Autoradiographic localization of subtypes of angiotensin II antagonist binding in the rat brain.
The non-peptide angiotensin II receptor compounds DuP 753 and WL 19 were utilized to detect subtypes of [125I]Sar1-Ile8-angiotensin II binding to angiotensin II receptors in the rat brain. In rat forebrain homogenates, DuP 753 and WL 19 produced a partial displacement of [125I]Sar1-Ile8-angiotensin II binding with DuP 753 displacing approximately 65% of the binding and WL 19 displacing approximately 35% of the binding. Using the techniques of quantitative receptor autoradiography, a distinct regional distribution of the subtypes of angiotensin II antagonist bind was detected. The angiotensin II-1 binding site (the receptor subtype preferentially displaced by DuP 753) appeared to predominate in the dipsogenic, cardiovascular and endocrine areas, including the subfornical organ, paraventricular and periventricular nuclei of the hypothalamus, anterior pituitary, dorsal motor nucleus of the vagus, nucleus of the solitary tract and the area postrema. Additional areas that contained predominantly the angiotensin II-1 receptor subtype were the ventral hippocampus, substantia gelatinosa of the trigeminal nucleus, nucleus of the lateral olfactory tract, piriform cortex and median preoptic nucleus. The angiotensin II-2 binding site (displaced by WL 19) was the predominant subtype in the thalamus, inferior olive, lateral septum, subthalamic nucleus, locus coeruleus, medial geniculate and medial amygdala. Several areas of the brain appeared to contain both receptor subtypes, including the superior and inferior colliculi, and the olfactory bulb. The angiotensin II-1 binding site was concentrated in areas of the brain involved in mediating angiotensin II effects on drinking, endocrine status and blood pressure. Localization of angiotensin II-2 sites in the thalamus and areas of the brain which process sensory information suggests a novel modulatory role for angiotensin II at this receptor subtype. These results indicate that DuP 753 and WL 19 are highly selective for angiotensin II binding site subtypes in the brain and that, in general these subtypes are compartmentalized in distinct brain regions. The non-peptide compounds used in these studies should provide excellent tools to discern the functional role of angiotensin II receptor subtypes in the brain.
Gehlert
D R
DR
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Gackenheimer
S L
SL
Schober
D A
DA
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D007093:Imidazoles / Q000378:metabolism; D019808:Losartan; D008297:Male; D011725:Pyridines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012504:Saralasin / Q000378:metabolism*; D013777:Tetrazoles / Q000378:metabolism; D014018:Tissue Distribution
D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D013777:Tetrazoles; D000804:Angiotensin II; C063457:WL 19; D012504:Saralasin; D019808:Losartan