C-terminal neuropeptide Y fragments are mast cell-dependent vasodepressor agents

Neuropeptide Y (NPY) is a well-established vasopressor agent present in sympathetic perivascular nerves. Recently, it was found that high doses of the peptide cause a biphasic pressor-depressor response upon intravenous administration. We now report that C-terminal NPY fragments (NPY-(18-36) and NPY-(22-36] given intravenously to conscious or pithed (areflexive) male Sprague-Dawley rats mimic the depressor component of the NPY-(1-36) response while displaying very low pressor activity. Additionally, we have found that the depressor component is blocked by the histamine H1-antagonist, mepyramine. Since the fragment, NPY-(22-36), was equipotent with NPY in inducing histamine release from isolated peritoneal mast cells, we conclude that short C-terminal NPY fragments, like NPY itself, act on mast cells to initiate histamine-mediated cardiovascular actions. Such actions may conceivably be accounted for by the abundance of positively charged amino acid residues in the C-terminus. Moreover, these fragments have little affinity for vascular NPY receptors, as indicated by their poor ability to displace iodinated NPY or peptide YY (PYY) from specific binding sites on vascular smooth muscle cells derived from rat aorta. In conclusion, we propose that short C-terminal NPY fragments, which contain several positively charged amino acid residues, retain the ability of NPY to release histamine from rat mast cells while being essentially devoid of direct vascular motor activity.