Aldosterone

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Aldosterone

Skeletal formula of the fictitious aldehyde form[1]

Ball-and-stick model of the 18-acetal-20-hemiketal form based on crystallography[2][3]
Names
IUPAC name
11β,21-Dihydroxy-3,20-dioxopregn-4-en-18-al
Systematic IUPAC name
(1S,3aS,3bS,9aR,9bS,10S,11aR)-10-Hydroxy-1-(hydroxyacetyl)-9a-methyl-7-oxo-1,2,3,3a,3b,4,5,7,8,9,9a,9b,10,11-tetradecahydro-11aH-cyclopenta[a]phenanthrene-11a-carbaldehyde
Other names
Aldocorten; Aldocortin; Electrocortin; Reichstein X; 18-Aldocorticosterone; 18-Oxocorticosterone
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.000.128 Edit this at Wikidata
IUPHAR/BPS
KEGG
MeSH Aldosterone
UNII
  • InChI=1S/C21H28O5/c1-20-7-6-13(24)8-12(20)2-3-14-15-4-5-16(18(26)10-22)21(15,11-23)9-17(25)19(14)20/h8,11,14-17,19,22,25H,2-7,9-10H2,1H3/t14-,15-,16+,17-,19+,20-,21+/m0/s1 checkY
    Key: PQSUYGKTWSAVDQ-ZVIOFETBSA-N checkY
  • InChI=1/C21H28O5/c1-20-7-6-13(24)8-12(20)2-3-14-15-4-5-16(18(26)10-22)21(15,11-23)9-17(25)19(14)20/h8,11,14-17,19,22,25H,2-7,9-10H2,1H3/t14-,15-,16+,17-,19+,20-,21+/m0/s1
    Key: PQSUYGKTWSAVDQ-ZVIOFETBBV
  • O=C(CO)[C@@H]4[C@@]3(C=O)C[C@H](O)[C@@H]2[C@@]1(/C(=C\C(=O)CC1)CC[C@H]2[C@@H]3CC4)C
Properties
C21H28O5
Molar mass 360.450 g·mol−1
Pharmacology
H02AA01 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Aldosterone is the main mineralocorticoid

atrial natriuretic hormone secreted by the heart.[7]

Aldosterone is part of the

plasma half-life of less than 20 minutes.[9] Drugs that interfere with the secretion or action of aldosterone are in use as antihypertensives, like lisinopril, which lowers blood pressure by blocking the angiotensin-converting enzyme
(ACE), leading to lower aldosterone secretion. The net effect of these drugs is to reduce sodium and water retention but increase the retention of potassium. In other words, these drugs stimulate the excretion of sodium and water in urine, while they block the excretion of potassium.

Another example is spironolactone, a potassium-sparing diuretic of the steroidal spirolactone group, which interferes with the aldosterone receptor (among others) leading to lower blood pressure by the mechanism described above.

Aldosterone was first isolated by Sylvia Tait (Simpson) and Jim Tait in 1953; in collaboration with Tadeusz Reichstein.[10][11][12]

Biosynthesis

The

17α-hydroxylase
).

Aldosterone and

oxidation. Moreover, aldosterone synthase is found within the zona glomerulosa at the outer edge of the adrenal cortex; 11β-hydroxylase is found in the zona glomerulosa and zona fasciculata
.

Steroidogenesis, showing aldosterone synthesis at upper-right corner.[13]

Aldosterone synthase is normally absent in other sections of the adrenal gland.[14]

Stimulation

Aldosterone synthesis is stimulated by several factors:

The secretion of aldosterone has a diurnal rhythm.[16]

Biological function

Aldosterone is the primary of several endogenous members of the class of mineralocorticoids in humans. Deoxycorticosterone is another important member of this class. Aldosterone tends to promote Na+ and water retention, and lower plasma K+ concentration by the following mechanisms:

  1. Acting on the nuclear
    Na+/K+ pumps
    , which pumps three sodium ions out of the cell, into the interstitial fluid and two potassium ions into the cell from the interstitial fluid. This creates a concentration gradient which results in reabsorption of sodium (Na+) ions and water (which follows sodium) into the blood, and secreting potassium (K+) ions into the urine (lumen of collecting duct).
  2. Aldosterone upregulates epithelial sodium channels (
    ENaCs) in the collecting duct
    and the colon, increasing apical membrane permeability for Na+ and thus absorption.
  3. Cl− is reabsorbed in conjunction with sodium cations to maintain the system's electrochemical balance.
  4. Aldosterone stimulates the secretion of K+ into the tubular lumen.[17]
  5. Aldosterone stimulates Na+ and water reabsorption from the gut, salivary and sweat glands in exchange for K+.
  6. Aldosterone stimulates secretion of H+ via the H+/ATPase in the
    intercalated cells
    of the cortical collecting tubules
  7. Aldosterone upregulates expression of NCC in the distal convoluted tubule chronically and its activity acutely.[18]

Aldosterone is responsible for the reabsorption of about 2% of filtered sodium in the kidneys, which is nearly equal to the entire sodium content in human blood under normal glomerular filtration rates.[19]

Aldosterone, probably acting through mineralocorticoid receptors, may positively influence neurogenesis in the dentate gyrus.[20]

Mineralocorticoid receptors

transcription
. Some of the transcribed genes are crucial for transepithelial sodium transport, including the three
channel-inducing factor
, respectively.

The MR is stimulated by both aldosterone and cortisol, but a mechanism protects the body from excess aldosterone receptor stimulation by glucocorticoids (such as cortisol), which happen to be present at much higher concentrations than mineralocorticoids in the healthy individual. The mechanism consists of an enzyme called

glycyrrhetinic acid
, can inhibit 11β-HSD and lead to a mineralocorticoid excess syndrome.

Control of aldosterone release from the adrenal cortex

The renin–angiotensin system, showing role of aldosterone between the adrenal glands and the kidneys[21]

Major regulators

The role of the renin–angiotensin system

Angiotensin is involved in regulating aldosterone and is the core regulation.[22] Angiotensin II acts synergistically with potassium, and the potassium feedback is virtually inoperative when no angiotensin II is present.[23] A small portion of the regulation resulting from angiotensin II must take place indirectly from decreased blood flow through the liver due to constriction of capillaries.[24] When the blood flow decreases so does the destruction of aldosterone by liver enzymes.

Although sustained production of aldosterone requires persistent

Voltage-gated Ca2+ channels have been detected in the zona glomerulosa of the human adrenal, which suggests that Ca2+ channel blockers may directly influence the adrenocortical biosynthesis of aldosterone in vivo.[26]

The plasma concentration of potassium

The amount of plasma renin secreted is an indirect function of the serum potassium[27][28] as probably determined by sensors in the carotid artery.[29][30]

Adrenocorticotropic hormone

Adrenocorticotropic hormone (ACTH), a pituitary peptide, also has some stimulating effect on aldosterone, probably by stimulating the formation of deoxycorticosterone, a precursor of aldosterone.[31] Aldosterone is increased by blood loss,[32] pregnancy,[33] and possibly by further circumstances such as physical exertion, endotoxin shock, and burns.[34][35]

Miscellaneous regulators

The role of
sympathetic nerves

The aldosterone production is also affected to one extent or another by nervous control, which integrates the inverse of carotid artery pressure,[29] pain, posture,[33] and probably emotion (anxiety, fear, and hostility)[36] (including surgical stress).[37] Anxiety increases aldosterone,[36] which must have evolved because of the time delay involved in migration of aldosterone into the cell nucleus.[38] Thus, there is an advantage to an animal's anticipating a future need from interaction with a predator, since too high a serum content of potassium has very adverse effects on nervous transmission.

The role of baroreceptors

Pressure-sensitive baroreceptors are found in the vessel walls of nearly all large arteries in the thorax and neck, but are particularly plentiful in the sinuses of the carotid arteries and in the arch of the aorta. These specialized receptors are sensitive to changes in mean arterial pressure. An increase in sensed pressure results in an increased rate of firing by the baroreceptors and a negative feedback response, lowering systemic arterial pressure. Aldosterone release causes sodium and water retention, which causes increased blood volume, and a subsequent increase in blood pressure, which is sensed by the baroreceptors.[39] To maintain normal homeostasis these receptors also detect low blood pressure or low blood volume, causing aldosterone to be released. This results in sodium retention in the kidney, leading to water retention and increased blood volume.[40]

The plasma concentration of sodium

Aldosterone levels vary as an inverse function of sodium intake as sensed via osmotic pressure.[41] The slope of the response of aldosterone to serum potassium is almost independent of sodium intake.[42] Aldosterone is increased at low sodium intakes, but the rate of increase of plasma aldosterone as potassium rises in the serum is not much lower at high sodium intakes than it is at low. Thus, potassium is strongly regulated at all sodium intakes by aldosterone when the supply of potassium is adequate, which it usually is in "primitive" diets.

Aldosterone feedback

Feedback by aldosterone concentration itself is of a nonmorphological character (that is, other than changes in the cells' number or structure) and is poor, so the electrolyte feedbacks predominate, short term.[34]

Associated clinical conditions

Hyperaldosteronism is abnormally increased levels of aldosterone, while hypoaldosteronism is abnormally decreased levels of aldosterone.

A measurement of aldosterone in blood may be termed a plasma aldosterone concentration (PAC), which may be compared to plasma renin activity (PRA) as an aldosterone-to-renin ratio.

Hyperaldosteronism

Secondary hyperaldosteronism, on the other hand, is due to overactivity of the renin–angiotensin system
.

Conn's syndrome
is primary hyperaldosteronism caused by an aldosterone-producing adenoma.

Depending on cause and other factors, hyperaldosteronism can be treated by surgery and/or medically, such as by

aldosterone antagonists
.

The ratio of renin to aldosterone is an effective screening test to screen for primary hyperaldosteronism related to

adrenal adenomas.[44][45] It is the most sensitive serum blood test to differentiate primary from secondary causes of hyperaldosteronism.[46] Blood obtained when the patient has been standing for more than 2 hours are more sensitive than those from when the patient is lying down. Before the test, individuals should not restrict salt and low potassium should be corrected before the test because it can suppress aldosterone secretion.[46]

Hypoaldosteronism

An ACTH stimulation test for aldosterone can help in determining the cause of hypoaldosteronism, with a low aldosterone response indicating a primary hypoaldosteronism of the adrenals, while a large response indicating a secondary hypoaldosteronism. The most common cause of this condition (and related symptoms) is Addison's disease; it is typically treated by fludrocortisone, which has a much longer persistence (1 day) in the bloodstream.

Additional images

References

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