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-[Sa r1]Ang II and the antagonist I-125-[Sar1Ile8]Ang II bind to bovine ute rus smooth muscle membranes in a time-dependent, reversible and satura ble 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 no n-competitive manner by decreasing the number of high affinity sites w ithout changing the binding affinity of the radioligand. 3. [Sar']Ang II also inhibited the binding of I-125-[Sar1Ile8]Ang II in a non-compe titive manner. 4. Dissociation of both radioligands from their recepto r sites was fast enough that pseudo irreversible occupancy of the bind ing sites could not account for the observed non-competitive inhibitio n. 5. Displacement studies using I-125-[Sar1Ile8]Ang II as the radioli gand 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 bovi ne uterine membranes. 7. The present findings are consistent with an a llosteric mechanism of antagonism for [Sar1Ile8]Ang II. The data are a lso consistent with a mechanism wherein agonist and antagonist ligands occupy different binding modes at the same receptor site and induce l ong-term conformational changes in the receptor which are idiosyncrati c with respect to the nature of the ligand. An emerging relationship b etween the actions of angiotensin peptides and non-peptide mimetics of angiotensin is presented.