Distribution of the non-AT1, non-AT2 angiotensin-binding site in the rat brain: preliminary characterization

The discovery of a novel, non-AT1, non-AT2 binding site for angiotensin II (Ang II) in the brain adds a new dimension to the brain angiotensin system. The distribution of the non-AT1, non-AT2 binding site in the rat brain was determined using radioligand-binding assays and in vitro receptor autoradiography. There is a marked rostral to caudal gradient of the density of this binding site from the olfactory bulbs to the cervical spinal cord, with a consistent binding affinity, K(d) approximately 1-3 nM. Binding is widespread throughout the brain, however, areas of very intense binding are present in a large number of brain regions. The olfactory nerve layer of the olfactory bulb has the highest binding site density. Very high binding site density is also seen in the cerebral cortex with highest binding density in pyriform, insular and entorhinal cortex. Very high binding occurs in brain regions associated with dopaminergic reward (nucleus accumbens, ventral tegmental area) and motor (substantia nigra, caudate/putamen) systems. Very high to high binding also occurs in brain regions associated with the development of Alzheimer's disease (nucleus basalis of Meynert, substantia innominata). Very high to high binding is also seen in brain regions associated with cardiovascular regulation (subfornical organ, median, medial and anteroventral preoptic nucleus, paraventricular nucleus of the hypothalamus, solitary tract nucleus), areas that harbor high densities of the AT1 Ang II receptor subtype. High non-AT1, non-AT2 binding site density is present in brain regions containing high levels of the AT2 Ang II receptor subtype (amygdala, several thalamic nuclei, superior colliculus). Very high binding is also present in the choroid plexus, peri-third ventricular ependyma, and the subcommissural organ. The widespread, yet discrete distribution of high levels of this binding site suggests that it could function as a component of the blood-brain barrier, as a highly specific angiotensinase, or as a receptor for Ang II that mediates known and novel functions of this peptide, or that it serves as a clearance receptor for Ang II.