The purpose of this study was to determine whether vasoactive intestinal peptide (VIP), a pleiotropic amphipathic peptide, interacts with rigid liposomes composed of gel phase phospholipids. We found that incubation of VIP with small unilamellar gel phase liposomes composed of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and egg phosphatidylglycerol (ePG) for 2 It at room temperature had no significant effects on VIP secondary structure. Moreover, suffusion of VIP (0.01, 0.1 and 1.0 nmol) incubated in saline or with DPPC/ePG liposomes (size, 30 and 100 nm) for 2 h at room temperature or 4 degreesC onto the intact hamster cheek pouch microcirculation. elicited a similar concentration-dependent vasodilation except for 0.01 nmol VIP (P < 0.05). By contrast, incubation of VIP with gel phase liposomes overnight at 4 degreesC significantly potentiated vasodilation evoked by all three concentrations of the peptide in comparison to aqueous VIP (P < 0.05). VIP-induced vasodilation, was liposome size-independent. The ratio of VIP to phospholipids in DPPC/ePG liposomes was concentration-independent. Collectively, these data indicate that short-term interactions of VIP with rigid phospholipid bilayers are limited resulting in only modest effects on VIP vasoreactivity in vivo. (C) 2003 Elsevier Science Inc. All rights reserved.