Nonpeptide AVE 0991 Is an Angiotensin-(1–7) Receptor Mas Agonist in the Mouse Kidney
- 1 October 2004
- journal article
- research article
- Published by Wolters Kluwer Health in Hypertension
- Vol. 44 (4) , 490-496
- https://doi.org/10.1161/01.hyp.0000141438.64887.42
Abstract
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 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 125 I-Ang-(1–7) to mouse kidney slices was displaced by AVE, whereas no effects were observed in the binding of 125 I-angiotensin II or 125 I-angiotensin IV. Furthermore, AVE displaced the binding of 125 I-Ang-(1–7) in Mas -transfected monkey kidney cells (COS) cells (IC 50 =4.75×10 −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 (AT 1 ) and AT 2 antagonists. Contrasting with these data, the antidiuretic effect of AVE was totally blocked by AT 2 antagonists and partially blocked (≈60%) by AT 1 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 AT 2 /AT 1 -related mechanisms, including functional antagonism, oligomerization or cross-talk, in the renal responses to AVE.Keywords
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