Pharmacological modulation of CRH-stimulated ACTH secretion by ketoconazole.

The effects of ketoconazole (KC) on secretion and biosynthesis of ACTH in rat anterior pituitary cells were investigated in vitro. KC inhibits the corticotropin releasing hormone (CRH) stimulated ACTH release from rat anterior pituitary fragments in a dose dependent fashion between 1.5 and 100 microM. The effect of CRH to release ACTH was fully restored after KC was removed from the medium. Similar effects were observed in primary cultures of rat anterior pituitary cells: KC decreased dose dependently the basal and CRH stimulated ACTH release. In addition, basal and CRH-stimulated mRNA coding for the ACTH precursor was reduced after preincubation with CK. The effects of KC on ACTH release and biosynthesis seems to be mediated by cyclic AMP (cAMP) since KC inhibits basal and CRH stimulated cAMP release and content within the same dose range. Since the stimulatory effect of cholera toxin, sodium fluoride and forskolin were dose dependently inhibited by KC and since the addition of dibutyryl cAMP abolished the inhibiting effect of KC, it is concluded that KC acts by inhibition of the catalytic component of the adenylate cyclase holoenzyme.