Hormonal Control of Blood Pressure

Question 1

What did Harry Goldblatt notice in post-mortems in 1934? What did this lead him yo discover?

Answer 1

Narrowing of the renal (kidney) blood vessels in patients who had died of hypertension.
This made him think “Could renal ischemia cause hypertension??”
He did experiments where he constricted the major renal arteries of dogs using a home-made adjustable silver clamp.
Partial constriction of both renal arteries resulted in a reproducible and persistent rise in blood pressure.
Goldblatt’s explanation for this rise in blood pressure was that the ischemic kidneys produced an “internal secretion” that caused hypertension.
Goldblatt’s discovery was spectacular, but nobody believed it at first
The scepticism was largely because of the technical difficulty of Goldblatt’s procedure, which few could reproduce.
However Goldblatt was proved right in 1939 when the identity of the “internal secretion” as the enzyme renin was confirmed.
Goldblatt was nominated in 1940 for a Nobel Prize for his work, but unfortunately the war intervened and he never received a prize.

Question 2

What is hormonal control of blood pressure mediated by?

Answer 2

The kidney

Question 3

Where does the main renal artery go as it enters the kidney? Where do these vessels terminate?

Answer 3

Divides into interlobar vessels
These divide into small arcuate (arch-shaped) arteries in the renal cortex
The arcuate arteries terminate in a little clump of capillaries in the cortex called a glomerulus

Question 4

What is each capillary glomerulus enclosed in?

Answer 4

Each capillary glomerulus is enclosed inside a bag of tissue called BOWMAN’S CAPSULE. The first stage of urine formation is the filtering of plasma from the glomerular capillaries into the space of the capsule

Question 5

Where does blood enter the glomerulus of each nephron? Where does it leave?

Answer 5

About 20% of the blood plasma is filtered through the glomerulus and enters the capsular space which empties into the proximal tubule.
The remaining 80% leaves in the efferent arteriole

Question 6

What does the difference in diameter between afferent and efferent arterioles cause?

Answer 6

Afferent arterioles have larger diameters than efferent arterioles, so there is considerable drop (???) in pressure between afferent and efferent arteriole.
This is the filtration pressure driving fluid through the endothelium of the capillaries into the capsular space

Question 7

Where do water and electrolytes from the plasma pass through?

Answer 7

They pass into the proximal (convoluted) tubule and through other parts of the kidney [discussed in a later lecture] to reach the distal (convoluted) tubule.

Question 8

What does a part of the distal tubule contact?

Answer 8

The point where the afferent and efferent arterials enter the glomerulus.

Question 9

What do the afferent and efferent arterioles, together with the distal tubule, form?

Answer 9

The juxtaglomerular apparatus (JGA)

Question 10

What cells line the distal tubule at the JGA? What do these cells control?

Answer 10

Special epithelial cells called the macula densa

These macula densa cells control the activity of a second set of specialised epithelial cells, the juxtaglomerular cells

Question 11

How is the proportion of plasma water filtered into the proximal tubule (glomerular filtration rate or GFR) kept constant?

Answer 11

By a process linking sodium concentration in the distal tubule fluid to vasoconstriction or dilation in the afferent arterioles; this is called tubuloglomerular feedback

Question 12

How does tubuloglomerular feedback maintain a constant glomerular filtration rate?

Answer 12

Sodium is absorbed at a fixed rate from the fluid filtered into the proximal tubule.
Thus a low sodium level in the distal tubule may be an index of a low glomerular filtration rate:
Because a fixed amount of sodium is being removed by uptake from the proximal tubule per minute, if the amount of sodium delivered to the tubule per minute in filtered fluid decreases (due to reduced filtration) then less sodium is left in the fluid reaching the distal tubule.
A low sodium concentration in the distal tubule triggers relaxation of the vascular smooth muscle of the afferent arteriole.
This increases the pressure in the glomerulus, increases filtration and thus increases delivery of sodium to the tubule.

Question 13

What else could a low sodium level in the distal tubule indicate? What does this cause?

Answer 13

A low sodium level in the distal tubule could also indicate a low concentration of sodium in the arterial blood.
When the sodium concentration in the distal tubular falls below a certain threshold, as well as initiating tubuloglomerular feedback the macula densa cells activate the juxtaglomerular cells to release the enzyme renin into the blood stream

Question 14

What happens to the renin released from the juxtaglomerular cells?

Answer 14

It passes into the venous blood, where it reacts with a globular protein angiotensinogen secreted by the liver.
Renin enzymically splits off a decapeptide angiotensin I from the angiotensinogen precursor.

Question 15

What happens when angiotensin I passes through the lungs?

Answer 15

It is further cleaved by endothelial-bound angiotensin-converting enzyme (ACE) into an octapeptide angiotensin II

Question 16

What happens when angiotensin II passes into the arterial blood?

Answer 16

In the arterioles it acts on a G-protein coupled receptor Angiotensin receptor 1 (AT1r) which activates phospholipase C and increases the cytosolic Ca2+ concentrations, which in turn triggers constriction of the smooth muscle of systemic arterioles.

Question 17

What is the overall function of renin, via its product angiotensin II?

Answer 17

It raises total peripheral resistance and afterload, and thus, assuming a constant cardiac output, raises blood pressure

Question 18

What is circulating blood volume partly controlled by?

Answer 18

Plasma sodium concentration

Question 19

What are normal serum levels? What happens if they are below this?

Answer 19

Between approximately 135 and 145 mmol/L

If blood plasma levels are below 135 mmol/L, this is hyponatremia

Question 20

What does low blood sodium cause?

Answer 20

Decreases the osmotic pressure of plasma
This osmotic pressure keeps water in the blood and if low it allows plasma water to move out of the blood into the extravascular interstitial space in tissues.
The tissues swell and the blood volume shrinks

Question 21

What can mild hyponatraemia cause? What about severe?

Answer 21

Mild hyponatremia can cause: 
o	Loss of energy and fatigue 
o	Confusion, Muscle weakness, 
Severe hyponatremia:
o	is serious as it can cause a rise in intracranial pressure this leads to Nausea and vomiting, headache, Spasms
o	Restlessness and irritability
o	If prolonged, Seizures & Coma

Question 22

How does angiotensin stimulate sodium reabsorption from tubular fluid?

Answer 22

Angiotensin II receptors are found on cells in the adrenal cortex as well as vascular smooth muscle.
These cells secrete the mineralocorticoid steroid hormone aldosterone into the bloodstream.
Aldosterone stimulates epithelial channel proteins (ENACs) in the epithelial cells lining the walls of the distal tubule downstream from the juxtaglomerular apparatus.
These channel proteins take up sodium from the fluid in the distal tubule and pump it back into the interstitial fluid.
The increased sodium reabsorption in the interstitial space passes down its concentration gradient into the renal venous blood

Question 23

How does low blood sodium decrease blood volume?

Answer 23

If plasma sodium levels are low, low osmotic pressure (OP) means water is lost from blood due to hydrostatic pressure (HP) as it passes through capillaries: circulating blood volume is reduced

Question 24

What happens to fluid exchange in normal state? What about in decreased plasma sodium concentration? And increased plasma sodium concentration?

Answer 24

Normal state: water flows out of initial part of capillary where HP>OP and back in at end where OP>HP ; no change in blood volume at end of capillary
Decreased plasma sodium concentration: more water flows out of initial part of capillary due to decreased osmotic pressure; this is not compensated by inflow of water in final part of capillary: net loss of water from blood
Increased plasma sodium concentration: less water flows out of initial part of capillary due to increased osmotic pressure, more water flows back in in later part of capillary; net gain of water into blood

Question 25

How does increasing blood sodium restore blood volume?

Answer 25

Aldosterone increases blood sodium levels and thus the osmotic pressure in the capillaries. This draws water into the capillaries, thus restoring blood volume

Question 26

How does arteriolar constriction increase blood volume?

Answer 26

Angiotensin II makes arterioles constrict: this reduces the hydrostatic pressure in capillaries downstream from the arteriole and thus alllows water to move into the blood from the tissues. This increases total circulating blood volume.

Question 27

How does blood volume vary in normal state? What about during arteriolar constriction?

Answer 27

Normal state: water flows out of initial part of capillary and back in at end; no change in blood volume at end of capillary
Arteriolar vasoconstriction: less water flows out of initial part due to reduced hydrostatic pressure in capillary; more water flows into capillary at end; blood volume increases

Question 28

Summarise the role of the release of renin in regulating blood volume by regulating blood sodium

Answer 28

Renin release is increased by low sodium in the distal tubular fluid. One reason for this is a low sodium concentration in the arterial blood. Low blood sodium is an indicator of low circulating blood volume
Renin released by low levels of sodium in the distal tubule stimulates aldosterone release from the adrenal cortex. Aldosterone stimulates sodium reabsorption in the tubule and this increases blood sodium concentration
Increased blood sodium raises the osmotic pressure in the blood and this increases osmotically-driven water reabsorption from interstitial fluid into the blood as the blood passes through capillaries.
Arteriolar vasoconstriction reduces the hydrostatic pressure in capillaries and thus also increases water reabsorption in the capillaries and circulating blood volume
Overall: By increasing blood sodium levels and by arteriolar vasoconstriction the renin system restores a low circulating blood volume back to normal

Question 29

Stimulation of what can trigger renin release?

Answer 29

Stimulation of the sympathetic nervous system via the renal nerve can trigger renin release. There are beta adrenoreceptors on the juxtaglomerular cells. Noradrenaline and adrenaline act directly on these beta receptors to produce renin release

Question 30

What is the role of renin after haemorrhage?

Answer 30

After haemorrhage, sympathetic stimulation of renin and antidiuretic hormone release help maintain circulating blood pressure and volume.

Question 31

Can the RAA system malfunction?

Answer 31

Suppose the renal artery or the afferent arterioles are narrowed due to atheroma formation, or some other factor which reduces blood flow into the kidney.
This will reduce filtration at normal blood pressure, so more sodium will be absorbed in the proximal tubule, which will lead to a reduced sodium concentration in the distal tubule.
The juxtaglomerular cells will increase renin release, causing chronically raised blood pressure and circulating blood volume.

Question 32

If hypertension is due to excess angiotensin action, what is a logical way to reduce hypertension with drugs?

Answer 32

Use drugs which block the effect of angiotensin

Question 33

What two main types of drug are used to treat hypertension?

Answer 33

1. ACE inhibitors: (e.g. captopril). These block angiotensin converting enzyme and thus prevent formation of Angiotensin II.
2. Angiotensin receptor antagonists (e.g. losartan). These block angiotensin receptors.

Question 34

What does excess aldosterone levels due to excess renin release mean in a hypertensive person?

Answer 34

The hypertensive person will be retaining too much sodium and water.

Question 35

What is another approach to medicating hypertension if the patient is retaining too much sodium and water?

Answer 35

Another another approach will be to use diuretic drugs which increase salt and water excretion.
Commonly used diuretics are:
1. Thiazide derivatives (eg bendroflumethiazide) these block a sodium-chloride symporter in the distal tubule (not the Enac channel)
2. Aldosterone antagonists (eg spironolactone)
3. Loop diuretics (to be discussed in a later lecture)

Question 36

What is bradykinin? How is it affected by ACE inhibitors? What patient group is particularly affected?

Answer 36

Bradykinin is a nine amino acid peptide. It causes tissue swelling and inflammation.
Angiotensin converting enzyme inhibitors (ACE inhibitors) increase bradykinin levels by inhibiting its degradation.
- Bradykinin is the cause of the dry cough in which afflicts many patients taking ACE inhibitor drugs.
This refractory cough is a common cause for stopping ACE inhibitor therapy, in which case angiotensin II receptor antagonists (ARBs) are the next line of treatment
The elevation of bradykinin with ACE inhibitors may also result in angioedema, edema in the subcutaneous tissues. People of African descent have up to 5x increased risk of ACE inhibitor induced angioedema due to a hereditary predisposing risk. ACE inhibitors are therefore not the first line drugs for treating hypertension in afro-caribbean patients