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(Hypertension. 2004;44:490.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Nonpeptide AVE 0991 Is an Angiotensin-(1–7) Receptor Mas Agonist in the Mouse Kidney

Sérgio Veloso Brant Pinheiro; Ana Cristina Simões e Silva; Walkyria Oliveira Sampaio; Renata Dutra de Paula; Elizabeth Pereira Mendes; Elizabete Dias Bontempo; João Bosco Pesquero; Thomas Walther; Natalia Alenina; Michael Bader; Markus Bleich; Robson Augusto Souza Santos

From the Departamento de Fisiologia e Biofísica (S.V.B.P., W.O.S., R.D.D., E.P.M., E.D.B., R.A.S.S.), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Brazil; Departamento de Pediatria (A.C.S.), Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil; Departamento de Biofísica da Universidade Federal de São Paulo, Brazil (J.B.P.); Department of Pharmacology (T.W.), Erasmus Medical Center, Rotterdam, Netherlands; Max-Delbrück Center for Molecular Medicine (N.A., M. Bader), Berlin, Germany; and Physiologisches Institut (M. Bleich), Christan-Albrechts-University of Kiel, Germany.

Correspondence to Robson Augusto Souza dos Santos, MD, PhD, Department of Physiology and Biophysics, Institute of Biological Sciences Federal University of Minas Gerais, Avenida Antônio Carlos, 6627 Pampulha, Belo Horizonte 31270-901 Minas Gerais, Brazil. E-mail marrob{at}dedalus.lcc.ufmg.br

It has been described recently that the nonpeptide AVE 0991 (AVE) mimics the effects of angiotensin-(1–7) [Ang-(1–7)] in bovine endothelial cells. In this study, we tested the possibility that AVE is an agonist of the Ang-(1–7) receptor Mas, in vitro and in vivo. In water-loaded C57BL/6 mice, AVE (0.58 nmol/g body weight) produced a significant reduction in urinary volume (0.06±0.03 mL/60 min [n=9] versus 0.27±0.05 [n=9]; P<0.01), associated with an increase in urinary osmolality. The Ang-(1–7) antagonist A-779 completely blocked the antidiuretic effect of AVE. As observed previously for Ang-(1–7), the antidiuretic effect of AVE after water load was blunted in Mas-knockout mice (0.37±0.10 mL/60 min [n=9] versus 0.27±0.03 mL/60 min [n=11] AVE-treated mice). In vitro receptor autoradiography in C57BL/6 mice showed that the specific binding of ¹²⁵I-Ang-(1–7) to mouse kidney slices was displaced by AVE, whereas no effects were observed in the binding of ¹²⁵I-angiotensin II or ¹²⁵I-angiotensin IV. Furthermore, AVE displaced the binding of ¹²⁵I-Ang-(1–7) in Mas-transfected monkey kidney cells (COS) cells (IC₅₀=4.75x10^–8 mol/L) and of rhodamine–Ang-(1–7) in Mas-transfected Chinese hamster ovary (CHO) cells. It also produced NO release in Mas-transfected CHO cells blocked by A-779 but not by angiotensin II type-1 (AT₁) and AT₂ antagonists. Contrasting with these data, the antidiuretic effect of AVE was totally blocked by AT₂ antagonists and partially blocked (60%) by AT₁ antagonists. The binding data, the results obtained in Mas-knockout mice and in Mas-transfected cells, show that AVE is a Mas receptor agonist. Our data also suggest the involvement of AT₂/AT₁-related mechanisms, including functional antagonism, oligomerization or cross-talk, in the renal responses to AVE.

Key Words: receptors, angiotensin • angiotensin • angiotensin II

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