A transient increase in skin blood flow in response to an innocuous local pressure application, defined as pressure-induced vasodilatation (PIV), delays the occurrence of ischemia, suggesting a protective feature against applied pressure. The PIV response depends on capsaicin-sensitive nerve fibres and calcitonin gene-related peptide (CGRP) has been shown to be involved. In these fibres, CGRP co-exists with pituitary adenylate cyclase activating polypeptide (PACAP). Three distinct receptors mediate the biological effects of PACAP: VPAC1 and VPAC2 receptors binding with the same affinity for PACAP and vasoactive intestinal peptide and PAC1 receptors showing high selectivity for PACAP. Because the receptors are widely expressed in the nervous system and in the skin, we hypothesised that at least one of them is involved in PIV development. To verify this hypothesis, we used [D-P-Cl-Phe6,Leu17]-VIP (non specific antagonist VPAC1/VPAC2 receptors), PG 97-269 (antagonist of VPAC1 receptors), PACAP(6-38) (antagonist of VPAC2/PAC1 receptors) and Max.d.4 (antagonist of PAC1 receptors) in anaesthetised rodents. The blockade of VPAC1/VPAC2, VPAC1 or VPAC2/PAC1 receptors eliminated the PIV response, whereas PAC1 blockade had no effect, demonstrating an involvement of VPAC1/VPAC2 receptors in PIV development. Moreover, endothelium-independent and -dependent vasodilator responses were unchanged by the VPAC1/VPAC2 antagonist. Thus, the absence of a PIV response following VPAC1/VPAC2 blockade cannot be explained by any dysfunction of the vascular smooth muscle nor of endothelial vasodilator capacity. The involvement of VPAC1/VPAC2 receptors in the PIV development seems to imply a series relationship in which each receptor type (CGRP, VPAC1, VPAC2) is necessary for the full transmission of the response.