Endocrinology, Vol 116, 1598-1602, Copyright © 1985 by Endocrine Society

ARTICLES

Efficacy of octa- and heptapeptide antagonists of angiotensin II as inhibitors of angiotensin III binding in the rat adrenal glomerulosa

JG Douglas, MC Khosla and FM Bumpus

Angiotensin III (Ang III) is a carboxy-terminal 7-amino acid analog of angiotensin II (Ang II) with similar receptor binding affinity and biological activity in adrenal glomerulosa. Specific competitive antagonists have been synthesized for both compounds, and structure- activity studies have demonstrated that Ang II (octapeptide) antagonists compete better for Ang II receptors in adrenal glomerulosa than do Ang III (heptapeptide) antagonists. These differences were observed in spite of only 1 amino acid difference in chain length of antagonist analogs. These earlier observations by our group provided support for the current hypothesis that Ang III binding would be preferentially inhibited by Ang III antagonists compared to Ang II antagonists. To accomplish these studies, we used [125I]Ang III and [125I]Ang II as ligands and 5 pairs of heptapeptide and octapeptide antagonists with identical substituent amino acids in the carboxy- terminal position. [Sar1,Ile8]- and des Asp1 [Ile8]Ang II did not differ in potency as antagonists of Ang II binding, but with 4 other pairs of antagonists, the octapeptide antagonists were more potent than the corresponding hepatapeptide antagonist. Six of 10 antagonists exhibited similar potencies as antagonists of equimolar concentrations of Ang II and Ang III. One heptapeptide antagonist was twice as potent against Ang III, and 3 octapeptide antagonists were more potent against Ang II. In general, the order of potencies of the 10 antagonists as inhibitors of Ang III binding was linearly related to their potencies against Ang II. Hence, our hypothesis of preferential activity of Ang III antagonists (compared to Ang II antagonists) as inhibitors of Ang III binding to adrenal glomerulosa was not borne out by the present studies. When this observation was combined with the finding of similar receptor densities of Ang III and Ang II receptors, we concluded that Ang III and Ang II probably bind to the same receptor site in the adrenal glomerulosa.