Angiotensin II (AII) 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 AII 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 greater than 10 microM) as inhibitors of AII-induced Ca2+ mobilization. The relative potencies of the AII antagonists at the Xenopus AII receptor were completely different from their activities at the two known mammalian AII receptor subtypes. These results indicate that the ligand-binding domain of the amphibian AII receptor has a unique conformation that distinguishes with high specificity between peptide and non-peptide AII antagonists. The amphibian AII receptor is pharmacologically distinct from the AT1 receptor subtype, which mediates phosphoinositide hydrolysis and Ca2+ mobilization in mammalian adrenal cells.