Aldosterone
[Ref: WG21:Chp20; AV6:p116-118]
Basics
Synthesis
Produced in zona glomerulosa
Zona glomerulosa lacks 17alpha-hydroxylase activity, but is the only zone that contains aldosterone synthase.
Steps of production
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Cholesterol converted to Pregnenolone
--> Progesterone
--> 11-Deoxycorticosterone
--> Corticosterone
--> 18-Hydroxycorticosterone
--> Aldosterone
NB:
- Aldosterone synthase is responsible for the last three steps
- Conversion from 11-deoxycorticosterone to corticosterone is normally by 11beta-hydroxylase in other part of adrenal gland.
--> In zona glomerulosa, 11beta-hydroxylase is absent and conversion is done by aldosterone synthase
- 17alpha-hydroxylase is also missing in zona glomerulosa
* Normally responsible for conversion of pregnenolone and progesterone into sex hormones
Halflife
Bound to protein slightly
Halftime is short: about 20 minutes
Metabolism
Most converted to tetrahydroglucuronide derivative in liver
Some converted to 18-glucuronide in liver and kidney
* Reverts back to free aldosterone at pH 1
* i.e. acid-labile conjugate
Less than 1% excreted in urine in free form.
Mineralocorticoid receptors
[WG21:p379]
11beta-hydroxysteroid dehydrogenase type 2
Mineralocorticoid receptors actually have higher affinity for glucocorticoids than glucocorticoid receptors do
* i.e. glucocorticoids bind to mineralocorticoid receptor better than to glucocorticoid receptors
However,
In kidney and other mineralocorticoid-sensitive tissues, enzyme (11beta-hydroxysteroid dehydrogenase type 2) is present that converts cortisol and corticosterone into steroid forms that do not bind to the mineralocorticoid receptors.
If this enzyme is absent or inhibited (e.g. by prolonged ingestion of licorice)
--> Cortisol has marked mineralocorticoid effect
--> Apparent mineralocorticoid excess syndrome
Apparent mineralocorticoid syndrome
- Symptoms of hyperaldosteronism
Actions
[WG21:p378]
Actions
Main Action:
* Sodium resorption
Other actions:
* Increase urinary K+ loss
* Increase urinary H+ loss
NB:
- Sodium is in effect reabsorbed in exchange for K+ and H+
--> Aldosterone increases urines K+ loss and urinary acidity
Sodium resorption
- Mainly by the cortical connecting tubule and cortical collecting duct.
- Sodium reabsorption is by principle cells
* Principle cells are also the site of water regulation by ADH
- Stimulate sodium transport by other epithelia such as sweat, salivary duct, intestine
--> All promote sodium retention
- Effect takes 10-30 minutes to develop and even longer to peak
Mechanism of action
[AV6:p117]
Cross freely into principle cells
--> Combine with mineralocorticoid receptors in the cytoplasm
--> Receptor acts as transcription factor
--> synthesis of specific mRNA and protein
--> Increase activity/number of apical sodium channel and basolateral Na-K ATPase pump
NB:
- Increase in ENaC is in 2 phases:
* Rapid effect by increasing insertion from cytoplasmic pool of ENaCs
* Slower effect by increasing synthesis of ENaCs
- ENaC is inhibited by amiloride [WG21:p34]
Significance of sodium retention effect
[AV6:p117]
Complete absence of aldosterone
--> 2% of filtered sodium would be excreted
Maximal aldosterone level
--> Almost no sodium excreted
Adrenal insufficiency
[WG21:p379]
Loss of mineralocorticosteroid leads to
- Na+ loss in urinary
- Na+ movement into cells
- Elevated plasma [K+]
- Decreased plasma [Na+]
* If ADH is still normal, then Na+ loss is greater than water loss
- Reduced ECF volume
--> Eventually hypotension and shock
Effect of excess mineralocorticoid
[WG21:p380]
- Prolonged K+ diuresis
--> K+ depletion
- H+ loss in urine
- Plasma [Na+] level is only slightly elevated
* Because water is retained as well
--> Increased ECF
Regulation
Factors affecting aldosterone secretion
[WG21:p381]
3 primary factors stimulating aldosterone release
- ACTH (transient effect only)
- Angiotensin II
- Increased in plasma [K+]
* Direct effect on adrenal cortex
Effect of ACTH
- Transient stimulatory effect on aldosterone
- Aldosterone output declines after 1-2 days of elevated ACTH
- Deoxycorticosterone (also a mineralocorticoid, see below) stays elevated
Role of angiotensin II
Angiotensin II binds to AT1 receptors in the zona glomerulosa
--> Act via G protein
--> Activating phospholipase C
--> In increased protein kinase C
Thus,
- Stimulates conversion of cholesterol to pregnenolone
- Stimulates conversion of corticosterone to 18-hydroxycorticosterone
NB:
- [AV6:p119] Only angiotensin II produces a change in aldosterone that is directly related to sodium balance
Effect of K+
Need to increase only by 1meq/L to stimulate aldosterone secretion
Acts by depolarising the cells
--> Opening up voltage-gated Ca2+ channels
--> Increase intracellular Ca2+
Increases sensitivity of zona glomerulosa to angiotensin II
Factors stimulating secretion of both aldosterone and glucocorticoids
- Surgery
- Anxiety
- Trauma
- Haemorrhage
* via ACTH and renin
- ACTH
Factors stimulating aldosterone secretion without effect on glucocorticoids
- High K+ intake
- Low Na+ intake
- Standing
- Secondary hyperaldosteronism
* Some cases of congestive heart failure
* Cirrhosis
* Nephrosis
Standing
Aldosterone release is increased in standing position because
- Decreased hepatic clearance
- Increase in renin and hence angiotensin II
ANP inhibiting aldosterone release
[AV6:p117]
[WG21:p383]
- ANP inhibits renin secretion and decrease responsiveness of the zona glomerulosa to angiotensin II
Interaction with ANP
In mineralocorticoid excess,
Once ECF expansion passes a certain point
--> Na+ excretion is increased in spite of actions of excess mineralocorticoids
--> Escape phenomenon
Probably due to increased secretion of ANP
Others
[KB-acidbase:7.2] Primary hyperaldosteronism often cause metabolic alkalosis with increase ECF, hypokalaemia and hypochloraemia.
Other steroids affecting Na+ excretion
- Deoxycorticosterone
* 3% of mineralocorticoid effect of aldosterone
- Progesterone
* Large doses cause natriuresis
