title: Characterization of a new selective antagonist for angiotensin-(1-7), D-pro7-angiotensin-(1-7).
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 microg/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.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Minas Gerais, Brazil. marrob@dedalus.Lcc.ufmg.br
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
authors.forename: Andréa S
authors.initials: AS
authors.lastname: Haibara
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Campagnole-Santos
authors.forename: Ana C
authors.initials: AC
authors.lastname: Simões e Silva
authors.forename: Renata D
authors.initials: RD
authors.lastname: Paula
authors.forename: Sérgio V B
authors.initials: SV
authors.lastname: Pinheiro
authors.forename: Maria Fátima
authors.initials: MF
authors.lastname: Leite
authors.forename: Virginia S
authors.initials: VS
authors.lastname: Lemos
authors.forename: Denise M R
authors.initials: DM
authors.lastname: Silva
authors.forename: Mateus T
authors.initials: MT
authors.lastname: Guerra
authors.forename: Mahesh C
authors.initials: MC
authors.lastname: Khosla
mesh_terms: D000803:Angiotensin I / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D046508:Culture Techniques; D008297:Male; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012076:Renal Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: C472420:D-Pro7-Ang-(1-7); D010446:Peptide Fragments; D012076:Renal Agents; D000804:Angiotensin II; D000803:Angiotensin I; C118790:angiotensin I (1-7)