80. Potent antiglucocorticoid activity of RU38486 on acth secretion in vitro and in vivo in the rat

Proulx-Ferland, Louise; Côté, Jérôme; Philibert, D.; Deraedt, R.

doi:10.1016/0022-4731(82)90294-1

Cited by 17 publications

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“…This increase may be explained by a slight glucocorticoid agonistic activity (not found at lower doses 14 ) or by the stimulatory effect of the drug on adrenocorticotropic hormone and endogenous corticosterone secretion or by both. 20 As previously shown by Philibert and colleagues, 13 the antiglucocorticoid compound suppressed glucocorticoid-induced diuresis as well as natriuresis. RU 38486 administration did not prevent the weight loss induced by the glucocorticoid agonist, which demonstrates that weight loss is not dependent on the transient increase in natriuresis.…”

Section: Discussionsupporting

confidence: 50%

Effects of antiglucocorticoids on glucocorticoid hypertension in the rat.

Grünfeld¹,

Eloy²,

Moura³

et al. 1985

Hypertension

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SUMMARY The early phase of hypertension induced in rats by a glucocorticoid agonist RU 26988 was studied. Systolic blood pressure increased by 35 mm Hg. Water and sodium urinary excretion increased transiently, and plasma volume decreased. Total and ouabain-sensitive sodium efflux, as well as rubidium efflux, were enhanced by glucocorticoid administration. Low salt intake did not prevent hypertension. Pretreatment with RU 38486, a steroid with antiglucocorticoid properties, largely prevented the rise in blood pressure ( + 10 mm Hg) and suppressed transient natriuresis and the decrease in plasma volume. Changes in total and ouabain-sensitive sodium efflux were completely prevented, whereas changes in rubidium efflux were only partly reversed. Similarly, administration of progesterone, a steroid with antiglucocorticoid effects, prevented glucocorticoid hypertension (+11 mm Hg) and vascular ionic changes. In contrast administration of RU 28318, an antimineralocorticoid agent, was without effect on glucocorticoid hypertension (+ 38 mm Hg). Progesterone or RU 38486 administered after glucocorticoid also decreased blood pressure. Present data indicate that glucocorticoid hypertension may be prevented or reversed in its early phase by steroid drugs with antiglucocorticoid properties. These drugs also appeared to prevent the sodium and rubidium flux abnormalities induced by glucocorticoid. We suggest that activation of the vascular glucocorticoid receptors may be involved in the pathophysiology of glucocorticoid hypertension. (Hypertension 7: 292-299, 1985 We therefore initiated a study of the in vivo effects of RU 26988 in the rat. RU 26988 is a specific glucocorticoid receptor agonist that exhibits high affinity for glucocorticoid receptor sites and does not compete with aldosterone for the mineralocorticoid receptor."12 We attempted to antagonize glucocorticoidinduced hypertension by administration of an antimineralocorticoid (RU 28318) and steroid derivatives known to bind competitively at the glucocorticoid receptor-progesterone and RU 38486. The latter steroid has mainly antiprogesterone properties; in vitro studies have also shown antiglucocorticoid activity. 13-I4 Lastly, we investigated the ionic changes induced by glucocorticoid and antiglucocorticoids on the rat tail artery after in vivo administration of the steroid drugs.

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Section: Discussionsupporting

confidence: 50%

Effects of antiglucocorticoids on glucocorticoid hypertension in the rat.

Grünfeld¹,

Eloy²,

Moura³

et al. 1985

Hypertension

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“…It possesses no agonist activity, but has both strong antiprogesterone and antiglucocorticoid properties in animals and humans (5)(6)(7)(8)(9). In humans, RU 486 has been found to abolish the negative feedback control of cortisol on the pituitaryadrenal axis and to inhibit the ACTH inhibitory activity of dexamethasone (9).…”

Section: R U 486 [17/3-hydroxy-ll|8-(4-dimethylaminophenyl)mentioning

confidence: 98%

RU 486 Inhibits Peripheral Effects of Glucocorticoids in Humans*

Gaillard

Poffet

Riondel

et al. 1985

The Journal of Clinical Endocrinology & Metabolism

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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.

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“…The synthetic steroid RU 486 binds with high affinity to progesterone and glucocorticosteroid receptors and shows strong antagonist activity to both progesterone and glucocorticosteroids in animal studies (1)(2)(3)(4)(5). In humans, the antiprogesterone activity of the compound was first evaluated and used for the interruption of the luteal phase of a normal cycle and of early pregnancy (6).…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, it antagonizes the inhibitory effect of dexamethasone on uridine incorporation in rat thymocytes and the dexamethasone induction of tyrosine aminotransferase by rat hepatoma cells (D. Philibert and R. Deraedt, personal communication); it also suppresses the inhibition of corticotropin (ACTH) secretion induced by corticosteroids in rat pituitary cells (5) and the dexamethasone action on cultured L-929 mouse fibroblasts (2). In rats in vivo, it antagonizes the effects of corticosteroids on liver glycogen and tryptophan pyrrolase, thymolysis, and diuresis (1) and the inhibition of ACTH secretion induced by dexamethasone (5).…”

mentioning

confidence: 99%

RU 486: a steroid with antiglucocorticosteroid activity that only disinhibits the human pituitary-adrenal system at a specific time of day.

Gaillard¹,

Riondel²,

Müller³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

188

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RU 486 is a synthetic steroid hormone antagonist which acts at the receptor level. It has both intrinsic antiprogesterone and antiglucocorticosteroid properties in animals. We investigated the antiglucocorticosteroid activity in humans by evaluating the pituitary-adrenal response to RU 486 in men and in pregnant and nonpregnant women. In nonpregnant women, RU 486 (-1 mg/kg of body weight per day) produced an interruption of the luteal phase without affecting the pituitary-adrenal axis, thereby indicating a more potent antiprogesterone than antiglucorticosteroid effect. In the course of pregnancy interruption by RU 486 (-4 mg/kg per day), there was a significant increase in plasma corticotropin, f-lipotropin, and cortisol concentrations. In normal men, RU 486 administration led to a dose-dependent stimulation of plasma corticotropin, -endorphin, and cortisol. This disinhibition of the pituitary-adrenal axis was only observed during the morning hours of the circadian rhythm. When administered concomitantly with 1 mg of dexamethasone at midnight, 6 mg of RU 486 per kg completely suppressed the dexamethasone inhibitory effect on the pituitary-adrenal axis. These results indicate that RU 486 is an antiglucocorticosteroid that disrupts the negative pituitary feedback of both the morning cortisol rise and administered dexamethasone. Furthermore, they demonstrate the possibility of optimizing the antiprogestational effect of the compound and its potential use for human fertility control by modifying the dose and the time of administration of the drug and thereby minimizing the antiglucocorticosteroid effect.RU 486 [17p8-hydroxy-11,-(4-dimethylaminophenyl)-17a-(prop-1-ynyl)-estra-4,9-dien-3-one] is a synthetic 19-nor-steroid with high binding affinity for progesterone and glucocorticosteroid receptors (1-4). In vitro and in vivo experiments in animals have established that RU 486 displays no agonist activity but is an antagonist to both progesterone and endogenous (cortisol) or synthetic (dexamethasone) glucocorticosteroids. In vitro, it antagonizes the inhibitory effect of dexamethasone on uridine incorporation in rat thymocytes and the dexamethasone induction of tyrosine aminotransferase by rat hepatoma cells (D. Philibert and R. Deraedt, personal communication); it also suppresses the inhibition of corticotropin (ACTH) secretion induced by corticosteroids in rat pituitary cells (5) and the dexamethasone action on cultured L-929 mouse fibroblasts (2). In rats in vivo, it antagonizes the effects of corticosteroids on liver glycogen and tryptophan pyrrolase, thymolysis, and diuresis (1) and the inhibition of ACTH secretion induced by dexamethasone (5).RU 486 was first used in humans to interrupt the luteal phase of the menstrual cycle and early pregnancy (6). In women who received RU 486 to induce abortion during weeks 6-8 of pregnancy, an increase in blood cortisol was observed. The present work was undertaken to investigate the possible antiglucocorticosteroid effect of RU 486 on the pituitary-adrenal axis in h...

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80. Potent antiglucocorticoid activity of RU38486 on acth secretion in vitro and in vivo in the rat

Cited by 17 publications

References 0 publications

Effects of antiglucocorticoids on glucocorticoid hypertension in the rat.

Effects of antiglucocorticoids on glucocorticoid hypertension in the rat.

RU 486 Inhibits Peripheral Effects of Glucocorticoids in Humans*

RU 486: a steroid with antiglucocorticosteroid activity that only disinhibits the human pituitary-adrenal system at a specific time of day.

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