Stalla G K, Stalla J, Huber M, Loeffler J P, Höllt V, von Werder K, Müller O A
Department of Internal Medicine, University of Munich, West Germany.
Endocrinology. 1988 Feb;122(2):618-23. doi: 10.1210/endo-122-2-618.
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 microM. 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.
体外研究了酮康唑（KC）对大鼠垂体前叶细胞促肾上腺皮质激素（ACTH）分泌、生物合成及环磷酸腺苷（cAMP）生成的影响。KC在1.5至100微摩尔浓度范围内，以剂量依赖方式抑制促肾上腺皮质激素释放因子（CRF）刺激的大鼠垂体前叶碎片中ACTH的释放。从培养基中去除KC后，CRF作为ACTH释放剂的作用完全恢复。在大鼠垂体前叶细胞原代培养物中也观察到类似效果。KC剂量依赖性地降低基础及CRF刺激的ACTH释放。此外，与KC预孵育后，编码ACTH前体的基础及CRF刺激的信使核糖核酸（mRNA）减少。KC对ACTH释放及生物合成的作用似乎由cAMP介导，因为KC在相同剂量范围内抑制基础及CRF刺激的cAMP释放及含量。由于霍乱毒素、氟化钠和福斯高林的刺激作用被KC剂量依赖性抑制，且加入双丁酰环磷腺苷（Bu）2cAMP可消除KC的抑制作用，因此得出结论，KC通过抑制腺苷酸环化酶全酶的催化成分发挥作用。
