This Article Full Text Full Text (PDF) All Versions of this Article: 41/3/737    most recent 01.HYP.0000052947.60363.24v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Santos, R. A.S. Articles by Khosla, M. C. Search for Related Content PubMed PubMed Citation Articles by Santos, R. A.S. Articles by Khosla, M. C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Cardiovascular Pharmacology ACE/Angiotension receptors Cell signalling/signal transduction Other hypertension Hypertension - basic studies Other Treatment Autonomic, reflex, and neurohumoral control of circulation Endothelium/vascular type/nitric oxide Other Vascular biology

(Hypertension. 2003;41:737.)
© 2003 American Heart Association, Inc.

Scientific Contributions

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; 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.

Correspondence to Robson A.S. Santos, MD, PhD, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil. E-mail marrob{at}dedalus.Lcc.ufmg.br

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

This article has been cited by other articles:

				L. D. Kluskens, S. A. Nelemans, R. Rink, L. de Vries, A. Meter-Arkema, Y. Wang, T. Walther, A. Kuipers, G. N. Moll, and M. Haas Angiotensin-(1-7) with Thioether Bridge: An Angiotensin-Converting Enzyme-Resistant, Potent Angiotensin-(1-7) Analog J. Pharmacol. Exp. Ther., March 1, 2009; 328(3): 849 - 854. [Abstract] [Full Text] [PDF]

				L. S. A. Capettini, S. F. Cortes, M. A. Gomes, G. A. B. Silva, J. L. Pesquero, M. J. Lopes, M. M. Teixeira, and V. S. Lemos Neuronal nitric oxide synthase-derived hydrogen peroxide is a major endothelium-dependent relaxing factor Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2503 - H2511. [Abstract] [Full Text] [PDF]

				R. Gonzalez-Villalobos, R. B. Klassen, P. L. Allen, K. Johanson, C. B. Baker, H. Kobori, L. G. Navar, and T. G. Hammond Megalin binds and internalizes angiotensin-(1-7) Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1270 - F1275. [Abstract] [Full Text] [PDF]

				C. H. de Castro, R. A. Souza dos Santos, A. J. Ferreira, M. Bader, N. Alenina, and A. Pinto de Almeida Evidence for a Functional Interaction of the Angiotensin-(1-7) Receptor Mas With AT1 and AT2 Receptors in the Mouse Heart Hypertension, October 1, 2005; 46(4): 937 - 942. [Abstract] [Full Text] [PDF]

				B. Gurzu, M. Costuleanu, S. M. Slatineanu, A. Ciobanu, and G. Petrescu Are Multiple Angiotensin Receptor Types Involved in Angiotensin (1-7) Actions on Isolated Rat Portal Vein? Journal of Renin-Angiotensin-Aldosterone System, June 1, 2005; 6(2): 90 - 95. [Abstract] [PDF]