Inhibition of aldosterone biosynthesis by 18-ethynyl-deoxycorticosterone.
The inhibiting effects of 18-ethynyl-deoxycorticosterone (18-E-DOC) as a mechanism-based inhibitor on the late steps of aldosterone biosynthetic pathway were examined in calf adrenal zona glomerulosa cells placed in the primary culture. Baseline and ACTH (10(-9) M)-, angiotensin-II (10(-8) M)-, and potassium (12 mM)-stimulated production of aldosterone and 18-hydroxycorticosterone were inhibited in a dose- and time-dependent manner. At 1 microM, 18-E-DOC produced a 73% inhibition, and at 10 microM, it produced a 94.6% inhibition of aldosterone secretion. Preincubation with 10 microM 18-E-DOC for 5 min followed by washing resulted in 75% inhibition of aldosterone secretion. The maximal degree of inhibition was reached after 60 min of preincubation. The degree of the inhibition of 18-hydroxycorticosterone production was almost same as that of aldosterone. Preincubation with 10 microM 18-E-DOC for 60 min, followed by extensive washing and reincubation with medium for 24 h, resulted in recovery to more than half the production of the control cells. Minimal changes occurred in the production of corticosterone (slight increase), 18-hydroxydeoxycorticosterone (slight increase) in zona glomerulosa cells, and cortisol (no changes) in zona fasciculata cells. These studies show that 18-E-DOC is a specific inhibitor of the late pathway of aldosterone biosynthesis. 18-E-DOC could be valuable as a therapeutic agent in those conditions associated with increased aldosterone production where a specific inhibitor would be useful.
Yamakita
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Department of Internal Medicine, University of South Florida Health Sciences Center, Tampa.
Chiou
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Gomez-Sanchez
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D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000450:Aldosterone / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009994:Osmolar Concentration; D013997:Time Factors; D015384:Zona Glomerulosa / Q000166:cytology / Q000378:metabolism*
D000451:Mineralocorticoid Receptor Antagonists; D003900:Desoxycorticosterone; D000450:Aldosterone; C071418:18-ethynyldeoxycorticosterone; D000324:Adrenocorticotropic Hormone