Apparent mineralocorticoid excess, pseudohypoaldosteronism, and urinary electrolyte excretion: toward a redefinition of mineralocorticoid action.
Patients with apparent mineralocorticoid excess (AME) have low or absent activity of the enzyme 11 beta OH steroid dehydrogenase (11SD), and inappropriately high intrarenal levels of cortisol resulting in Na+ retention and hypertension. Pseudohypoaldosteronism (PHA), in contrast, is characterized by salt wasting despite hyperaldosteronemia, reflecting low or absent mineralocorticoid receptors (MR). Although AME is presumed to reflect inappropriate cortisol occupancy of MR, several features also suggest inappropriate occupancy of glucocorticoid receptors (GR). To test this possibility, we administered carbenoxolone, which is known to block 11SD, to four patients with PHA, and observed marked mineralocorticoid effects, e.g., antinatriuresis and elevated plasma bicarbonate. To further test the possibility that occupancy of renal GR may induce a classical mineralocorticoid response, we administered the highly specific glucocorticoid RU 28362 to adrenalectomized rats and showed that it has profound antinatriuretic effects. Finally, by selectively blocking MR with RU 28318 or GR with RU 38486, we have shown that corticosterone, the physiologic glucocorticoid in rats, has an antinatriuretic effect in adrenalectomized rats via either MR or GR occupancy. Previous studies have clearly shown that MR are inherently nonselective and have equivalent intrinsic affinity for aldosterone, corticosterone, and cortisol. The present studies suggest that this nonselectivity includes the nuclear response element to which either MR or GR may bind to elicit a mineralocorticoid effect, and further underscore the importance of the enzyme 11SD in the specific mineralocorticoid action of aldosterone.
Funder
J W
JW
Medical Research Centre, Prince Henry's Hospital, Melbourne, Victoria, Australia.
Pearce
P T
PT
Myles
K
K
Roy
L P
LP
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000315:Adrenalectomy; D000450:Aldosterone / Q000502:physiology; D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D001639:Bicarbonates / Q000097:blood; D002229:Carbenoxolone / Q000494:pharmacology; D002648:Child; D004573:Electrolytes / Q000652:urine*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000502:physiology; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D008901:Mineralocorticoids / Q000502:physiology*; D009318:Natriuresis / Q000187:drug effects; D011546:Pseudohypoaldosteronism / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology
D000732:Androstanols; D001639:Bicarbonates; D004573:Electrolytes; D008901:Mineralocorticoids; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid; D013148:Spironolactone; D015735:Mifepristone; D000450:Aldosterone; C049154:11,17-dihydroxy-6-methyl-17-(1-propynyl)androsta-1,4,6-triene-3-one; C041006:RU 28318; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone; D006854:Hydrocortisone