Adrenal Gland: V Aldosterone
42-year-old Mr J-P T was referred to the hypertension clinic of his local hospital as his GP had established that he had hypertension in the order of 180–190/105–110. An ECG showed evidence of early left ventricular hypertrophy but fundoscopy was normal. Blood tests were taken and the results showed Na+ 144 mmol/L, K+ 2.8 mmol/L, with alkalosis and normal renal function. Repeated tests confirmed the hypokalaemia. Estimation of plasma renin and aldosterone at 0800 h with the patient recumbent showed elevated aldosterone concentrations and suppressed renin activity, consistent with a diagnosis of primary hyperaldosteronism. An abdominal MRI scan was done that revealed a 4 cm mass in the left adrenal gland. Mr T was treated with spironolactone to control his blood pressure and correct the hypokalaemia and after 8 weeks his blood pressure was normalized and he underwent adrenal surgery and removal of a left sided adrenal adenoma. Postoperatively, the spironolactone was withdrawn and his blood pressure remained within normal limits on no therapy.
Aldosterone is the physiological mineralocorticoid of the body. In other words, it is an adrenal corticosteroid which affects cation concentrations and movements, specifically those of sodium (Na+) and potassium (K+).
Biosynthesis of aldosterone (Fig. 20a). Deoxycorticosterone (DOC), a weaker mineral ocorticoid, is also secreted. Both are synthesized in the zona glomerulosa, which lacks the enzyme 17-hydoxylase. Progesterone is hydroxylated at C21 and C11-b, resulting in corticosterone, which is hydroxylated at C18 and then oxidized to an aldehyde. This is shown as the last reaction product in what is called the hemiacetal form and is the form in which it is predominantly present. The secretion of aldosterone is controlled by the renin–angiotensin system (Chapter 36) and, to a lesser extent, by ACTH. Essentially, hyperkalaemia (raised blood K+), ACTH and angiotensin II can increase aldosterone release.
Mechanism of action of aldosterone (Fig. 20b). Aldosterone stimulates the active transport of sodium through the epithelial cell wall. In common with the other steroid hormones, aldos- terone stimulates de novo synthesis of proteins, which enhance sodium transport in the epithelial cell of the distal convoluted tubule of the kidney, the site of aldosterone action in the nephron (Fig. 20c). The aldosterone receptor is also regulated by concentrations of aldosterone, higher concentrations of which reduce its production. Glucocorticoids bind to the aldosterone receptor with comparable affinity; furthermore, the same nuclear response element serves both glucocorticoid and aldosterone receptors. Nevertheless, glucocorticoids have only minor mineralocorticoid action because glucocorticoids are rapidly metabolized in cells that are principal targets for aldosterone. Conversely, aldosterone binds weakly to glucocorticoid receptors, explaining its glucocorticoid effect when administered in high doses. The drug spironolactone competes with aldosterone for its receptor.
There are three main theories to account for aldosterone action: (i) the hormone increases the number of sodium channels in the apical membrane; (ii) it increases the number of Na+K+-ATPase molecules; (iii) it increases adenosine triphosphate (ATP) molecule number within the cell. The hormone stimulates fatty acid synthesis and may alter membrane phospholipid composition as part of its mechanism of action.
Recent research suggests that aldosterone antagonists such as spironolactone may be useful for treatment of atrial fibrillation, given that aldosterone may be important in the aetiology of this cardiac disease.
The term pseudohypoaldosteronism encompasses rare genetic syndromescharacterized by hypertension and hypokalaemic alkalosis. Apparent mineralocorticoid excess (AME) is an autosomal dominant condition due to mutations in the gene encoding 11-β hydroxysteroid dehydrogenase Type II resulting in excessive glucocorticoid stimulation of mineralocorticoid receptors in the kidney. Liddle’s syndrome is an autosomal dominant syndrome associated with abnormal functioning of epithelial Na channels causing sodium retention. AME is also mimicked by excess liquorice ingestion which blocks 11-β