The ability of neuropeptide Y to mediate responses in the murine cutaneous microvasculature:: an analysis of the contribution of Y1 and Y2 receptors

1 The ability of neuropeptide Y (NPY) to modulate skin blood flow, oedema formation and neutrophil accumulation was investigated. Experiments were designed to examine the possible contribution of the Y-2 receptor, in addition to the Y-1 receptor, through use of Y-2 receptor knockout mice (Y-2(-/-)) and selective receptor antagonists. 2 The development of a Tc-99m clearance technique for the measurement of microvascular blood flow changes in mouse dorsal skin revealed a dose-dependent ability of picomole amounts of NPY, and also of the Y-1-preferred agonist Pro(34)NPY and the Y-2-preferred agonist PYY(3-36) to decrease blood flow. 3 The Y-1 receptor antagonist BIBO3304 blocked responses to the Y-1 agonist at the lower doses, but only partially inhibited at the higher doses tested in Y-2(+/+). In Y-2(-/-) receptor mice, the responses to the Y2 agonist were abolished at the lower doses and partially reduced at the highest dose tested, while those to the Y-1 agonist were similar in both Y-2(+/+) and Y-2(-/-) receptor mice. 4 In Y-2(+/+) receptor mice, the simultaneous injection of the Y-2 antagonist BIIE0246 with BIBO3304 abolished Y-2 agonist-induced decreases in blood flow over the dose range used(10-100 pmol). When the Y-2 receptor antagonist BIIE0246 was given alone, it was not able to significantly affect the PYY(3-36)-induced response, whereas the Y-1 receptor antagonist BIBO3304 partially (P<0.001) inhibited the decrease in blood flow evoked by PYY(3-36) at the highest dose. 5 NPY did not mediate either oedema formation, even when investigated in the presence of the vasodilator calcitonin gene-related peptide (CGRP), or neutrophil accumulation in murine skin. 6 We conclude that the major vasoactive activity of NPY in the cutaneous microvasculature is to act in a potent manner to decrease blood flow via Y-1 receptors, with evidence for the additional involvement of postjunctional Y-2 receptors. Our results do not provide evidence for a potent proinflammatory activity of NPY in the cutaneous microvasculature.