The Y 1 receptor subtype mediates the cardiovascular changes evoked by NPY administered into the posterior hypothalamic nucleus of conscious rat

Abstract

An earlier study showed that the neuropeptide Y (NPY) receptor antagonist PYX-2 blocks the enhancement of a carbachol (CCh)-evoked pressor response produced by prior NPY administration into the posterior hypothalamic nucleus (PHN). The Y receptor subtype that mediates this response, and an increase in mean arterial pressure (MAP) and heart rate, remained unknown due to the lack of selectivity of PYX-2 for the Y receptor subtypes. Thus, the present study was undertaken to elucidate the Y receptor subtype responsible for mediating the NPY-evoked cardiovascular responses from the PHN by determining the rank order of potency of several NPY-related peptides for increasing MAP, and by correlating the pressor response evoked by these peptides to reported K i's and IC 50's for the Y 1, Y 2, Y 4 and Y 5 receptor subtypes. The pharmacological profile (PYY≥NPY≥[Leu 31,Pro 34]NPY≥NPY 13–36≥hPP) and correlations suggest that the Y 1 and/or Y 5 receptor subtypes mediate these cardiovascular changes. Administration of the relatively non-selective Y receptor antagonist PYX-2 or the selective Y 1 receptor antagonist BIBP 3226 into the PHN prior to NPY completely blocked the cardiovascular responses. BIBP 3226 also blocked the cardiovascular changes evoked by [Leu 31,Pro 34]NPY, NPY 13–36 and human pancreatic polypeptide (hPP). In contrast, neither BIBP 3226 nor PYX-2 inhibited the cardiovascular changes induced by peptide YY (PYY) or CCh microinjection into the PHN. These results show that NPY and PYY act on different receptors to mediate their respective cardiovascular changes from the PHN with NPY stimulating the Y 1 receptor.