Published Online
on January 20, 2003

A more recent version of this article appeared on March 1, 2003

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Submitted on September 19, 2002
Revised on November 13, 2002

Characterization of a New Selective Antagonist for Angiotensin-(1-7), D-Pro⁷-Angiotensin-(1-7)

Robson A.S. Santos^*; Andréa S. Haibara; Maria José Campagnole-Santos; Ana C. Simões e Silva; Renata D. Paula; Sérgio V.B. Pinheiro; Maria de Fátima Leite; Virginia S. Lemos; Denise M.R. Silva; Mateus T. Guerra; and Mahesh C. Khosla

From the Department of Physiology and Biophysics, Institute of Biological Sciences (R.A.S.S., A.S.H., M.J.C.-S., R.D.P., S.V.B.P., M.d.F.L., V.S.L., D.M.R.S., M.T.G.), and the Department of Pediatrics, School of Medicine (A.C.S.e.S.), Federal University of Minas Gerais, Minas Gerais, Brazil, and the Cleveland Clinic Foundation (M.C.K.), Cleveland, Ohio.

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

Abstract--Angiotensin-(1-7) [Ang-(1-7)] has biological actions that can often be distinguished from those of angiotensin II (Ang II). Recent studies indicate that the effects of Ang-(1-7) are mediated by specific receptor(s). We now report the partial characterization of a new antagonist selective for Ang-(1-7), D-Pro⁷-Ang-(1-7). D-Pro⁷-Ang-(1-7) (50 pmol) inhibited the hypertensive effect induced by microinjection of Ang-(1-7) [4±1 vs 21±2 mm Hg, 25 pmol Ang-(1-7) alone] into the rostral ventrolateral medulla without changing the effect of Ang II (16±2.5 vs 19±2.5 mm Hg after 25 pmol Ang II alone). At 10^-7 mol/L concentration, it completely blocked the endothelium-dependent vasorelaxation produced by Ang-(1-7) (10^-10 to 10^-6 mol/L) in the mouse aorta. The antidiuresis produced by Ang-(1-7) (40 pmol/100 g body weight) in water-loaded rats was also blocked by its analog [1 µg/100 g body weight; 3.08±0.8 vs 1.27±0.33 mL in Ang-(1-7)-treated rats]. D-Pro⁷-Ang-(1-7) at a molar ratio of 40:1 did not change the hypotensive effect of bradykinin. Moreover, D-Pro⁷-Ang-(1-7) did not affect the dipsogenic effect produced by intracerebroventricular administration of Ang II (11.4±1.15 vs 8.8±1.2 mL/h after Ang II) and did not show any demonstrable angiotensin-converting enzyme inhibitory activity in assays with the synthetic substrate Hip-His-Leu and rat plasma as a source of enzyme. Autoradiography studies with ¹²⁵I-Ang-(1-7) in mouse kidney slices showed that D-Pro⁷-Ang-(1-7) competed for the binding of Ang-(1-7) to the cortical supramedullary region. In Chinese hamster ovary cells stably transfected with the AT₁ receptor subtype, D-Pro⁷-Ang-(1-7) did not compete for the specific binding of ¹²⁵I-Ang-II in concentrations up to 10^-6 mol/L. There was also no significant displacement of Ang II binding to angiotensin type 2 receptors in membrane preparations of adrenal medulla. These data indicate that D-Pro⁷-Ang-(1-7) is a selective antagonist for Ang-(1-7), which can be useful to clarify the functional role of this heptapeptide.

Key words: angiotensin antagonists • angiotensin II • angiotensin-(1-7) • D-Pro⁷-Ang-(1-7) • diuresis

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