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Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances.

Contents

Physiology

The name mineralocorticoid derives from early observations that these hormones were involved in the retention of sodium, a mineral. The primary endogenous mineralocorticoid is aldosterone, although a number of other endogenous hormones (including progesterone and deoxycorticosterone) have mineralocorticoid function.

Aldosterone acts on the kidneys to provide active reabsorption of sodium and an associated passive reabsorption of water, as well as the active secretion of potassium in the principal cells of the cortical collecting tubule and active secretion of protons via proton ATPases in the lumenal membrane of the intercalated cells of the collecting tubule. This in turn results in an increase of blood pressure and blood volume.

Aldosterone is produced in the cortex of the adrenal gland and its secretion is mediated principally by angiotensin II but also by adrenocorticotrophic hormone (ACTH) and local potassium levels.

Mode of action

The effects of mineralocorticoids are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and signaling cascades.

Steroidogenesis, showing mineralocorticoids in ellipse at top right. Note that it is not a strictly bounded group, but a continuum of structures with increasing mineralocorticoid effect, with the primary example aldosterone at top.
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Genomic mechanisms

Mineralocorticoids bind to the cytosolic mineralocorticoid receptor. This type of receptor gets activated upon ligand binding. After a hormone binds to the corresponding receptor, the newly formed receptor-ligand complex test itself into the cell nucleus, where it binds to many hormone response elements (HRE) in the promoter region of the target genes in the DNA.

The opposite mechanism is called transrepression. The hormone receptor without ligand binding interacts with heat shock proteins and prevents the transcription of targeted genes.

Aldosterone and cortisol (a glucosteroid) have similar affinity for the mineralocorticoid receptor; however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. An enzyme exists in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids. This enzyme, 11-beta hydroxysteroid dehydrogenase type II (Protein:HSD11B2), catalyzes the deactivation of glucocorticoids to 11-dehydro metabolites. Licorice is known to be an inhibitor of this enzyme and chronic consumption can result in a condition known as pseudohyperaldosteronism.

18 hydroxy 11 deoxycorticosterone (also designated 18OH-DOC) is a steroid hormone probably used to conserve sodium and stimulate hydrogen ion (or acid) excretion. 18OH-DOC lowers urine pH but has no affect on potassium excretion.[1] This would seem to indicate that 18OH-DOC's primary purpose is to stimulate hydrogen ion or ammonium excretion. Under low sodium intake 18 OH DOC is increased in serum.[2] There is a marked increase in serum 18OH DOC after injection of insulin[3] and this may be due to the hypokalemic (low serum potassium) tendency after a rise in insulin[4] which in turn would make the serum more acidic. Since 18OH-DOC lowers urine pH (increases acidity) but has no affect on potassium excretion, this would seem to indicate that 18OH-DOC's primary purpose is to stimulate hydrogen ion or ammonium excretion. Its use by the body to conserve potassium would be indirect by virtue of hydrogen ion's interference with potassium excretion.[5] This interference is further indicated because injecting sodium bicarbonate or even hyperventilating (breathing rapidly beyond need) can triple potassium excretion.[6] The daily rhythm for potassium and hydrogen ion excretion show a rather close inverse relationship,[7] which gives additional circumstantial support to the supposition that they compete at a common site. 18OH-DOC is strongly dependent on the potassium cell or plasma content, because in potassium deficient rats markedly less 18OH-DOC is converted to 18OH-corticosterone and less yet if sodium is deficient.[8]

ACTH (a peptide hormone) has a large affect on 18OH DOC, causing 18OH DOC to go down to zero when ACTH does.[9] This could be for the primary purpose of keeping serum immune enzymes and cell fluids at a high pH (alkaline) during internal infection, but not doing so during the intestinal infection of diarrhea, during which disease the resulting dehydration forces ACTH to decline.[10] It probably is important normally to keep the vacuoles where pathogens are digested at a high pH because if the pH or alkalinity is not high enough, the pathogens inside the immune cells are not digested [11] and thus released intact. So when an intestinal disease is not calling for ACTH to decline, the indirect potassium conserving attribute of 18OH-DOC by virtue of stimulating acid excretion would be valuable, as would increased acid excretion during internal disease.

18OH DOC may act primarily by blocking aldosterone's effect on potassium, and must have aldosterone to assist it with sodium. Nichols, et al., have been able to show that injection of 18OH-DOC, which raised blood levels of this hormone ten times, were more retentive of sodium than a similar amount of aldosterone. So there must be a synergism involved. At the same time, the ratio of sodium to potassium excretion declined very little for 18OH-DOC, while for aldosterone, the ratio fell to as little as 1/3 that of control men.[12] This implies a considerable sparing of potassium by 18OH-DOC. Urine potassium excretion is not altered by 18OH-DOC injection.[12]

Angiotensin II has very little effect on 18OH-DOC and is ambiguous (nor does serum potassium above 4.8 mEq/liter (187 mg)).[13] This last is not surprising since 18OH-DOC should not be used by the body at high serum potassium. Under low sodium intake, 18OH-DOC rises in the serum.[2] ACTH causes a marked increase in 18OH-DOC,[14] probably by a generalized affect on the zona fasciculata of the adrenal cortex where 18OH-DOC is synthesized. So when it is necessary for sodium to be unloaded during the dehydration induced decline of ACTH [10] during diarrhea in order to preserve osmotic pressure, the resulting 18OH-DOC decline would assist in this.

18OH-DOC is deeply involved in one of the three forms (at least) of hypertension (high blood pressure).[15]

Pathophysiology

Hyperaldosteronism (the syndrome caused by elevated aldosterone) generally results from adrenal cancers. The two main resulting problems:

  1. Hypertension and edema due to excessive Na+ and water retention.
  2. Accelerated excretion of potassium ions (K+). With extreme K+ loss there is muscle weakness and eventually paralysis.

Underproduction, or hypoaldosteronism, leads to the salt-wasting state associated with Addison's disease, although classical congenital adrenal hyperplasia and other disease states may also cause this situation.

Pharmacology

An example of a synthetic mineralocorticoid is fludrocortisone (Florinef). Important mineralocorticoid inhibitors are spironolactone and eplerenone.

References

  1. ^ Damasco MC, Díaz F, Ceñal JP, Lantos CP (1979). "Acute effects of three natural corticosteroids on the acid-base and electrolyte composition of urine in adrenalectomized rats". Acta Physiologica Latino Americana 29 (6): 305–14. PMID 263223. 
  2. ^ a b Williams GH, Braley LM, Underwood RH (July 1976). "The regulation of plasma 18-hydroxy 11-deoxycorticosterone in man". The Journal of Clinical Investigation 58 (1): 221–9. doi:10.1172/JCI108453. PMID 180059. 
  3. ^ Sparano F, Mercuri MA, Giaquinto G, Odoardi A, Sulon J, Sciarra F (November 1978). "18-Hydroxy-11-deoxycorticosterone response to insulin in normal man". Journal of Steroid Biochemistry 9 (11): 1061–3. doi:10.1016/0022-4731(78)90032-8. PMID 745404. 
  4. ^ Flatman JA, Clausen T (October 1979). "Combined effects of adrenaline and insulin on active electrogenic Na+-K+ transport in rat soleus muscle". Nature 281 (5732): 580–1. doi:10.1038/281580a0. PMID 226892. 
  5. ^ Berliner RW, Kennedy TJ, Orloff J (September 1951). "Relationship between acidification of the urine and potassium metabolism; effect of carbonic anhydrase inhibition on potassium excretion". The American Journal of Medicine 11 (3): 274–82. doi:10.1016/0002-9343(51)90165-9. PMID 14877833. 
  6. ^ Kilburn KH (March 1966). "Movements of potassium during acute respiratory acidosis and recovery". Journal of Applied Physiology 21 (2): 679–84. PMID 5934480. 
  7. ^ Milis JN, Stanbury SW (February 1954). "A reciprocal relationship between K+ and H+ excretion in the diurnal excretory rhythm in man". Clinical Science (London, England : 1979) 13 (1): 177–86. PMID 13141435. 
  8. ^ Müller J (March 1980). "11 beta-hydroxylation of 18-hydroxy-11-deoxycorticosterone by rat adrenal tissue: zone specificity and effect of sodium and potassium restriction". Journal of Steroid Biochemistry 13 (3): 253–7. doi:10.1016/0022-4731(80)90002-3. PMID 7190202. 
  9. ^ Tan SY, Mulrow PJ (April 1978). "Regulation of 18-hydroxydeoxycorticosterone in the rat". Endocrinology 102 (4): 1113–7. doi:10.1210/endo-102-4-1113. PMID 217614. 
  10. ^ a b Aguilera G, Lightman SL, Kiss A (January 1993). "Regulation of the hypothalamic-pituitary-adrenal axis during water deprivation". Endocrinology 132 (1): 241–8. doi:10.1210/en.132.1.241. PMID 8380375. 
  11. ^ Ahluwalia J, Tinker A, Clapp LH, et al. (February 2004). "The large-conductance Ca2+-activated K+ channel is essential for innate immunity". Nature 427 (6977): 853–8. doi:10.1038/nature02356. PMID 14985765. 
  12. ^ a b Nicholls MG, Fraser R, Hay G, Mason P, Torsney B (November 1977). "Urine electrolyte response to 18-hydroxy-11-deoxycorticosterone in normal man". Clinical Science and Molecular Medicine 53 (5): 493–8. PMID 22421. 
  13. ^ Biglieri EG, Lopez JM (October 1977). "Adrenocorticotropin and plasma aldosterone concentration and deoxycorticosterone in man". Annals of the New York Academy of Sciences 297: 361–72. doi:10.1111/j.1749-6632.1977.tb41867.x. PMID 211909. 
  14. ^ Moore TJ, Braley LM, Williams GH (July 1978). "Stimulation of 18-hydroxy-11-deoxycorticosterone secretion by angiotensin II and potassium". Endocrinology 103 (1): 152–5. doi:10.1210/endo-103-1-152. PMID 744066. 
  15. ^ Melby JC, Dale SL, Grekin RJ, Gaunt R, Wilson TE (1972). "18-Hydroxy-11-deoxycorticosterone (18-OH-DOC) secretion in experimental and human hypertension". Recent Progress in Hormone Research 28: 287–351. PMID 4347162. 

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