RECIPROCAL MODULATION OF THE BINDING OF ANGIOTENSIN AGONISTS AND ANTAGONISTS TO ANGIOTENSIN RECEPTORS IN SMOOTH-MUSCLE

1. Direct ligand binding studies have shown that the agonist I-125-[Sar1]Ang II and the antagonist I-125-[Sar1Ile8]Ang II bind to bovine uterus smooth muscle membranes in a time-dependent, reversible and saturable manner; both ligands had the same number of high affinity sites. 2. [Sar1Ile8]Ang II inhibited the binding of I-125-[Sar1]Ang II in a non-competitive manner by decreasing the number of high affinity sites without changing the binding affinity of the radioligand. 3. [Sar']Ang II also inhibited the binding of I-125-[Sar1Ile8]Ang II in a non-competitive manner. 4. Dissociation of both radioligands from their receptor sites was fast enough that pseudo irreversible occupancy of the binding sites could not account for the observed non-competitive inhibition. 5. Displacement studies using I-125-[Sar1Ile8]Ang II as the radioligand provided evidence for the existence of two binding sites when the displacing ligand was [Sar1]Ang II but not when the displacing ligand was [Sar1Ile8]Ang II. 6. GTPSgammaS had no discernible effect on the binding of either I-125-[Sar1]Ang II or I-125-[Sar1Ile8]Ang II to bovine uterine membranes. 7. The present findings are consistent with an allosteric mechanism of antagonism for [Sar1Ile8]Ang II. The data are also consistent with a mechanism wherein agonist and antagonist ligands occupy different binding modes at the same receptor site and induce long-term conformational changes in the receptor which are idiosyncratic with respect to the nature of the ligand. An emerging relationship between the actions of angiotensin peptides and non-peptide mimetics of angiotensin is presented.