IDENTIFICATION AND CHARACTERIZATION OF ANGIOTENSIN-II RECEPTOR SUBTYPES IN HUMAN BRAIN

Autoradiographic and homogenate binding studies using the radioligand, [I-125]angiotensin II, identified a heterogeneous distribution of specific binding sites (defined by angiotensin II, 1.0 muM) throughout the human forebrain. Highest AT receptor densities were detected in the paraventricular nucleus, median eminence, substantia nigra, putamen and caudate nucleus (2.4, 1.2, 1.0, 0.30 and 0.24 fmol/mg tissue equivalent, respectively). The AT1 receptor antagonist, losartan (1.0 muM) competed for the majority of the specific binding. [I-125]Angiotensin II-specific binding (although not consistently above non-specific binding levels) was also detected in various other brain regions (e.g. amygdala, entorhinal cortex, frontal cortex, hippocampus, inferior colliculus, nucleus accumbens, parietal cortex, periaquaductal grey, superior colliculus, striate cortex, temporal cortex, thalamus). In the presence of losartan (1.0 muM), angiotensin II, saralasin, losartan and PD123177 competed for [I-125]angiotensin II binding to membranes prepared from the cerebellum or substantia nigra with a rank order of affinity; angiotensin II = saralasin > PD123177 > losartan. In the presence of PD123177 (1.0 muM), the rank order of affinity of losartan and PD123177 was reversed. These studies indicate the presence of both AT1 and AT2 receptor subtypes within various regions of the human forebrain.