Gastric inhibitory polypeptide stimulates glucocorticoid secretion in rats, acting through specific receptors coupled with the adenylate cyclase-dependent signaling pathway

Gastric inhibitory polypeptide (GIP) is a 42-amino acid peptide, belonging to the VIP-secretin-glucagon superfamily, some members of this group are ab le to regulate adrenocortical function. GIP-receptor mRNA has been detected in the rat adrenal cortex, but investigations on the effect of GIP on ster oid-hormone secretion in this species are lacking. Hence, we have investiga ted the distribution of GIP binding sites in the rat adrenal gland and the effect of their activation in vivo and in vitro. Autoradiography evidenced abundant [I-125]GIP binding sites exclusively in the inner adrenocortical l ayers, and the computer-assisted densitometric analysis of autoradiograms d emonstrated that. binding was displaced by cold GIP, but not by either ACTH or the selective ACTH-receptor antagonist corticotropin-inhibiting peptide (CIP). The intraperitoneal (IP) injection of GIP dose-dependently raised c orticosterone, but not aldosterone plasma concentration: the maximal effect ive dose (10 nmol/rat) elicited a twofold increase. GIP did not affect aldo sterone and cyclic-AMP release by dispersed zona glomerulosa cells. In cont rast, GIP enhanced basal corticosterone secretion and cyclic-AMP release by dispersed inner adrenocortical cells in a concentration-dependent manner, and the maximal effective concentration (10(-7) M) evoked 1.5- and 2.4-fold rises in corticosterone and cyclic-AMP production, respectively. GIP (10(- 7) M) did not display any additive or potentiating effect on corticosterone and cyclic-AMP responses to submaximal or maximal effective concentrations of ACTH. The corticosterone secretagogue action of 10(-7) M CIP was abolis hed by the protein kinase A (PKA) inhibitor H-89 (10(-5) M), and unaffected by CIP (10(-6) M). Collectively, these findings indicate that GIP exerts a moderate but statistically significant stimulatory effect on basal glucoco rticoid secretion in rats, acting through specific receptors coupled with t he adenylate cyclase/PKA-dependent signaling pathway. (C) 1999 Elsevier Sci ence Inc. All rights reserved.