INCREASED POTENCY OF NEUROPEPTIDE Y TO ANTAGONIZE  2 -ADRENOCEPTOR FUNCTION IN THE NUCLEUS TRACTUS SOLITARII OF THE SPONTANEOUSLY HYPERTENSIVE RAT S. -N. YANG*, D. R. FIOR*, A. C. HANSSON*‡, A. CINTRA*, M. CASTELLANO†, U. GANTEN‡, D. GANTEN‡, L. F. AGNATI*, and K. FUXE* *Division of Cellular and Molecular Neurochemistry, Department of Neuroscience, Karolinska Institutet, Doktorsringen 12, S-17177, Stockholm ,Sweden †Scienze Mediche, Universita ` degli Studi di Brescia, 25100, Brescia Italy ‡Max-Delbru ¨ck-Centrum fu ¨r Molekulare Medizin, 13122, Berlin ,Germany Abstract––The regulation by neuropeptide Y of  2 -adrenoceptors in the nucleus tractus solitarii was evaluated in the adult normotensive Wistar Kyoto rat and the adult spontaneously hypertensive rat. The microinjection of a submaximal dose of l-noradrenaline (800 pmol in 50 nl) alone into the nucleus tractus solitarii produced a significant reduction in the mean arterial blood pressure in either strain. The threshold dose (1 pmol in 50 nl) of neuropeptide Y(1–36) for the vasodepressor response in the Wistar Kyoto rat was five times higher than that (0.2 pmol in 50 nl) in the spontaneously hypertensive rat. Furthermore, neuropeptide Y(1–36) at 0.2 pmol in 50 nl could significantly counteract the vasodepressor response to l-noradrenaline (800 pmol in 50 nl) in the spontaneously hypertensive rat, but not in the Wistar Kyoto rat, in which 1 pmol in 50 nl of neuropeptide Y(1–36) must be employed to counteract the vasodepressor response to l-noradrenaline (800 pmol in 50 nl), although the vasodepressor responses are of a similar magnitude. The in situ hybridization and quantitative receptor autoradiographical experiments showed that the  2A -adrenoceptor messenger RNA levels and the B max value of the  2 -adrenoceptor agonist [ 3 H]p-aminoclonidine binding sites measured in the nucleus tractus solitarii of the spontaneously hypertensive rat were substantially lower than those in the Wistar Kyoto rat. The quantitative receptor autoradiographical results were consistent with the cardiovascular results and showed that in the spontaneously hypertensive rat, neuropeptide Y(1–36) at 1 nM led to a significant increase in the K d value of [ 3 H]p-aminoclonidine binding sites. In the Wistar Kyoto rat, neuropeptide Y(1–36) produced this effect only at 10nM. The present study provides evidence for an increase of the potency of neuropeptide Y(1–36) to antagonistically modulate  2 -adrenoceptors in the nucleus tractus solitarii of the spon- taneously hypertensive rat. This enhanced antagonistic action may partly be related to a reduction in the number of  2A -adrenoceptors in the nucleus tractus solitarii of the spontaneously hypertensive rat, since a decrease has been observed in the  2A -adrenoceptor messenger RNA levels and the 2-adrenoceptor binding sites in the spontaneously hypertensive rat. This increased potency of neuropeptide Y(1–36) to antagonize  2 -adrenoceptor function in the nucleus tractus solitarii of the spontaneously hypertensive rat may contribute to the development of high blood pressure in this hypertensive strain. 1998 IBRO. Published by Elsevier Science Ltd. Key words: neuropeptide, noradrenaline, in situ hybridization, quantitative receptor autoradiography, cardiovascular control, hypertension Several lines of evidence show that neuropeptide Y (NPY) and catecholamine transmission lines in the brain play an important physiological role in the control of autonomic activi- ties. 6,7,11,13,26,36,37,48,55,56,66 One of the most import- ant targets of NPY and catecholamines is the nucleus tractus solitarii, 13,22,57,62,66 the major relay nucleus involved in the cardiovascular reflex. 13,15,54,57 Immunocytochemical studies have revealed that NPY/catecholamine co-storing neurons and nerve terminals exist in the nucleus tractus solitarii of the rat. 12,18 Furthermore, the cardiovascular part of the nucleus tractus solitarii is densely labelled by NPY receptor 4,22,24,33,38 and  2 -adrenoceptor radiolig- ands. 56,67 Both immunocytochemical and in situ hy- bridization studies have demonstrated that the  2A - adrenoceptor subtype dominates in the nucleus tractus solitarii. 45,49,51 Biochemical and cardiovascu- lar experiments have indicated that the interaction between NPY and catecholamine transmission lines through NPY/ 2 -adrenoceptor interaction in the nucleus tractus solitarii can take place at the To whom correspondence should be addressed. A bbreviations: aCSF, artificial cerebrospinal fluid; EDTA, ethylenediaminetetra-acetate; NPY, neuropeptide Y; PBS, phosphate-buffered saline; SHR, spontaneously hy- pertensive rat; SSC, standard saline citrate; WKY, nor- motensive Wistar Kyoto rat. Pergamon N euroscience Vol. 78, No. 3, pp. 803–813, 1997 Copyright  1997 IBRO. Published by Elsevier Science Ltd Printed in Great Britain. All rights reserved 0306–4522/97 $17.00+ 0.00 PII: S0306-4522(96)00487-3 803