Other physiological considerations of protective mechanisms of mineralocorticoid action.
Mineralocorticoid receptors (MR) are protected from the effects of endogenous glucocorticoids (GC) in mineralocorticoid (MC) target tissues such as the kidney and the parotid gland. This protection is thought to be provided by 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD). 11 beta-OHSD metabolizes cortisol (in humans) and corticosterone (B) (in the rat) to cortisone and 11-dehydro-B, their respective inactive dehydro products. We have previously shown that the antinatriuretic actions of the MC deoxycorticosterone (DOC) are amplified in carbenoxolone (CBX) treated adrenalectomized (ADX) rats. CBX is believed to inhibit 11 beta-OHSD activity; DOC, however, is not a substrate for this enzyme. We now report on 11-desoxycortisol (11-desoxy-F) and 2 alpha-methylcortisone, substances which possess no intrinsic antinatriuretic activity, are not metabolized by 11 beta-OHSD and yet cause Na+ retention in CBX-treated ADX rats. Given that none of the above steroids are substrates for 11 beta-OHSD it is unlikely that the inhibition of this enzyme is involved in the unmasking of the Na+ retention observed when these substances are given to CBX-treated animals. These results provide further evidence for an additional protective mechanism, that protects MR from the inappropriate binding of excessive amounts of endogenous MCs.
Souness
G W
GW
Department of Pathology and Laboratory Medicine, Miriam Hospital, Providence, RI 02906.
Myles
K
K
Morris
D J
DJ
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology; D003345:Corticosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D003348:Cortisone / Q000031:analogs & derivatives / Q000494:pharmacology; D003350:Cortodoxone / Q000494:pharmacology; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D008297:Male; D008901:Mineralocorticoids / Q000494:pharmacology*; D009318:Natriuresis / Q000187:drug effects; D011188:Potassium / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
D008901:Mineralocorticoids; C087311:2-methylcortisone; D000450:Aldosterone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; C003552:11-dehydrocorticosterone; D002229:Carbenoxolone; D011188:Potassium; D003348:Cortisone; D003345:Corticosterone; D003350:Cortodoxone