The receptor is activated by mineralocorticoids such as aldosterone and its precursor deoxycorticosterone as well as glucocorticoids , like cortisol . In intact animals, the mineralocorticoid receptor is "protected" from glucocorticoids by co-localization of an enzyme, Corticosteroid 11-beta-dehydrogenase isozyme 2 (. 11β-hydroxysteroid dehydrogenase 2; 11β-HSD2), that converts cortisol to inactive cortisone. It also responds to some progestins . Spironolactone and eplerenone are steroidal MR antagonists of the spirolactone group.
We used the mineralocorticoid receptor-selective antagonist eplerenone (EPL) to test the role of mineralocorticoid receptors in mediating the transition from hypertrophy to failure in mice with chronic pressure overload caused by ascending aortic constriction (AAC). One week after AAC, mice were randomized to regular chow or chow containing EPL (200 mg/kg per day) for an additional 7 weeks. EPL had no significant effect on systolic blood pressure after AAC. Eight weeks after AAC, EPL treatment improved survival (94% versus 65%), attenuated the increases in LV end-diastolic (+/- versus +/- mm) and end-systolic (+/- versus +/- mm) dimensions, and ameliorated the decrease in fractional shortening (42+/-2% versus 34+/-4%). EPL also decreased myocardial fibrosis, myocyte apoptosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2. These beneficial effects of EPL were associated with less myocardial oxidative stress, as assessed by 3-nitrotyrosine staining, reduced expression of the adhesion molecule intercellular adhesion molecule-1, and reduced infiltration by macrophages.
The pathogenesis of these disorders has been elucidated. Summarized briefly, renal mineralocorticoid receptors bind aldosterone and cortisol with similar affinity. Although the plasma concentration of cortisol is approximately 100-fold higher than aldosterone, activation of mineralocorticoid receptors by cortisol is normally limited due to its conversion to inactive cortisone at the sites of aldosterone action by the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2) [ 1 ]. This conversion is impaired in AME because of a mutation in the 11-beta-HSD2 gene and with licorice ingestion because of a compound in licorice (glycyrrhetinic acid) that inhibits the enzyme [ 2 ]. (See 'Pathogenesis' below.)