Dantrolene inhibits adrenal steroidogenesis by a mechanism independent of effects on stored calcium release.
The muscle relaxant dantrolene has been widely used in signal transduction studies as an inhibitor of intracellular calcium release. However, in vivo studies have shown that the drug may inhibit steroidogenesis by a mechanism which is distinct from its effects on calcium mobilization. Using freshly isolated cells and mitochondria from the outermost regions of bovine adrenal cortex we have shown that dantrolene (0.2 mM) significantly inhibits steroid synthesis stimulated by either angiotensin II (AII) or by addition of various precursors. Our results suggest that dantrolene inhibits the rate-limiting steps of adrenocortical steroidogenesis, i.e. the intramitochondrial conversion of cholesterol to pregnenolone (for both aldosterone and cortisol) and the conversion of corticosterone to aldosterone (for aldosterone), by a mechanism independent from its known effects on calcium release. A possible alternative mechanism may involve direct inhibition of cytochrome P450-dependent hydroxylation reactions.
Thomson
I
I
M.R.C. Blood Pressure Unit, Western Infirmary, Glasgow, Scotland, U.K.
Shepherd
R M
RM
Fraser
R
R
Kenyon
C J
CJ
D015069:18-Hydroxycorticosterone / Q000494:pharmacology; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D003345:Corticosterone / Q000378:metabolism; D003620:Dantrolene / Q000494:pharmacology*; D006854:Hydrocortisone / Q000096:biosynthesis*; D006888:Hydroxycholesterols / Q000378:metabolism / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011284:Pregnenolone / Q000378:metabolism
D006888:Hydroxycholesterols; D000804:Angiotensin II; D000450:Aldosterone; D015069:18-Hydroxycorticosterone; D011284:Pregnenolone; D003620:Dantrolene; D002118:Calcium; D003345:Corticosterone; D006854:Hydrocortisone