The hyperplastic adrenal glands of chronically ACTH-administered rats display enhanced glucocorticoid secretory response to gastric inhibitory polypeptide

Gastric inhibitory polypeptide (GIP), a gastrointestinal hormone released after feeding, has been recently found to evoke a moderate glucocorticoid secretory effect in the rat. We have investigated whether a prolonged (from 1 to 3 weeks) infusion with ACTH changes the responsiveness of rat adrenal zonae fasciculata (ZF) and reticularis (ZR) to GIP. As expected, ACTH treatment caused hypertrophy of adrenals, rise in the plasma corticosterone concentration, and increase in the basal production of both corticosterone and cyclic-AMP by dispersed ZF/R cells. GIP evoked a net increase in corticosterone plasma concentration, and corticosterone and cyclic-AMP release by dispersed ZF/R cells in ACTH-untreated rats. ACTH infusion enhanced in vivo and in vitro adrenal responses to GIP in relation to the duration of treatment. The protein kinase A (PKA) antagonist H-89 abolished corticosterone response to GIP of ZF/R cells from either untreated and ACTH-treated rats. Autoradiography evidenced [125I]GIP binding sites in the ZF/R, and computer-assisted densitometry showed that their number significantly increased as a function of the duration of ACTH infusion. [125I]GIP binding was displaced by an excess of cold GIP, and unaffected by ACTH. Taken together, these findings suggest that prolonged ACTH treatment induces ZF/R cell glucocorticoid hyper-responsiveness to GIP in rats, probably through the up-regulation of adenylate cyclase/PKA-coupled GIP receptors.