The effect of the antimineralocorticoid RU 28318 on aldosterone biosynthesis in vitro

Perroteau, Isabelle; Netchitaïlo, P.; Delarue, Catherine; Leboulenger, F.; Philibert, D.; Deraedt, R.; Vaudry, Hubert

doi:10.1016/0022-4731(84)90395-9

Cited by 21 publications

(10 citation statements)

References 14 publications

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“…After the electrical measurements, another medium change was performed, in which the appropriate steroid hormones and receptor antagonists or vehicle (ethanol) alone, were added. MC stimulation was obtained by the addition of 100 nM aldosterone plus the GC receptor blocker, RU 38486 (10 ,M) (8); GC stimulation was obtained with 100 nM dexamethasone plus the MC receptor blockers, spironolactone (10 ,uM) or RU 28318 (10 MM) (9). A similar GC stimulation can be produced by the specific GC agonist RU 28362 (unpublished data).…”

Section: Methodsmentioning

confidence: 99%

“…The certainty with which one can produce a "pure" GC or MC effect has been dramatically enhanced by the recent introduction of several synthetic steroid hormones that are specific agonists or antagonists of these receptors (8,9). The availability of these compounds, together with the discovery of a cell culture system that demonstrates stimulation of electrogenic Na+ transport by either GC or MC (5), has provided an excellent opportunity to examine some ofthese questions in greater detail and with greater precision.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cellular responses to steroids in the enhancement of Na+ transport by rat collecting duct cells in culture. Differences between glucocorticoid and mineralocorticoid hormones.

Laplace

Husted²,

Stokes³

1992

J. Clin. Invest.

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It has recently been discovered that both mineralocorticoid (MC) and glucocorticoid (GC) hormones can stimulate electrogenic Na' absorption by mammalian collecting duct cells in culture. In primary cultures of rat inner medullary collecting duct (IMCD) cells, 24-h incubation with either MC or GC agonist stimulates Na+ transport approximately threefold. We have now determined that the effects were not additive, but the time courses were different. As aldosterone is known to stimulate citrate synthase, Na+/K' ATPase activity, and ouabain binding in cortical collecting duct principal cells, we determined the effects of steroids on these parameters in IMCD cells. MC and GC agonists both produced a small increase in citrate synthase activity. There was no increase in Na + / K+ ATPase activity but specific ouabain binding was increased more than twofold by either agonist. To determine the role ofapical Na+ entry in the steroid-induced effects, the Na+ channel inhibitor, benzamil, was used. Benzamil did not alter the stimulation of citrate synthase activity by either steroid. In contrast, GC stimulation of ouabain binding was prevented by benzamil, whereas MC stimulation was not. We conclude that there are differences in the way that MC and GC hormones produce an increased Na+ transport. Both appear to produce translocation (or activation) of pumps into the basolateral membrane. GC stimulation of pump translocation requires increased Na+ entry whereas MC stimulation does not. (J. Clin. Invest. 1992.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cellular responses to steroids in the enhancement of Na+ transport by rat collecting duct cells in culture. Differences between glucocorticoid and mineralocorticoid hormones.

Laplace

Husted²,

Stokes³

1992

J. Clin. Invest.

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“…In prolonged spironolactone-treated patients, spironolactone bodies were detected in the zona glomerulosa of human and the adrenal cortex of rat, although its functional significance remains to be elucidated [18, 19]. There is, however considerable evidence that spironolactone inhibits adrenal cell aldosterone production [20–23]. It is also well documented that spironolactone binds and blocks cytochrome P450 enzymes involved in steroidogenesis [24–26].…”

Section: Introductionmentioning

confidence: 99%

Contrasting Effects of Eplerenone and Spironolactone on Adrenal Cell Steroidogenesis

et al. 2008

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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.

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“…RU28318 has been reported to be superior to the more traditional anti-mineralocorticoid, spironolactone, in terms of having a higher in vivo anti-mineralocorticoid activity and a lower anti-androgen activity [7]. However, in vitro receptor binding studies suggest that RU28318 may have considerable interaction with GR [8,9].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of RU28318 and RU40555 as selective mineralocorticoid receptor and glucocorticoid receptor antagonists, respectively: receptor measures and functional studies

Kim

Cole

Kalman

et al. 1998

The Journal of Steroid Biochemistry and Molecular Biology

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Corticosterone regulates a wide range of physiological parameters. Two receptors for corticosterone have been identi®ed, the mineralocorticoid (type I) receptor (MR) and the glucocorticoid (type II) receptor (GR). To determine the relative role of these two receptors in mediating the effects of endogenous corticosterone, many studies have relied on the use of putative selective corticosteroid receptor antagonists. This study further examined the in vivo receptor selectivity of two compounds, RU28318 and RU40555 that are believed to be selective antagonists for MR and GR, respectively. Acute treatment of adrenalectomized rats with RU28318 (10±50 mg/kg) selectively decreased ex-vivo available MR binding in the hippocampus, whereas acute treatment with RU40555 (10±30 mg/kg) selectively decreased available GR binding in the hippocampus and pituitary. These receptor binding measures suggest that RU28318 in vivo selectively occupied MR, and that RU40555 in vivo selectively occupied GR. In functional studies, RU28318 (50 mg/kg) blocked the normalizing effect of aldosterone (120 m mg/kg) on saline intake of adrenalectomized rats. RU40555 (30 mg/kg) blocked the suppressive effect of dexamethasone (50 m mg/kg) on acute stress-induced corticosterone secretion. These studies further support the in vivo corticosteroid receptor selectivity of these two compounds and con®rms their effective corticosteroid antagonistic properties. #

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The effect of the antimineralocorticoid RU 28318 on aldosterone biosynthesis in vitro

Cited by 21 publications

References 14 publications

Cellular responses to steroids in the enhancement of Na+ transport by rat collecting duct cells in culture. Differences between glucocorticoid and mineralocorticoid hormones.

Cellular responses to steroids in the enhancement of Na+ transport by rat collecting duct cells in culture. Differences between glucocorticoid and mineralocorticoid hormones.

Contrasting Effects of Eplerenone and Spironolactone on Adrenal Cell Steroidogenesis

Evaluation of RU28318 and RU40555 as selective mineralocorticoid receptor and glucocorticoid receptor antagonists, respectively: receptor measures and functional studies

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