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Title: Functional assessment of angiotensin II and bradykinin analogues containing the paramagnetic amino acid TOAC
Authors: Santos, Edson L. [UNIFESP]
Souza, Kely de Picoli [UNIFESP]
Sabatini, Regiane A. [UNIFESP]
Martin, Renan P. [UNIFESP]
Fernandes, Litiam [UNIFESP]
Nardi, Daniela T. [UNIFESP]
Malavolta, Luciana [UNIFESP]
Shimuta, Suma I. [UNIFESP]
Nakaie, Clovis R. [UNIFESP]
Pesquero, Joao B. [UNIFESP]
Universidade Federal de São Paulo (UNIFESP)
Keywords: TOAC
angiotensin II
G-protein coupled receptors
Issue Date: 1-Feb-2008
Publisher: Elsevier B.V.
Citation: International Immunopharmacology. Amsterdam: Elsevier B.V., v. 8, n. 2, p. 293-299, 2008.
Abstract: This study characterized pharmacologically the functional responses to agonists angiotensin II (AngII) and bradykinin (BK) derivatives containing the TOAC (2,2,6,6-tetramethylpiperidine-Noxyl-4-amino-4-carboxylic acid) spin [abet at the N-terminal (TOAC(1)-AngII and TOAC(0)-BK) and internal (TOAC(3)-AngII and TOAC(3)-BK) positions of these vasoactive peptides. Affinity constants of the ligands for AT(1) and B-2 receptors were evaluated in vitro by binding assays and biological effects by extracellular acidification rates and in vivo by blood pressure responses. in contrast to internally labeled analogues (TOAC(3)-AngII or TOAC(3)-BK), the TOAC(1)-AngII and TOAC(0)-BK derivatives dose-dependently increased the extracellular acidification rate in adherent cultured Chinese hamster ovary (CHO) cells expressing AT, or B2 receptors, respectively. in addition, TOAC(1)-AngII induced an increase in blood pressure when injected intravenously in awaken rats although with a potency four times smaller when compared to native AngII. Similarly to BK, TOAC(0)-BK dose-dependently decreased blood pressure when injected intra-arterially in rats with a lower potency when compared to the native peptide. On the contrary, TOAC(3)-AngII or TOAC(3)-BK did not provoke any alteration in blood pressure levels. in summary, our results confirmed that the insertion of TOAC-probe in the N-terminal region of peptides does not significantly modify the affinity or biological activity in vitro and in vivo conditions and could be an important toool to evaluate peptide-receptor interaction mechanism. Conversely, possibly due to the unique bend-inducing property of the cyclic TOAC probe, its insertion at position 3 in both AngII and BK structures seems to restrict the interaction and the activation of the AT, and B2 receptors. (c) 2007 Elsevier B.V. All rights reserved.
ISSN: 1567-5769
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