland

Question 43

Which molecule is involved in triggering the ENaC transporters to degenerate?

Answer 43

Nedd4-2

Question 44

How can hypertension lead to the development of left ventricular hypertrophy?

Answer 44

Hypertension generates an increase in afterload and therefore the heart has to work harder to eject the same volume of blood during systole. Over time the increased workload can lead to the development of left ventricular hypertrophy (thickening of the myocardium).

Question 45

Name a hormone (other than aldosterone) that acts in the distal tubule and collecting ducts to reduce loss of water in the urine

Answer 45

ADH

Question 46

Explain how mutations in the C-terminus of the ENaC channel subunits lead to the hypertension observed in Liddle’s syndrome

Answer 46

Mutations cause the loss of the interaction domains in the C terminus of the ENaC subunits –> Inability for Nedd4-2 to bind to the channel –> increased activation of the ENaC –> Increased retention of sodium and water in the blood –> Increase in blood volume and therefore an increase in blood pressure.