RU 486 Inhibits Peripheral Effects of Glucocorticoids in Humans*

Abstract

RU 486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one] is a synthetic steroid receptor antagonist. To evaluate the peripheral antiglucocorticoid action of this compound, we investigated its ability to antagonize cutaneous steroid-induced vasoconstriction. This phenomenon, produced by three different topical steroids in six normal men, was consistently and significantly attenuated or abolished by oral administration of 6 mg/kg RU 486. This demonstration of a peripheral action of RU 486 is important in relation to the potential therapeutic use of this well tolerated drug in states of hypercortisolism. It also indicates that the cutaneous vasoconstrictor effects of topical steroids are mediated by occupancy of glucocorticoid receptors.

Glucocorticoids and Cardiovascular Disease

“…With respect to reducing GR-dependent signalling, the challenge has been to reduce glucocorticoid action selectively in the blood vessel wall and/or in metabolically important tissues such as liver and adipose tissue, without: i) impairing negative feedback control of the HPA axis, producing compensatory hypercortisolaemia; ii) reducing glucocorticoid action in immune cells, producing a pro-inflammatory state; or iii) preventing an effective cortisol response during stress. Agents that inhibit cortisol biosynthesis or antagonise ligand binding to GR (119,120) are likely to fall at one of these hurdles. However, inhibition of the cortisolgenerating enzyme 11b-HSD1 may be safe and successful (4, 61).…”

Glucocorticoid antagonists

“…These data suggest that glucocorticoids may be involved in the regulation of arterial tension in the mammal although so far this has been supposed to be controlled mostly by the brain mineralocorticoid receptor [55]. In fact, oral administration of Mifepristone abolished vasoconstriction produced by topical application of glucocorticoids in normal men [56]. In addition, it also lowered the intraocular pressure in the rabbit eye [57].…”

Pituitary adenomas, some diagnostic and therapeutical aspects

“…In normal humans, mifepristone blocks glucocorticoid negative feedback at the hypothalamic-pituitary level, inducing a compensatory increase in plasma corticotropin and cortisol levels [54]. After one single-dose oral gift of 400 mg, mifepristone induces a response that lasts at least 34 h. When ketoconazole is unable to lower cortisol production and if the clinical condition requires a rapid, more or less acute total blockade of cortisol receptors (i.e.…”