Hypertension affects one-third of the adult population and is a growing problem due to the increasing incidence of obesity and diabetes. Brain RAS (renin–angiotensin system) hyperactivity has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. We have identified in the brain RAS that APA (aminopeptidase A) and APN (aminopeptidase N), two membrane-bound zinc metalloproteases, are involved in the metabolism of AngII (angiotensin II) and AngIII (angiotensin III) respectively. The present review summarizes the main findings suggesting that AngIII plays a predominant role in the brain RAS in the control of BP (blood pressure). We first explored the organization of the APA active site by site-directed mutagenesis and molecular modelling. The development and the use in vivo of specific and selective APA and APN inhibitors EC33 and PC18 respectively, has allowed the demonstration that brain AngIII generated by APA is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over BP in conscious hypertensive rats. This identified brain APA as a potential therapeutic target for the treatment of hypertension, which has led to the development of potent orally active APA inhibitors, such as RB150. RB150 administered orally in hypertensive DOCA (deoxycorticosteroneacetate)-salt rats or SHRs (spontaneously hypertensive rats) crosses the intestinal, hepatic and blood–brain barriers, enters the brain, generates two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and normalize BP for several hours. The decrease in BP involves two different mechanisms: a decrease in vasopressin release into the bloodstream, which in turn increases diuresis resulting in a blood volume reduction that participates in the decrease in BP and/or a decrease in sympathetic tone, decreasing vascular resistance. RB150 constitutes the prototype of a new class of centrally acting antihypertensive agents and is currently being evaluated in a Phase Ib clinical trial.
Skip Nav Destination
Article navigation
Review Article|
April 03 2014
A new strategy for treating hypertension by blocking the activity of the brain renin–angiotensin system with aminopeptidase A inhibitors
Ji Gao;
Ji Gao
*Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, CIRB, Collège de France, INSERM U1050, Paris, F-75231, France
Search for other works by this author on:
Yannick Marc;
Yannick Marc
*Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, CIRB, Collège de France, INSERM U1050, Paris, F-75231, France
†Quantum Genomics, Massy, F-91300, France
Search for other works by this author on:
Xavier Iturrioz;
Xavier Iturrioz
*Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, CIRB, Collège de France, INSERM U1050, Paris, F-75231, France
Search for other works by this author on:
Vincent Leroux;
Vincent Leroux
*Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, CIRB, Collège de France, INSERM U1050, Paris, F-75231, France
Search for other works by this author on:
Fabrice Balavoine;
Fabrice Balavoine
†Quantum Genomics, Massy, F-91300, France
Search for other works by this author on:
Catherine Llorens-Cortes
*Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, CIRB, Collège de France, INSERM U1050, Paris, F-75231, France
Correspondence: Dr Catherine Llorens-Cortes (email [email protected]).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
July 24 2013
Revision Received:
February 25 2014
Accepted:
February 27 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 127 (3): 135–148.
Article history
Received:
July 24 2013
Revision Received:
February 25 2014
Accepted:
February 27 2014
Citation
Ji Gao, Yannick Marc, Xavier Iturrioz, Vincent Leroux, Fabrice Balavoine, Catherine Llorens-Cortes; A new strategy for treating hypertension by blocking the activity of the brain renin–angiotensin system with aminopeptidase A inhibitors. Clin Sci (Lond) 1 August 2014; 127 (3): 135–148. doi: https://doi.org/10.1042/CS20130396
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() |