CHARACTERIZATION OF NEUROPEPTIDE-Y (NPY) RECEPTORS IN HUMAN CEREBRAL-ARTERIES WITH SELECTIVE AGONISTS AND THE NEW Y-1 ANTAGONIST BIBP-3226

1 We have characterized pharmacologically the receptor subtype(s) responsible for the neuropeptide Y (NPY)-induced vasoconstriction in human cerebral arteries. NPY, PW and several of their derivatives with well defined affinities at the known Y-1 and Y-2 receptor subtypes were used. Moreover, we tested the ability of the new Y-1 receptor antagonist, BIBP 3226, to antagonize the NPY-induced cerebral vasoconstriction. 2 NPY, PYY and their agonists with high affinities at the Y-1 receptor subtype ([LeU(31)-pro(34)]-Npy and [Leu(31)-Pro(34)]-PYY) elicited strong, long lasting and concentration-dependent contractions of human cerebral arteries. Compounds with Y-2 affinity such as PYY3-36 or NPY13-36 either elicited a submaximal contraction at high concentrations or failed to induce any significant vasomotor response. Also, the application of NPY or the specific Y-1 agonist, [Leu(31)-Pro(34)]-NPY, to human cerebral vessels pretreated with the Y-1 agonist, NPY13-36, resulted in contractile responses identical to those obtained when these compounds were tested without prior application of NPY13-36. 3 The order of agonist potency at the human cerebrovascular receptor was: [Leu(31)-Pro(34)]-NPY = [Leu(31)-Pro(34)]-PYY greater than or equal to NPY>PYY>PYY3-36 > > > NPY13-36, which corresponded to that reported previously at the neuronal and vascular Y-1 receptors. 4 Increasing concentrations (10(-9)-10(-6) M) of the Y-1 receptor antagonist, BIBP 3226, to human cerebral vessels caused a parallel and rightward shift in the NPY dose-response curves without any significant change in the maximal contractile response. The calculated pA(2) was 8.52+/-0.13, a value compatible with the reported affinity at the rodent and human Y-1 receptor. 5 We conclude that Y-1 receptors exclusively, mediate the NPY-induced contraction in human cerebral arteries and we show that BIBP 3226 is a potent and competitive antagonist of this Y-1-mediated vasoconstriction.