Metabolism alters the selectivity of angiotensin-(1-7) receptor ligands for angiotensin receptors.
The present study examined whether metabolism of the putative angiotensin-(1-7) receptor agonist and antagonist [angiotensin-(1-7) and D-alanine(7) angiotensin-(1-7), respectively] altered their ability to interact with angiotensin AT(1), AT(2), and AT(4) receptor subtypes. Both angiotensin-(1-7) and D-alanine(7) angiotensin-(1-7) competed with low affinity for (125)I-sarcosine(1), isoleucine(8) angiotensin II binding to AT(1) and AT(2) receptors in rat liver and adrenal medulla membranes, respectively, and competed with low affinity for (125)I-angiotensin IV binding to AT(4) receptors in bovine kidney epithelial cell membranes. In vitro renal metabolism of the angiotensin-(1-7) receptor ligands (incubating peptides with rat cortical tissue homogenates) had minimal influence on low-affinity binding to AT(1) and AT(2) receptors, yet caused a significant and dramatic shift toward high-affinity binding for AT(4) receptors. Low-affinity angiotensin II binding to the AT(4) receptor was also shifted toward high-affinity binding following renal metabolism of the peptide. Conversely, angiotensins with high affinity for the AT(4) receptor (e.g., angiotensin IV) were shifted toward low-affinity binding states following peptide metabolism. Incubation of (125)I-angiotensin-(1-7) with rat cortical tissue generated the high-affinity AT(4) receptor ligand (125)I-angiotensin-(3-7), whereas the renal metabolism of (125)I-angiotensin II generated both (125)I-angiotensin-(3-7) and (125)I-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 AT(4) receptor and could potentially contribute to the biologic actions of the parent peptide in the kidney.
Handa
Rajash K
RK
Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, College of Veterinary Medicine, Washington State University, Pullman, Washington.
D000803:Angiotensin I / Q000378:metabolism*; D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002460:Cell Line; D007668:Kidney / Q000378:metabolism*; D008024:Ligands; D010446:Peptide Fragments / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism*
C090830:AT4 receptor; D000809:Angiotensins; D008024:Ligands; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000803:Angiotensin I; C118790:angiotensin I (1-7)