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Published Online
on July 30, 2007

Hypertension. 2007
Published online before print July 30, 2007, doi: 10.1161/HYPERTENSIONAHA.107.094987
A more recent version of this article appeared on October 1, 2007
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Submitted on May 24, 2007
Revised on June 11, 2007

Evidence for Mas-Mediated Bradykinin Potentiation by the Angiotensin-(1-7) Nonpeptide Mimic AVE 0991 in Normotensive Rats

Mariana B.L. Carvalho; Fernanda V. Duarte; Raphael Faria-Silva; Beatrix Fauler; Leonor T. da Mata Machado; Renata D. de Paula; Maria J. Campagnole-Santos; and Robson A.S. Santos*

From the Laboratory of Hypertension, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.

* To whom correspondence should be addressed. E-mail: marrob{at}dedalus.lcc.ufmg.br.

Abstract—We evaluated the effect of the nonpeptide mimic of angiotensin (Ang)-(1-7), AVE 0991, on the hypotensive effect of bradykinin (BK). Increasing doses of intra-arterial or intravenous BK were administered before and 30 minutes after the beginning of AVE 0991 infusion. The effect of AVE 0991 on plasma Ang-converting enzyme activity was tested using Hip-His-Leu as the substrate. The interaction of AVE 0991 with Ang-converting enzyme in vivo was tested by determining its effect on the pressor action of Ang I or Ang II. AVE 0991 produced a significant and similar potentiation of intra-arterial or intravenous bradykinin. AVE 0991 did not inhibit plasma Ang-converting enzyme activity in vitro or the pressor effect of Ang I in vivo. NW-nitro-L-arginine methyl ester or D-Ala7-Ang-(1-7) administration abolished the BK potentiating effect of AVE 0991. We further examined the BK-potentiating effect of AVE 0991, evaluating its effect on NO production in rabbit endothelial cells. The NO release was measured using the 4-amino-5-methylamino-2'-7'-difluorofluorescein diacetate. A synergistic effect of AVE 0991 and BK on NO release was observed. These results suggest that AVE 0991 potentiates bradykinin through an Ang-converting enzyme–independent, NO-dependent receptor Mas-mediated mechanism. This effect may contribute to the improvement of endothelial function by AVE 0991 in vivo.
Key words: bradykinin • angiotensin (1-7) • AVE 0991 • NO • endothelial function




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