Metabolism Alters the Selectivity of Angiotensin-(1-7) Receptor Ligands for Angiotensin Receptors

Abstract

Abstract. The present study examined whether metabolism of the putative angiotensin-(1-7) receptor agonist and antagonist [angiotensin-(1-7) and D-alanine7angiotensin-(1-7), respectively] altered their ability to interact with angiotensin AT1, AT2, and AT4receptor subtypes. Both angiotensin-(1-7) and D-alanine7angiotensin-(1-7) competed with low affinity for125I-sarcosine1, isoleucine8angiotensin II binding to AT1and AT2receptors in rat liver and adrenal medulla membranes, respectively, and competed with low affinity for125I-angiotensin IV binding to AT4receptors in bovine kidney epithelial cell membranes.In vitrorenal metabolism of the angiotensin-(1-7) receptor ligands (incubating peptides with rat cortical tissue homogenates) had minimal influence on low-affinity binding to AT1and AT2receptors, yet caused a significant and dramatic shift toward high-affinity binding for AT4receptors. Low-affinity angiotensin II binding to the AT4receptor was also shifted toward high-affinity binding following renal metabolism of the peptide. Conversely, angiotensins with high affinity for the AT4receptor (e.g., angiotensin IV) were shifted toward low-affinity binding states following peptide metabolism. Incubation of125I-angiotensin-(1-7) with rat cortical tissue generated the high-affinity AT4receptor ligand125I-angiotensin-(3-7), whereas the renal metabolism of125I-angiotensin II generated both125I-angiotensin-(3-7) and125I-angiotensin IV. These results reveal that renal metabolism of angiotensin-(1-7) receptor ligands and angiotensin II yields products that have high affinity for the AT4receptor and could potentially contribute to the biologic actions of the parent peptide in the kidney.