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

Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, College of Veterinary Medicine, Washington State University, Pullman, Washington.

Correspondence to Dr. Rajash K. Handa, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, College of Veterinary Medicine, Washington State University, Pullman WA 99164-6520. Phone: 509-335-6624; Fax: 509-335-4650; E-mail: Handa{at}vetmed.wsu.edu

Abstract. The present study examined whether metabolism of the putative angiotensin-(1-7) receptor agonist and antagonist [angiotensin-(1-7) and D-alanine⁷ angiotensin-(1-7), respectively] altered their ability to interact with angiotensin AT₁, AT₂, and AT₄ receptor subtypes. Both angiotensin-(1-7) and D-alanine⁷ angiotensin-(1-7) competed with low affinity for ¹²⁵I-sarcosine¹, isoleucine⁸ angiotensin II binding to AT₁ and AT₂ receptors in rat liver and adrenal medulla membranes, respectively, and competed with low affinity for ¹²⁵I-angiotensin IV binding to AT₄ 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 AT₁ and AT₂ receptors, yet caused a significant and dramatic shift toward high-affinity binding for AT₄ receptors. Low-affinity angiotensin II binding to the AT₄ receptor was also shifted toward high-affinity binding following renal metabolism of the peptide. Conversely, angiotensins with high affinity for the AT₄ receptor (e.g., angiotensin IV) were shifted toward low-affinity binding states following peptide metabolism. Incubation of ¹²⁵I-angiotensin-(1-7) with rat cortical tissue generated the high-affinity AT₄ receptor ligand ¹²⁵I-angiotensin-(3-7), whereas the renal metabolism of ¹²⁵I-angiotensin II generated both ¹²⁵I-angiotensin-(3-7) and ¹²⁵I-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 AT₄ receptor and could potentially contribute to the biologic actions of the parent peptide in the kidney.

This article has been cited by other articles:

				R. K. Handa, S. E. Handa, and M. K. S. Elgemark Autoradiographic analysis and regulation of angiotensin receptor subtypes AT4, AT1, and AT(1---7) in the kidney Am J Physiol Renal Physiol, November 1, 2001; 281(5): F936 - F947. [Abstract] [Full Text] [PDF]

				R. K. HANDA Characterization and Signaling of the AT4 Receptor in Human Proximal Tubule Epithelial (HK-2) Cells J. Am. Soc. Nephrol., March 1, 2001; 12(3): 440 - 449. [Abstract] [Full Text]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673