Mineralocorticoids: aldosterone
Aldosterone is involved in the regulation of the metabolism of sodium and potassium,and is the main mineralocorticoid. Aldosterone and its principal antagonist, spironolactone, have been known for more than forty years.
Metabolism of aldosterone
Aldosterone is synthesized in the glomerular part of the adrenal cortex where there is no 17-alpha-hydroxylase activity but an 18-hydroxylase activity. Aldosterone results from cholesterol which is transformed successively into pregnenolone, progesterone, deoxycorticosterone, corticosterone, 18-hydroxycorticosterone and finally aldosterone. Aldosterone is also synthesized in heart and vessels which however do not secrete it in plasma.
The factors which increase aldosterone secretion are by order of importance: angiotensin II and III, the rise in kalemia and ACTH. The factors which decrease its secretion are atrial natriuretic peptide and dopamine.
Aldosterone in plasma, contrary to cortisol, is not highly bound to plasma proteins. Its plasma concentration is much increased during congestive heart failure.
Aldosterone is inactivated by reactions of reduction and conjugation.
Effect on fluid and electrolytes
The essential effect of aldosterone is renal: it induces sodium retention and increases potassium elimination.
Aldosterone has fast, almost immediate effects (less than one hour), and delayed effects appearing two to three hours after its administration during for six to twelve hours, even twenty-four hours. Its fast effects are the consequence of its membrane action by stimulation of the Na+/H+ exchanger which induces the absorption of Na+ at the apical pole of the parietal cells of the nephron. The rise in the intracellular sodium concentration then activates the Na+/K+- ATPase pump and the reabsorption of sodium.
Its late effects results from its nuclear action: aldosterone penetrates in the cell, binds to a cytoplasmic receptor, and the complex formed penetrates into the nucleus where it activates specific zinc finger receptors and induces the synthesis of specific proteins called AIP, aldosterone induced proteins, such as the Na+/K+-ATPASE pump located at the basal pole of the cells of the distal nephron and of the colon. The decrease of the intracellular sodium concentration under the effect of Na+/K+-ATPASE induces its passive reabsorption at the apical pole by sodium channels. The increase in intracellular K+ induces its elimination.
Moreover, aldosterone, by reinforcing intercellular junctions, reduces the passive diffusion of electrolytes.
In addition to its renal effect, aldosterone has a direct action on vascular smooth muscles which it constricts. It could worsen congestive heart failure.
Pperhaps via its effects on electrolytes, aldosterone has a positive inotropic effect and a coronary vasoconstrictor effect.
Note:
Cortisol present in the epithelial cells of the renal tubule can also stimulate the mineralocorticoid receptors, but it is inactivated by its conversion into cortisone under the influence the 11-ß-hydroxysteroid-deshydrogenase or oxydo-reductase. The inhibition of this enzyme by certain compounds leads to an increase in intracellular cortisol and the appearance of a syndrome of apparent mineralocorticoid excess.
The mineralocorticoid effect of glycirrhizinic acid present in certain drinks containing liquorice and of one of its derivatives, carbenoxolone (which was used for the treatment of gastric ulcer), results from the inhibition of the 11-ß-hydroxysteroid-deshydrogenase and intracellular accumulation of cortisol.
Therapeutic use
The only therapeutic use of a mineralocorticoid is the treatment of its deficiency. As aldosterone itself is not marketed, one uses
- desoxycortone which, is not absorbed by the digestive tract and has to be given by intramuscular injection.
- fludrocortisone or 9-a-fluorocortisol which, in addition to its glucocorticoid effect, has an extremely powerful mineralocorticoid effect, more than 100 times that of cortisol, and is taken by oral route
The main adverse effects of mineralocorticoid are edema and arterial hypertension, direct consequences of their action.
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