BRAIN ANGIOTENSIN RECEPTOR FUNCTION, CONTROL, & ANATOMY

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The long-term objective is to characterize angiotensinergic activity in the CNS. The first specific aim is to examine the brain angiotensin (Ang II) receptor pharmacology using homogenate radioligand binding techniques. These studies will examine whether brain Ang II receptors exist in more than one subtype. The binding affinity of Ang II receptor sites for 125I-Sar-1,Ile8-Ang II in different brain areas will be determined. If significant differences in binding affinity are observed, this will suggest that multiple brain Ang II receptor subtypes exist. Further studies of Ang II receptor subtypes will use Ang II analogs to discriminate subtypes with different affinities for different analogs. These studies will be extended to examine the Ang II receptor site pharmacology in discrete nuclei of the brain using quantitative in vitro autoradiography of 125I-Sar-1,Ile8-Ang II binding to tissue sections. Further studies will investigate the existence of interconvertible high and low affinity agonist binding states of the brain Ang II receptor. The binding of a radiolabeled antagonist of Ang II will be carried out in the presence of varying concentrations of Ang II or its agonist analogs in the presence and absence of guanosine triphosphate (GTP) or a stable analog of GTP. Similar studies of other receptor systems including Ang II receptors in peripheral tissues have demonstrated high and low affinity states of the receptors. The second specific aim is to examine the functional neuroanatomy of the brain Ang II receptor. These studies will primarily involve analysis of Ang II binding in discrete brain regions using in vitro receptor autoradiography. Rats will be subjected to various treatments, e.g., chronic and acute intraventricular administration of Ang II or its antagonist, electrolytic or chemical lesions of specific brain areas, specific neurotransmitter containing neurons or specific subcellular elements of neurons. Based upon the alterations in radiolabeled Ang II binding to various brain regions, these studies should lead to a characterization of the neuronal elements in the brain which contain Ang II receptors, the sites in the brain which send projections to brain areas containing Ang II receptors, the neurotransmitter subtype (e.g., noradrenergic, dopaminergic) of neurons containing And II receptors, the neurotransmitter and/or neurohormonal role of Ang II in the brain, and whether angiotensinergic activity regulates Ang II receptors in the brain.