Contrasting Effects of Eplerenone and Spironolactone on Adrenal Cell Steroidogenesis

Abstract

Summary Spironolactone and eplerenone are widely used as mineralocorticoid antagonists. Spironolactone has several nonspecific actions including inhibition of androgen receptor and steroid hormone biosynthesis. While studies have shown that eplerenone does not exhibit nonspecific actions on androgen receptor, its effects on steroid hormone production have not been reported. Herein, the effects of eplerenone (0.1 to 30 µM) and spironolactone (0.1 to 30 µM) on steroid production were examined in human adrenocortical H295R cells. Spironolactone inhibited basal production of cortisol (91%) and aldosterone (53%). Treatment of H295R cells with angiotensin II (Ang II) for 24 h increased aldosterone production by 11-fold. Spironolactone inhibited Ang II stimulation of aldosterone production by 80%. Addition of pregnenolone increased aldosterone (9-fold) and cortisol (3-fold) production. Spironolactone inhibited pregnenolone metabolism to aldosterone (67%) and cortisol (74%). The inhibitory effects of spironolactone occurred at concentrations far higher than those needed to block mineralocorticoid receptor, suggesting an action directly on the enzymes involved in steroid production. In contrast, eplerenone did not inhibit basal, Ang II, forskolin, pregnenolone-stimulated cortisol or aldosterone production. Together, these data demonstrate that opposed to spironolactone, pharmacologic concentrations of eplerenone do not inhibit adrenal cell aldosterone or cortisol production.

Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats

“…The lower plasma aldosterone may then lead to less uptake of aldosterone into the hypothalamus, resulting in lower hypothalamic content. Alternatively, independent of the MR, as one of its nonspecific actions, spironolactone may directly inhibit enzymes involved in steroid biosynthesis (32), thereby preventing increases in hypothalamic aldosterone by high salt intake.…”

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…Racial difference in response to MR blockade may exist: African Americans with heart failure are less responsive to the renal effect of spironolactone and develop less hyperkaliemia (Cavallari et al, 2004); this is not the case with eplerenone (Flack et al, 2003). It has been reported that spironolactone (at micromolar concentrations) inhibits aldosterone biosynthesis (Netchitailo et al, 1985) and blocks enzymes involved in steroidogenesis (Penhoat et al, 1988;Ye et al, 2009). In contrast, eplerenone (1-30 mM) did not impair basal and angiotensin II-induced cortisol and aldosterone production in human adrenocortical H295R cells (Ye et al, 2009).…”

“…It has been reported that spironolactone (at micromolar concentrations) inhibits aldosterone biosynthesis (Netchitailo et al, 1985) and blocks enzymes involved in steroidogenesis (Penhoat et al, 1988;Ye et al, 2009). In contrast, eplerenone (1-30 mM) did not impair basal and angiotensin II-induced cortisol and aldosterone production in human adrenocortical H295R cells (Ye et al, 2009). Thus spironolactone and eplerenone have differential effects on steroidogenesis.…”

Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate

“…This antiandrogen effect has been used to benefit in the treatment of hirsutism6 and acne 7. Spironolactone has also been shown to inhibit cytochrome P450 which is necessary for the synthesis of androgens in the adrenal glands and testis8 and reduces the production of cortisol and aldosterone 9…”