ANGIOTENSIN RECEPTOR SUBTYPES IN THE RAT BRAIN

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The objectives of the proposal are to characterize angiotensin receptor subtypes in the rat brain and define subtype specificity for the dipsogenic and pressor action of angiotensin II (AII) in this organ. Recent studies, using new AII receptor subtype selective compounds have defined receptor subtypes in peripheral organs but multiple AII receptor populations in the central nervous system have yet to be characterized. The initial aim is to utilize two non-peptidic subtype selective compounds, DuP 753 and PD123177, to document the localization of receptor subtypes in the rat brain by competitive receptor autoradiography. The analysis will include receptor populations at approximately thirty different nuclei. The analysis of competition curves for each nucleus will test both one and two site models to estimate if receptor populations are exclusively one subtype or a mixture of two. Preliminary studies to characterize receptor subtypes indicate that a re-evaluation of peptidic analogues is warranted. In particular, possible subtype specificity of the naturally occurring congener, angiotensin III (AIII) will be examined. Establishment of a receptor subtype selective for AIII will fuel the argument supporting a specific physiological action of the peptide. Studies of AII receptors in peripheral tissues indicate a subtype whose binding is enhanced by sulfhydryl reducing agents (SH-RA) while several receptor populations in the central nervous system are largely unaffected by SH-RAS. To test the hypothesis that both are identical, experiments will re-examine the effect of SH-RAs at the brain sites after elimination of possible contaminating subtypes by DuP753. It is predicted that the approach will reveal enhanced binding at remaining receptors by a SH-RA, consistent with the effects observed in peripheral tissues. The second part of the proposal addresses functional aspects of AII receptor subtype classification. Specifically, the subtype selective antagonists, DuP753 and PD123177, will be used to test which receptor subtype mediates centrally induced AII pressor and dipsogenic actions. The scientific importance of linking physiological functions of AII with specific receptor subtypes is complemented with the therapeutic ramifications. The newly-developed antagonist compounds show therapeutic potential with respect to cardiovascular disease, and the current studies will assist in the prediction of possible actions and side-effects.