Lecture 20 - Volume regulation

Question 1

What is Juxtaglomerular apparatus (JGA)?

Answer 1

The complex of the late distal tubule in association with the renal afferent arteriole.

Question 2

What is the aim of the renin-angiotensin-aldosterone system?

Answer 2

To increase the effective circulating volume

Question 3

What are the two main physiological triggers for aldosterone release?

Answer 3

ATII and Hyperkalaemia.

Question 4

Why must there be two triggers for aldosterone release?

Answer 4

The convergence of these signalling pathways means that, were aldosterone alone the only regulator of ATII action of the kidney, K+ and volume regulation could not be independently regulated. This leads to the implication that ATII must have other renal actions.

Question 5

Why must we be able to inhibit the renin-angiotensin system?

Answer 5

In order to control blood pressure

Question 6

What are the four different locations where renin-angiotensin can be inhibited?

Answer 6

• ACE inhibitors
• AT1 inhibitors
• Aldosterone receptor antagonists
• Renin inhibition

Question 7

What are angiotensin II receptors?

Answer 7

• The main receptors in the periphery for the effect of ATII is the AT1 receptor.
• It is mainly coupled through Gg, so it is linked to an increase in IP3/DAG signalling and increased Ca2+ release from intracellular stored (e.g., in smooth muscle cells and the granule cells of the juxtaglomerular apparatus)
• The inhibitors of AT1 receptors, the ‘sartans’ don’t have the side effect of coughing that ACE inhibitors can have so while more expensive, they are commonly prescribed for hypertension.

Question 8

What are the four key actions of angiotensin II?

Answer 8

1. Increase Na+/H+ exchange in the proximal tubule, hence proximal Na+ and water reabsorption.
2. Increase in aldosterone release from the adrenal cortex, which increases distal Na+ absorption.
3. Cause ADH release.
4. Causes thirst

Question 9

What can haemorrhage lead to?

Answer 9

• Decreased vascular volume, decreased venous pressure, decreased cardiac filling, decreased cardiac output, decreased circulating volume
• Decreased blood pressure, increased sympathetic activity, increased rain release
• With decrease in blood pressure, sensed by afferent arteriole, causing a fall in wall tension and causes release of renin

Question 10

What are the effects of activating sympathetic innervation of afferent arteriole?

Answer 10

• vasoconstriction upstream of the granule cells causes a further fall in the pressure sensed by these cells, and hence amplifies the fall in wall pressure generated by a fall in blood pressure.
• Direct stimulation of renin release from the granule cells.
• Afferent arteriole vasoconstriction drops glomerular hydrostatic pressure to the glomerulus and hence lower GFR.

Question 11

Describe sympathetic effector transmission in the afferent arteriole

Answer 11

• The key recognised sympathetic transmitter is noradrenaline
• On the vascular smooth muscle cells, vasoconstriction is caused by an action of alpha1-adrenoreceptors. These are Gg coupled.
• On the granule cells (for the regulation of renin release) the main receptors are beta1-adrenoreceptors. as elsewhere, these are Gs coupled.

Question 12

What is meant by the third stimulus to renin release?

Answer 12

• With a fall in the blood volume, the venous pressure falls, as the venous system is the main source of capacitance in the circulation.
• This fall in venous pressure causes a fall in the pressure in the vasa recta, hence an increase in the uptake of fluid from the renal interstitial space.
• This means a greater loss of fluid from the filtrate, particularly in the descending limb of the loop of henle
• This decrease Na+ delivery to the distal tubule, which acts a further stimulus to renin release.

Question 13

Describe ADH release following haemorrhage

Answer 13

• Decreased cardiac filling, activation of the baroreceptor reflex, and the central actions of ATII all cause an increase in the release of ADH following haemorrhage.
• This release leads to an increase in water reabsorption and hence the maintenance of circulating volume.
• This effect will lower osmolality because the mechanism does not retain Na+. So, the acute response to haemorrhage will involve hyponatraemia.

Question 14

What is the interaction between osmoregulation and volume regulation?

Answer 14

• Volume regulation disturbs osmoregulation.
• The body accepts decreased osmolality in order to maintain low volume.
• The primary effect of ADH will be to drop osmolality.

Question 15

What is Atrial natriuretic peptide (ANP)?

Answer 15

• An 28-amino acid peptide with a 17-amino acid ring. Increased venous return leads to increased atrial filling, leads to increase ANP release.
• ANP travels to the kidney, acts on ANPa,b receptors activating the intrinsic guanylyl cyclase activity (increased cGMP).

Question 16

What are some sites and mechanisms of the action go ANP downstream of cGMP?

Answer 16

• Causes a receptor-mediated increase in cGMP, which dilates the afferent glomerular arteriole, increasing GFR (which increases Na+ delivery to the kidney).
• Decreased Na+/Cl co-transport activity in the distal tubule
• Decreases ENaC and Na+/K+ ATPase activity in the cortical collecting duct.

Question 17

What is the net effect of ANP?

Answer 17

Increase in renal na+ excretion in the urine, hence it is natriuretic

Question 18

Describe the role of prostaglandins

Answer 18

• Both PGE2 and PGI2 (prostacyclin) are produced tonically.
• Both increase Na+ excretion
• If this tonic system is inhibited, this will lead to a fall in prostaglandins and hence Na+ retention
• In people with normal renal function this effect of NSAIDs may be insignificant but it becomes more important in renal failure.

Question 19

Where is dopamine synthesised and what is its role?

Answer 19

• Synthesised in the kidneys, mainly by the epithelial cells in the proximal tubule, in part from sympathetic nerve terminals.
• Dopamine tonically acts via both, receptors to increase cAMP, and decrease the activity of the Na+/H+ exchanger in the proximal tubule.
• This leads to increased Na+ excretion.