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Pituitary adenylate cyclase-activating polypeptide: a novel, long-lasting, endothelium-independent vasorelaxant

https://doi.org/10.1016/0014-2999(91)90511-NGet rights and content

Abstract

The vasoactivity of the 27- and 38-amino acid forms of the novel peptide pituitary adenylate cyclase-activating polypeptide (PACAP) was tested in vitro. Both forms of PACAP caused endothelium-independent vasodilation (assayed by their vasodilator action on rabbit aorta). When superfused for 1 min the relaxation EC50 of PACAP27 was 23 ± 8 nM and of PACAP38 was 152 ± 66 nM. PACAP was 100-fold more potent than vasoactive intestinal polypeptide (VIP) (PACAP27 shows 68% amino acid sequence homology with VIP), and had a prolonged duration of action, a 1 min exposure to 1 μM PACAP27 lasting 135 ± 7 min and to 1 ft M PACAP38 108 ± 3 min. Adenylate cyclase activity in homogenates of rabbit aortic smooth muscle cells was increased by PACAP27 and PACAP38 with ECsoS of 4.4 and 0.73 nM, respectively. PACAP27 and PACAP38 are potent, long-lasting, endothelium-independent vasodilators.

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    Furthermore, its direct inhibitory effect on plasma extravasation and edema at the level of the vascular endothelium can also be assumed. This is supported by the presence of PAC-1 on endothelial cells (Abu-Hamdan et al., 2006), but numerous data indicate a relaxing action of PACAP on the vascular smooth muscle (Fahrenkrug et al., 2000; Dalsgaard et al., 2003), independent of the endothelium (Warren et al., 1991, 1992). On the basis of these data, the role of endogenous PACAP in acute neurogenic edema formation in the skin is pro-inflammatory, whereas the effect of the exogenous peripherally administered peptide is inhibitory on sensory neuropeptide release (Nemeth et al., 2006; Helyes et al., 2007).

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    This role is supported by studies in dogs, in which high doses of PACAP1-27 and PACAP1-38 induced hypertension after a transient hypotension, indicating a concentration-dependent effect of PACAP in all body vessels.50 Others,49 however, did not observe hypertension at concentrations of 10−12 mol/L, but showed that both PACAP1-38 and PACAP1-27 stimulated a marked vasodilatation in humans, which was 100× higher than that for VIP. In accordance with our study, a study investigating the systemic vasodepressive effect of PACAP in rodents demonstrated that the effects of PACAP were significantly weaker than those of VIP, indicating a limited systemic vasodepressive effect of PACAP both in rodents and humans at moderate physiological concentrations.51,52

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