Peptide antagonists of angiotensin-induced adrenal catecholamine release

The effect of analogs of angiotensin (modified with an Ile-substituted for Phe) was studied in the isolated, retrogradely perfused adrenal of the cat. Continuous differential analysis of norepinephrine and epinephrine output was quantified with an automated trihydroxyindole procedure. [Ile8]-angiotensin I and [Ile7]-angiotensin III exhibited negligible secretory activity, in contrast to the stimulatory effects of [Ile8]-angiotensin II (10-20% activity relative to angiotensin II). [Ile8]-angiotensin I blocked angiotensin II-induced catecholamine secretion and a pA2 value of 8.50 was obtained. [Ile7]-angiotensin III was an especially potent antagonist of angiotensin II and a pA2 value of 10.4 was calculated for this heptapeptide analog. The pA2 value for [Ile8]-angiotensin II, a partial agonist in the adrenal medulla was 9.33. These three analogs were equally effective against secretion induced by the corresponding unsubstituted homologs (Ang I and Ang III). These data suggest that all these angiotensin peptides interact with a common receptor. [Ile8]-angiotensin I and [Ile7]-angiotensin III had no effect on adrenal medullary responses induced by KCl, nicotine and bradykinin. These structural analogs of angiotensin are pure competitive antagonists of angiotensin in the cat adrenal chromaffin cell.