Neuropeptide Y induced attenuation of catecholamine synthesis in the rat mesenteric arterial bed.

The effect of neuropeptide Y (NPY) on the basal and nerve stimulation-induced increase in norepinephrine synthesis was studied in the isolated and perfused mesenteric arterial bed of the rat. Tyrosine hydroxylation, the rate-limiting step in catecholamine (CA) biosynthesis, was assessed by measuring the accumulation of DOPA in the perfusate/superfusate overflow after perfusion of the mesenteric arterial bed with the decarboxylase inhibitor m-hydroxybenzyl hydralazine (NSD-1015). Treatment with NDS-1015 resulted in a time-dependent increase in DOPA production and nerve stimulation (8 Hz, supramaximal voltage, 2 ms duration) increased DOPA production even further. NPY I to 100 nM was observed to produce a concentration-dependent attenuation in both the basal and nerve stimulation-induced increase in DOPA formation. To come to an understanding of the NPY receptor subtype mediating the inhibition of CA synthesis, the rank order of potency of a series of NPY analogs with varying selectivity for NPY receptor subtypes including intestinal polypeptide (PYY), PYY 13-36, Leu(36) Pro(34) NPY, human pancreatic polypeptide (h-PP), and rat pancreatic polypeptide (r-PP) were determined. In addition, the effect of various selective NPY antagonists on the inhibitory effect of NPY was also examined. These included the Y-1 antagonist BIB03304, the Y-2 antagonist BIIE0246, and the Y-5 antagonist CGP71683. The IC50's for NPY, PYY, PYY13-36, Leu(31) Pro(34) NPY, and hPP in inhibiting CA synthesis were 5, 7, 15, 30, and 33nM respectively. rPP failed to inhibit CA synthesis. All 3 of the NPY antagonists produced attenuation of the NPY-induced inhibition of CA synthesis, but it took a combination of all 3 to completely block the effect of a maximal inhibitory concentration of NPY. These results demonstrate that NPY inhibits CA synthesis in the perfused mesenteric arterial bed and can do so by activation of a variety of receptors including the Y-1, Y-2, and Y-5.