Angiotensin II binding sites in the rat fetus: characterization of receptor subtypes and interaction with guanyl nucleotides
Angiotensin II (AII) receptor subtypes were studied in the 18-day gestation fetal rat, using two non-peptide AII antagonists: (2-n-butyl-4-chloro-5-hydroxymethyl-1-(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)me thyl)imidazol) (DuP 753; type 1 (AT 1 ) specific), and 1-(4-amino-3-methylpenyl)methyl-5-diphenacetyl-4,5,6,7-tetrahydro-1-H-imidaz o[4,5-c]pyridine-6-carboxylic acid (PD 123 177; type 2 (AT 2 ) specific). Autoradiography using 125 I-[Sar 1 ,Ile 8 ]AII showed that 10 μM PD 123 177 decreased binding to near-nonspecific levels in skin, skeletal muscle and adrenal medulla, whereas 10 μM DuP 753 blocked binding in the liver and lung. Studies in skin and liver membranes confirmed the autoradiographic data: AT 1 receptors were predominant in the liver (95%), and AT 2 in the skin (97%). There was no cross-reactivity between receptor subtype and the heterologous antagonist up to a concentration of 10 μM. In both skin and liver, 2 mM dithiothreitol enhanced the binding of AT 2 receptors by increasing receptor affinity, but inhibited binding of AT 1 by decreasing the receptor number. In the absence of antagonists, guanyl nucleotides, added at equilibrium, caused marked dissociation of 125 I-AII binding in liver membranes, but had minimal effect in skin. However, dissociation occurred in the skin when AT 2 sites were blocked with 10 μM PD 123 177, and in liver, dissociation was not observed when AT 1 sites were blocked with DuP 753. Hence, in contrast to classical AII target tissues, which contain predominantly AT 1 , most of the sites in fetal skin and skeletal muscle are AT 2 . The demonstration that the effects of guanyl nucleotides are selective for receptor subtype suggests that the AT 1 receptor, but not the AT 2 , is coupled to cell function via guanyl nucleotide binding proteins. The functional importance of the AT 2 receptors and their role in fetal physiology is under current investigation.
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