IN VITRO EFFECTS OF THEOPHYLLINE AND AMINOGLUTHETIMIDE UPON BASAL AND ACTH INDUCED cAMP LEVELS AND STEROID OUTPUT BY THE NORMAL HUMAN ADRENAL GLAND

Abstract

The in vitro effects of theophylline and aminogluthetimide upon basal and ACTH stimulated cAMP, cortisol and aldosterone responses of normal human adrenocortical tissue were evaluated. Theophylline increased basal cAMP levels and cortisol output, however, basal aldosterone output was depressed. Theophylline in concert with ACTH depressed cortisol and aldosterone output. Aminogluthetimide alone did not affect basal cAMP levels, however, the normal cAMP response to ACTH was delayed in aminogluthetimide pre-treated adrenals. Aminogluthetimide also depressed basal and ACTH stimulated cortisol and aldosterone output with the latter being more sensitive. The findings indicate that both theophylline and aminogluthetimide produce effects upon the adrenal in addition to inhibition of phosphodiesterase and cholesterol side-chain cleavage, respectively. Further, theophylline depression of ACTH stimulated steroid output may be helpful in understanding the interplay between a number of factors in the control of adrenal steroid biosynthesis and release. Numerous inhibitory drugs have been employed to help elucidate the mecha¬ nism of ACTH action upon adrenocortical tissue. Two commonly used drugs in this regard are theophylline, a phosphodiesterase inhibitor (Halkerston 1975), and aminogluthetimide, a competitive inhibitor of adrenal cholesterol side chain cleavage activity (Kahnt

Aminoglutethimide, a Steroidogenesis Inhibitor, Abolishes Hormonal Induction of Ornithine Decarboxylase in Steroidogenic Tissues: Evidence for Its Role as cAMP-Dependent Protein Kinase Inhibitor

“…Table 4 shows that AMG severely reduced the increase in ovarian ODC elicited by cAMP, suggesting that some step downstream cAMP production in the signaling pathway is affected by AMG. This result is also in harmony with previous reports claiming that AMG does not have a significant effect on cAMP formation (22). To assess the possible action of AMG on protein kinase A, we used an in vitro system designed to test putative effectors of protein kinase A and protein kinase C activity.…”