VIP antagonist demonstrates differences in VIP- and PHI-mediated stimulation and inhibition of ACTH and...

Previous studies in our laboratory have demonstrated that PVN administration of equimolar doses of VIP and PHI induce similar increases in plasma ACTH and CORT concentrations via the release of CRF and vasopressin in fasted, freely moving rats studied during the early light cycle. The purpose of these investigations was to determine whether VIP and PHI act via the same receptor and/or mechanism. Individual studies involving the PVN administration of either VIP or PHI in doses ranging from 0.3 to 30.0 nmol/rat demonstrated that VIP increases both ACTH and CORT secretion throughout the administered range. In contrast, PHI was an effective stimulant in doses up to 15 nmol/rat but had no effect on either ACTH or CORT at a dose of 30 nmol/rat thus yielding a bell-shaped dose-response curve. When increasing doses of PHI (0.15-3.0 nmol/rat) were administered against a background of VIP (3.0 nmol/rat) predictably additive responses were observed; however, when increasing doses of VIP (0.15-3.0 nmol/rat) were administered with PHI (3.0 nmol/rat) only the higher doses of VIP facilitated the PHI-induced secretion while the lower doses of VIP actually reduced the PHI-induced ACTH secretion. Finally, pretreatment with [Lys1, Pro2,5, Arg3,4, Tyr6]-VIP, anVIP (1.5 nmol/rat) totally suppressed VIP-induced ACTH secretion but had no effect on PHI-induced secretion. These studies collectively suggest that VIP and PHI utilize different receptors/mechanisms to regulate HPA secretion. Furthermore, when a range of doses of anVIP (1.5-30.0 nmol/rat) was tested against VIP (3.0 nmol/rat), ACTH secretion was totally suppressed at all doses of the antagonist. However, the maximal reduction of CORT secretion occurred at the lowest dose of anVIP and increasing doses were less and less effective, suggesting that not only PHI but VIP may also stimulate and inhibit HPA secretion. While both the stimulatory and the inhibitory actions of PHI appear to involve ACTH, only the stimulatory action of VIP is ACTH-dependent.