Angiotensin II receptor subtypes and biological responses in the adrenal cortex and medulla.
Angiotensin II (AII) receptor subtypes and their potential coupling mechanisms were studied using recently developed peptide and nonpeptide antagonists in rat and bovine adrenal zona glomerulosa cells, as well as in membranes prepared from rat and bovine adrenal cortex and medulla. Comparison of the potencies of these novel antagonists to displace 125I-[Sar1,Ile8]AII from its binding sites revealed two distinct AII binding sites in membranes prepared from rat adrenal capsules (zona glomerulosa) and from rat adrenal inner zones containing the medulla. About 85% of the binding sites of the glomerulosa zone and 30% of those of the inner zones were of the AT1 subtype, with relative affinities for the nonpeptide antagonists Dup 753 and PD 123177 and the peptide antagonist CGP 42112A in the order of Dup 753 much greater than CGP 42112A greater than PD 123177. In contrast, the relative binding potencies for the other (AT2) population of binding sites were CGP 42112A greater than PD 123177 much greater than Dup 753. Neither AII nor its peptide antagonist [Sar1,Ile8]AII could distinguish between the two sets of binding sites. The effects of the new antagonists on functional responses of rat adrenal glomerulosa cells demonstrated that both AII-stimulated aldosterone production and the AII-induced inhibition of adrenocorticotropic hormone-stimulated cAMP formation were mediated by the AT1 receptor subtype. In bovine adrenals, only AT1 receptors were detected in membranes prepared from the cortex and the medulla, as well as in cultured glomerulosa cells. The relative inhibitory potency of Dup 753 was lower by an order of magnitude at bovine than at rat AT1 receptors. The inhibition of AII-induced aldosterone production by the various antagonists was closely correlated with their inhibitory potencies on 125I-[Sar1,Ile8]AII binding to bovine glomerulosa cells. These data suggest that the known effects of AII in adrenal glomerulosa cells are mediated through the AT1 receptor subtype and that the distribution and/or specificity of the AT2 receptors shows marked species variations.
Balla
T
T
Endocrinology and Reproduction Research Branch, National Institutes of Child Health, National Institutes of Health, Bethesda, Maryland 20892.
Baukal
A J
AJ
Eng
S
S
Catt
K J
KJ
D000302:Adrenal Cortex / Q000737:chemistry / Q000187:drug effects*; D000313:Adrenal Medulla / Q000737:chemistry / Q000187:drug effects*; D000450:Aldosterone / Q000096:biosynthesis; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000494:pharmacology; D002417:Cattle; D000242:Cyclic AMP / Q000096:biosynthesis; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000032:analysis*; D013777:Tetrazoles / Q000494:pharmacology; D015384:Zona Glomerulosa / Q000187:drug effects / Q000378:metabolism
D001713:Biphenyl Compounds; D007093:Imidazoles; D009842:Oligopeptides; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C060894:CGP 42112A; D000450:Aldosterone; D000242:Cyclic AMP; D019808:Losartan