Comparative Receptor-Binding Properties of Heptapeptide and Octapeptide Antagonists of Angiotensin II in Rat Adrenal Glomerulosa and Uterine Smooth Muscle*

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Abstract
Pharmacological studies in the rat and other species using angiotensin II (Ang II) antagonists suggest that the structural requirements of Ang II antagonists differ in smooth muscle and adrenal target tissues. Specifically, heptapeptide antagonists preferentially inhibit steroidogenic responses to Ang II, while octapeptide antagonists preferentially inhibit pressor responses to Ang II. We have compared the ability of a number ofhepta- and octapeptide antagonists to inhibit [125I]iodo-Ang II receptor binding in rat uterine smooth muscle and adrenal target tissues. The purpose was to determine whether variable receptor-binding affinities in these tissues could account for the differences observed in vivo. A number of similarities was noted in the two target tissues. First, each of the octapeptide antagonists was a more potent inhibitor of Ang II binding than its corresponding 2–8 heptapeptide antagonist. Second, there was a linear relationship between the dose ratios of receptor binding in the adrenal and in smooth muscle for the group of 10 antagonists (y = 1.2x + 0.2; r = 0.99). The order of potency was similar for the majority of antagonists. The order from most to least potent was: [Sar1,Thr(Me)8] > [Sar1,Ile8] = [Sar1,Thr8] > [Sar1,Ala8] ≥ des-Asp1 [He8] > [Sar1,Ser8] > des-Asp1-[Ala8]Ang II. However, the majority of antagonists did possess lower Kds is in the adrenal than in smooth muscle. The physiological relevance of the observed binding affinities in uterine smooth muscle was confirmed by the fact that there was good correspondance between the dose ratios (Kd Ang II/Kd antagonist) of receptor binding in smooth muscle and dose ratios from rat pressor assays (r = 0.85). The correlation was equally as good when dose ratios of binding were compared to a pA2 values derived using rabbit aortic strip (r = 0.88). This suggests that relative binding affinity is a major determinant of the efficacy of octa- and heptapeptide antagonists of Ang II in smooth muscle. Thus, these studies demonstrate that differences in receptor-binding affinities do not account for the observations in vivo that heptapeptide antagonists are more active in inhibiting Ang II-stimulated steroidogenesis. We have established quite convincingly that the orders of potency of a series of octapeptide and heptapeptide analogs of Ang II in competing for specific receptors in uterine smooth muscle and adrenal glomerulosa are similar. Further, receptors in both tissues exhibit higher affinities for octapeptide analogs. Finally, inhibition of the binding of Ang II to adrenal glomerulosa is more readily achieved than is inhibition of binding to uterine smooth muscle. (Endocrinology106: 120, 1980)