title: Renal action of progesterone and 18-substituted derivatives.
abstract: The recently synthesized progesterone (P) derivatives, 18-vinylprogesterone (18VP) and 18-ethynylprogesterone (18EP), are potent inhibitors of aldosterone synthesis by adrenal glands. To evaluate the potential interest of these compounds as antihypertensive drugs, we determined whether they also interact with renal mineralocorticosteroid receptors (MR) in kidney and, if so, whether they mimic or antagonize aldosterone action. For this purpose, we evaluated the potency of 18VP and 18EP 1) to displace [3H]aldosterone binding in cytosolic fractions of kidney from adrenalectomized rats and 2) to interfere with aldosterone-induced stimulation of Na(+)-K(+)-ATPase in the collecting tubule of adrenalectomized rats. The properties of 18VP and 18EP were compared with those of their precursor progesterone and of the antimineralocorticosteroid spironolactone. The binding of [3H]aldosterone was restricted to cytosolic MR by presaturating glucocorticosteroid receptor with RU 38486. All compounds tested displaced [3H]aldosterone binding with the following efficiency: spironolactone greater than aldosterone greater than P greater than 18VP greater than 18EP; apparent Kd varied between 0.66 and 16.4 nM. Spironolactone, P, and 18VP antagonized aldosterone-induced stimulation of Na(+)-K(+)-ATPase in the collecting tubule, whereas 18EP mimicked the mineralocorticosteroid action. The different steroids tested altered Na(+)-K(+)-ATPase stimulation and aldosterone binding with the same order of potency.
authors.affiliation: Unité de Recherche sur les Communications Hormonales, Institut National de la Santé et de la Recherche Médicale, Unité 33, Bicètre, France.
authors.forename: M E
authors.initials: ME
authors.lastname: Rafestin-Oblin
authors.forename: B
authors.initials: B
authors.lastname: Couette
authors.forename: C
authors.initials: C
authors.lastname: Barlet-Bas
authors.forename: L
authors.initials: L
authors.lastname: Cheval
authors.forename: A
authors.initials: A
authors.lastname: Viger
authors.forename: A
authors.initials: A
authors.lastname: Doucet
mesh_terms: D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D011374:Progesterone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology
chemical_list: D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid; C069555:18-ethynylprogesterone; D013148:Spironolactone; D000450:Aldosterone; D011374:Progesterone; C069554:18-vinylprogesterone; D000254:Sodium-Potassium-Exchanging ATPase