Interaction of vasoactive intestinal peptide (VIP) and N‐terminally modified VIP analogs with rat pancreatic, hepatic and pituitary membranes

Abstract

Six vascoactive intestinal peptide (VIP) analogs inhibited [¹²⁵I]iodo-VIP and [¹²⁵I]iodo-helodermin binding to high-affinity VIP receptors in rat hepatic membrances. They also stimulated adenylate cyclase activity through these receptors, their decreasing order of potency being VIP > [d-Ala⁴]VIP > [d-Asp³]VIP > [d-Ser²]VIP > [d-His¹]VIP > [d-Phe²]VIP > [d-Arg²]VIP, with the latter two peptides acting as partial agonists only. All VIP analogs tested on rat pancreatic membranes were able to stimulate adenylate cyclase, their order of potency being very similar to that observed on hepatic membranes. [d-Ser²]VIP, [d-His¹]VIP, [d-Arg²]VIP and [d-Phe²]VIP were partial agonists with an intrinsic activity of, respectively, 0.8, 0.7, 0.35 and 0.09 as compared to that of VIP = 1.0. [d-Phe²]VIP competitively and selectively inhibited VIP-stimulated adenylate cyclase activity (K_i= 0.1 μM). On male rat anterior pituitary homogenates the order of potency of the peptides was VIP > [d-Ala⁴]VIP > [d-Asp³]VIP > [D-Ser²]VIP > [D-His¹] and [d-His¹]VIP acted as partial agonists. Besides, [d-Phe²]VIP and [d-Arg²]VIP were inactive as well as unable to inhibit VIP-stimuated adenylate cyclase activity. These results indicated that (a) the efficacy of VIP receptor/effector coupling depended on the tissue tested; (b) the possibility exists to design a VIP antagonist by appropriate modification in the N-terminal moiety of the molecule.