TRV027 is a biased agonist for the Angiotensin (Ang)-II type 1 receptor (AT1R), able to recruit β-arrestin 2 independently of G-proteins activation. β-arrestin activation in the central nervous system (CNS) was suggested to oppose the effects of Ang-II. The present study evaluates the effect of central infusion of TRV027 on arterial pressure (AP), autonomic function, baroreflex sensitivity (BRS), and peripheral vascular reactivity. Spontaneously hypertensive (SH) and Wistar Kyoto (WKY) rats were treated with TRV027 for 14 days (20 ng/h) delivered to the lateral ventricle via osmotic minipumps. Mechanistic studies were performed in HEK293T cells co-transfected with AT1R and Ang converting enzyme type 2 (ACE2) treated with TRV027 (100 nM) or Ang-II (100 nM). TRV027 infusion in SH rats (SHR) reduced AP (~20 mmHg, P<0.05), sympathetic vasomotor activity (ΔMAP = −47.2 ± 2.8 compared with −64 ± 5.1 mmHg, P<0.05) and low-frequency (LF) oscillations of AP (1.7 ± 0.2 compared with 5.8 ± 0.4 mmHg, P<0.05) compared with the SHR control group. TRV027 also increased vagal tone, improved BRS, reduced the reactivity of mesenteric arteries to Ang-II and increased vascular sensitivity to phenylephrine (Phe), acetylcholine, (ACh), and sodium nitroprusside (SNP). In vitro, TRV027 prevented the Ang-II-induced up-regulation of ADAM17 and in contrast with Ang-II, had no effects on ACE2 activity and expression levels. Furthermore, TRV027 induced lesser interactions between AT1R and ACE2 compared with Ang-II. Together, these data suggest that due to its biased activity for the β-arrestin pathway, TRV027 has beneficial effects within the CNS on hypertension, autonomic and vascular function, possibly through preserving ACE2 compensatory activity in neurones.
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The 3D structure of recombinant human deoxyribonuclease I. The N-terminal leucine shown in yellow at the top of the structure was selected for PEGylation of the protein. The amino acids shown in yellow towards the bottom of the protein are those interacting with globular actin, a potent inhibitor of human deoxyribonuclease I; for details, see pages 1439–1452.
Research Article|
July 23 2018
Central administration of TRV027 improves baroreflex sensitivity and vascular reactivity in spontaneously hypertensive rats
Alynne Carvalho-Galvão;
Alynne Carvalho-Galvão
1Centro de Biotecnologia, Universidade Federal da Paraíba, João Pessoa, Brazil
2Department of Pharmacology and Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State, University Health Sciences Center, New Orleans, LA, U.S.A.
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Blessing Ogunlade;
Blessing Ogunlade
3Department of Pharmacology, College of Medicine, Howard University, Washington, DC, U.S.A.
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Jiaxi Xu;
Jiaxi Xu
2Department of Pharmacology and Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State, University Health Sciences Center, New Orleans, LA, U.S.A.
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Cristiane R.A. Silva-Alves;
Cristiane R.A. Silva-Alves
1Centro de Biotecnologia, Universidade Federal da Paraíba, João Pessoa, Brazil
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Leônidas G. Mendes-Júnior;
Leônidas G. Mendes-Júnior
1Centro de Biotecnologia, Universidade Federal da Paraíba, João Pessoa, Brazil
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Drielle D. Guimarães;
Drielle D. Guimarães
1Centro de Biotecnologia, Universidade Federal da Paraíba, João Pessoa, Brazil
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Josiane C. Cruz;
Josiane C. Cruz
1Centro de Biotecnologia, Universidade Federal da Paraíba, João Pessoa, Brazil
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Thyago M. Queiroz;
Thyago M. Queiroz
4Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, Brazil
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Camille M. Balarini;
Camille M. Balarini
1Centro de Biotecnologia, Universidade Federal da Paraíba, João Pessoa, Brazil
5Centro de Ciências da Saúde, Universidade Federal da Paraíba, João Pessoa, Brazil
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Valdir A. Braga;
Valdir A. Braga
1Centro de Biotecnologia, Universidade Federal da Paraíba, João Pessoa, Brazil
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Catalin M. Filipeanu;
Catalin M. Filipeanu
3Department of Pharmacology, College of Medicine, Howard University, Washington, DC, U.S.A.
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Eric Lazartigues;
2Department of Pharmacology and Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State, University Health Sciences Center, New Orleans, LA, U.S.A.
Correspondence: Maria do Socorro de França-Silva ([email protected]) or Eric Lazartigues ([email protected])
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Maria do Socorro de França-Silva
1Centro de Biotecnologia, Universidade Federal da Paraíba, João Pessoa, Brazil
Correspondence: Maria do Socorro de França-Silva ([email protected]) or Eric Lazartigues ([email protected])
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Publisher: Portland Press Ltd
Received:
March 20 2018
Revision Received:
June 08 2018
Accepted:
June 13 2018
Accepted Manuscript online:
June 14 2018
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Clin Sci (Lond) (2018) 132 (14): 1513–1527.
Article history
Received:
March 20 2018
Revision Received:
June 08 2018
Accepted:
June 13 2018
Accepted Manuscript online:
June 14 2018
Citation
Alynne Carvalho-Galvão, Blessing Ogunlade, Jiaxi Xu, Cristiane R.A. Silva-Alves, Leônidas G. Mendes-Júnior, Drielle D. Guimarães, Josiane C. Cruz, Thyago M. Queiroz, Camille M. Balarini, Valdir A. Braga, Catalin M. Filipeanu, Eric Lazartigues, Maria do Socorro de França-Silva; Central administration of TRV027 improves baroreflex sensitivity and vascular reactivity in spontaneously hypertensive rats. Clin Sci (Lond) 31 July 2018; 132 (14): 1513–1527. doi: https://doi.org/10.1042/CS20180222
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