The Stimulatory Effect of Vasoactive Intestinal Peptides on the Cortisol Production of Guinea Pig Zona Fasciculata Cells: an Extra-ACTH Regulatory Model of the Adrenocortical Function

The effect of vasoactive intestinal peptide (VIP) on cortisol production was studied in a primary culture enriched with guinea pig Zona Fasciculata (ZF) cells. In ZF cells, VIP stimulates cortisol secretion and enhances the steroidogenic action of ACTH. Compared to ACTH on an equal molar basis, the cortisol-stimulatory effect of VIP is at least 10-fold less potent. As VIP exhibits a wide range of biological actions with widespread distribution in the body, the steroidogenic action of VIP on the adrenal glands is not tissue-specific. There are VIP receptors in ZF cells. With the aid of a VIP receptor antagonist, we found that ACTH and VIP mutually bind each other's receptors with an affinity-ranking order of ACTH > VIP receptor antagonist > VIP. VIP stimulates cortisol production most likely through the cyclic AMP (cAMP) signaling pathway. Both ACTH receptors and the VIP receptors bind VIP receptor antagonist more avidly than VIP, but the bindings do not lead to a consequential effect on cAMP production and cortisol secretion. However, the VIP receptor antagonist counteracted ACTH and VIP to lower both cAMP and cortisol production. In addition, ASIF and BNP-32, which are the proven ACTH receptor antagonists, reduced the cortisol-stimulatory effect of ACTH and VIP. These results suggest that besides ACTH, VIP be an important factor in regulating the cortisol secretion from the adrenal cortex at the site of ACTH receptors. In cases with hypercortisolemia being detected concomitantly with normal or low ACTH levels, we may need to investigate the influential role of VIP.