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Ketoconazole Inhibits Corticotropic Cell Function in Vitro^*

Departments of Internal Medicine (G.K.S., J.S., M.H., K.v. W., O.A.M.) and Physiology (V.H.), University of Munich Munich
The Department of Neuropharmacology, Max-Planck Institute of Psychiatry (J.-P.L.) Martinsried, West Germany

Address requests for reprints to: Dr. Giinter K. Stalla, Department of Internal Medicine, University of Munich, Ziemssenstr fle 1, D-8000 Munich 2, West Germany.

Abstract

The effects of ketoconazole (KC) on secretion and biosynthesis of ACTH and generation of cAMP in rat anterior pituitary cells were investigated in vitro. KC inhibits CRF-stimulated ACTH release from rat anterior pituitary fragments in a dose-dependent fashion between 1.5 and 100 µM. The effect of CRF as a releaser of ACTH was fully restored after KC was removed from the medium. Similar effects were observed in primary cultures of rat anterior pituitary cells. KC dose-dependently decreased basal and CRF-stimulated ACTH release. In addition, basal and CRF-stimulated mRNA coding for the ACTH precursor were reduced after preincubation with KC. The effects of KC on ACTH release and biosynthesis seem to be mediated by cAMP, since KC inhibits basal and CRF-stimulated cAMP release and content within the same dose range. Since the stimulatory effects of cholera toxin, sodium fluoride, and forskolin were dose-dependently inhibited by KC and since the addition of (Bu)₂cAMP abolished the inhibiting effect of KC, it is concluded that KC acts by inhibition of the catalytic component of the adenylate cyclase holoenzyme. (Endocrinology 122: 618–623,1988)

Footnotes

^* This work was supported by the Deutsche Forschungsgemeinschaft (Mu 585/2-3).

Received February 2, 1987.

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