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RS Chang and VJ Lotti
Department of New Lead Pharmacology, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
The nonpeptide angiotensin II antagonists Dup-89 and WL-19 displaced specific 125I-angiotensin II binding in rat whole adrenal in a clearly biphasic manner, indicating the presence of high (nanomolar) and low (micromolar) affinity sites, each representing approximately 50% of the total maximal number of binding sites. Displacement studies using sufficient concentrations of either antagonist to prevent binding to its respective high affinity site revealed that the high affinity binding sites for Dup-89 and WL-19 were distinct and corresponded to the low affinity site of the other. Both binding sites were also present in the adrenal capsule (cortex) and adrenal decapsulated (medulla) tissue. The two 125I-angiotensin II binding sites were also differentiated by their sensitivity to dithiothreitol and the relative affinities of angiotensin II, angiotensin III, and their respective Sar1,Ile8- and Ile7-substituted antagonist analogs. Only Dup-89 (KB = 13 nM) was effective in antagonizing angiotensin II-stimulated aldosterone release from dispersed adrenal capsular cells, indicating that this functional response is mediated by an action upon the 125I- angiotensin II binding site at which Dup-89 has high affinity. Collectively, the data provide additional strong support for the presence of two distinct angiotensin II receptor subtypes in the rat adrenal.
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