VIP/PACAP receptor mediation of cutaneous active vasodilation during heat stress in humans

Abstract

Vasoactive intestinal peptide (VIP) is implicated in cutaneous active vasodilation in humans. VIP and the closely related pituitary adenylate cyclase activating peptide (PACAP) act through several receptor types: VIP through VPAC1 and VPAC2 receptors and PACAP through VPAC1, VPAC2, and PAC1 receptors. We examined participation of VPAC2 and/or PAC1 receptors in cutaneous vasodilation during heat stress by testing the effects of their specific blockade with PACAP6-38. PACAP6-38 dissolved in Ringer's was administered by intradermal microdialysis at one forearm site while a control site received Ringer's solution. Skin blood flow was monitored by laser-Doppler flowmetry (LDF). Blood pressure was monitored noninvasively and cutaneous vascular conductance (CVC) calculated. A 5- to 10-min baseline period was followed by approximately 70 min of PACAP6-38 (100 microM) perfusion at one site in normothermia and a 3-min period of body cooling. Whole body heating was then performed to engage cutaneous active vasodilation and was maintained until CVC had plateaued at an elevated level at all sites for 5-10 min. Finally, 58 mM sodium nitroprusside was perfused through both microdialysis sites to effect maximal vasodilation. No CVC differences were found between control and PACAP6-38-treated sites during normothermia (19 +/- 3%max untreated vs. 20 +/- 3%max, PACAP6-38 treated; P > 0.05 between sites) or cold stress (11 +/- 2%max untreated vs. 10 +/- 2%max, PACAP6-38 treated, P > 0.05 between sites). PACAP6-38 attenuated the increase in CVC during whole body heating when compared with untreated sites (59 +/- 3%max untreated vs. 46 +/- 3%max, PACAP6-38 treated, P < 0.05). We conclude that VPAC2 and/or PAC1 receptor activation is involved in cutaneous active vasodilation in humans.

Fig. 1.

Summary of attenuating effect of 100 μM PACAP6–38 on the vasodilation induced by 30 μM PACAP38 in 4 subjects. PACAP6–38 did not alter basal cutaneous vascular conductance (CVC) levels (P > 0.05). PACAP38 increased CVC significantly from basal levels in the absence and presence of PACAP6–38 (P < 0.05); however, the vasodilation induced by PACAP38 was significantly reduced by PACAP6–38 (P < 0.05).

Fig. 2.

Whole body heat stress protocol. This protocol was designed to examine the effects of antagonism of VPAC2 and PAC2 receptors for VIP and pituitary adenylate cyclase activating peptide (PACAP) on the cutaneous vasodilation induced by whole body heat stress. Two intradermal microdialysis sites were used to perfuse intradermal microdialysis fibers with Ringer's solution alone at an untreated control site and with 100 μM PACAP6–38, a VPAC2/PAC1 receptor antagonist. Maximal cutaneous vasodilation was achieved at the end of the study by perfusion with 58 mM sodium nitroprusside (SNP) at both sites. The perfusion rate at all microdialysis sites was 3 μl/min. Tsk, skin temperature.

Fig. 3.

CVC response to the body heating protocol in 1 subject. Perfusion with 100 μM PACAP6–38 Ringer's began 10 min into the study. Periods of whole body cooling (CS) and heating are indicated. Perfusion with 58 mM SNP began at 120 min. The site receiving PACAP6–38 showed less vasodilation during heat stress than did the control site.

Fig. 4.

Summary of CVC responses. Under normothermic conditions during perfusion of both microdialysis sites with Ringer's solution, CVC values, expressed as a percentage of their respective maxima, did not differ significantly (P > 0.05 between sites). In normothermia, changing the perfusion of one site to 100 μM PACAP6–38 in Ringer's did not produce any significant difference with CVC at sites perfused with Ringer's alone (P > 0.05). Cold stress significantly reduced CVC at both sites compared with normothermia (Normo) (P < 0.05). These responses did not differ between sites (P > 0.05). During heat stress, CVC increased at both microdialysis sites compared with normothermia (P < 0.05); however, this increase was significantly attenuated at sites perfused with 100 μM PACAP6–38 (P < 0.05, PACAP6–38 vs. Ringer's).