NOVEL ANGIOTENSIN-II ANTAGONISTS DISTINGUISH AMPHIBIAN FROM MAMMALIAN ANGIOTENSIN-II RECEPTORS EXPRESSED IN XENOPUS-LAEVIS OOCYTES

Angiotensin II (All) stimulates rapid increases in cytosolic Ca2+ concentrations in Xenopus laevis oocytes after binding to specific receptors located in the surrounding follicular cells. In follicular oocytes, the peptide All receptor antagonists saralasin (IC50 = 25 nM) and CGP 42112A (IC50 = 400 nM) were orders of magnitude more potent than the non-peptide antagonists DuP 753 and PD-123177 (IC50 > 10-mu-M) as inhibitors of All-induced Ca2+ mobilization. The relative potencies of the All antagonists at the Xenopus All receptor were completely different from their activities at the two known mammalian All receptor subtypes. These results indicate that the ligand-binding doman of the amphibian All receptor has a unique conformation that distinguishes with high specificity between peptide and non-peptide All antagonists. The amphibian All receptor is pharmacologically distinct from the AT(1) receptor subtype, which mediates phosphoinositide hydrolysis and Ca2+ mobilization in mammalian adrenal cells.