All d-VIP mitigates vasodilation elicited by l-VIP, micellar l-VIP and micellar PACAP1-38, but not PACAP1-38, in vivo

The purpose of this study was to determine whether all d-vasoactive intestinal peptide (VIP), an inactive optical isomer of l-VIP, modulates the vasorelaxant effects of human l-VIP and pituitary adenylate cyclase activating peptide (PACAP)1-38, two ubiquitous and pleiotropic neuropeptides that activate VPAC1 and VPAC2, two VIP subtype receptors, in the intact peripheral microcirculation. Using intravital microscopy, we found that suffusion of all d-VIP had no significant effects on arteriolar diameter in the intact hamster cheek pouch. However, all d-VIP significantly attenuated l-VIP-induced vasodilation in a concentration-dependent fashion (P < 0.05). Likewise, all d-VIP significantly attenuated the vasorelaxant effects of l-VIP associated with sterically stabilized phospholipid micelles (SSM; P < 0.05). Although all d-VIP had no significant effects on l-PACAP1-38-induced vasodilation, it abrogated PACAP1-38 in SSM-induced responses (P < 0.05). The effects of all d-VIP were specific because it had no significant effects on acetylcholine-, nitroglycerin- and bradykinin-induced vasodilation. Taken together, these data indicate that all d-VIP attenuates the vasorelaxant effects of random coil and α-helix l-VIP as well as those of α-helix but not random coil PACAP in the intact peripheral microcirculation in a specific fashion. These effects are mediated, most likely, through interactions with VPAC1/VPAC2 receptors. We suggest that all d-VIP could be exploited as a novel, safe and active targeting moiety of VPAC1/VPAC2 receptors in vivo.