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Inhibition of Aldosterone Biosynthesis by 18-Ethynyl- Deoxycorticosterone^*

NORIYOSHI YAMAKITA, SHIRLEY CHIOU and CELSO E. GOMEZ-SANCHEZ

Department of Internal Medicine, University of South Florida Health Sciences Center, and the James A. Haley Veterans Hospital Tampa, Florida 33612
Third Department of Internal Medicine, Gifu University School of Medicine (N. Y.) Gifu, Japan

Address all correspondence and requests for reprints to: Celso E. Gomez-Sanchez, M.D., James A. Haley Veterans Hospital, 13000 Bruce B. Downs Boulevard, VAH 111 M, Tampa, Florida 33612.

Abstract

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 timedependent manner. At 1 µM, 18-E-DOC produced a 73% inhibition, and at 10 nM, it produced a 94.6% inhibition of aldosterone secretion. Preincubation with 10 µM 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 µM 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. (Endocrinology 129: 2361–2366,1991)

Footnotes

^* This work was supported by Medical Research Funds from the Department of Veterans Affairs and NIH Grant HL-27255.

On sabbatical leave from Gifu University and supported by a grant from the Ministry of Education, Culture, and Science of Japan.

Received May 6, 1991.