A new strategy for treating hypertension by blocking the activity of the brain renin–angiotensin system with aminopeptidase A inhibitors

2014 ◽  
Vol 127 (3) ◽  
pp. 135-148 ◽  
Author(s):  
Ji Gao ◽  
Yannick Marc ◽  
Xavier Iturrioz ◽  
Vincent Leroux ◽  
Fabrice Balavoine ◽  
...  
Keyword(s):  
Antihypertensive Agents ◽  
Renin Angiotensin System ◽  
Site Directed Mutagenesis ◽  
Hypertensive Rats ◽  
Vasopressin Release ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Obesity And Diabetes ◽  
Aminopeptidase A ◽  
The Brain

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.

P4554Central-acting aminopeptidase a inhibitors for new treatment of hypertension: from discovery to clinical trial

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C Llorens-Cortes ◽  
Y Marc ◽  
R Hmazzou ◽  
M Keck ◽  
A Flahault ◽  
...  
Keyword(s):  
Sulfonic Acid ◽  
Extracellular Volume ◽  
Antihypertensive Agents ◽  
Renin Angiotensin System ◽  
Drug Candidate ◽  
Hypertensive Rats ◽  
Vasopressin Release ◽  
Spontaneously Hypertensive ◽  
Aminopeptidase A ◽  
The Brain

Abstract The hyperactivity of the brain renin–angiotensin system (RAS) has been implicated in the development and maintenance of arterial hypertension (HTA). Our aim was to demonstrate that normalizing brain RAS hyperactivity could constitute a new therapeutic approach for HTA treatment We first demonstrated in the brain that aminopeptidase A (APA) is the enzyme generating angiotensin III (AngIII) from AngII. Then, using the specific and selective APA inhibitor, EC33 ((3S)-3-amino-4-sulfanyl-butane-1-sulfonic acid), we showed that AngIII is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over blood pressure (BP) in hypertensive rats. This suggests that brain APA may be a potential therapeutic target for HTA treatment. We then designed RB150 {4,4-dithio[bis(3-aminobutyl sulfonic acid)]}, an orally active prodrug of EC33. RB150, given orally in conscious deoxycorticosterone acetate-salt (DOCA-salt) rats or spontaneously hypertensive rats, crosses the intestinal, hepatic and blood-brain barriers, enters the brain, where it is cleaved by brain reductases, generating two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and induce a marked and sustained decrease in BP. The RB150-induced BP decrease is due to a reduced vasopressin release, which increases diuresis, reducing extracellular volume, a decrease in sympathetic tone, leading to a reduction of vascular resistances and the improvement of the baroreflex function (Figure below). RB150 was renamed firibastat by OMS. Phase Ia/Ib clinical trials showed that firibastat is clinically and biologically well-tolerated in healthy volunteers. Firibastat could constitute the first drug candidate of a new class of antihypertensive agents targeting the brain RAS, the clinical efficacy of which (Phase IIa and Phase IIb) in hypertensive patients was achieved. Acknowledgement/Funding INSERM, College de France, ANR LabCom, Quantum Genomics

scholarly journals The Prorenin and (Pro)renin Receptor: New Players in the Brain Renin-Angiotensin System?

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Wencheng Li ◽  
Hua Peng ◽  
Dale M. Seth ◽  
Yumei Feng
Keyword(s):  
Renin Angiotensin System ◽  
Ang Ii ◽  
Future Perspectives ◽  
Vasopressin Release ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Treatment Of Hypertension ◽  
High Level ◽  
The Brain

It is well known that the brain renin-angiotensin (RAS) system plays an essential role in the development of hypertension, mainly through the modulation of autonomic activities and vasopressin release. However, how the brain synthesizes angiotensin (Ang) II has been a debate for decades, largely due to the low renin activity. This paper first describes the expression of the vasoconstrictive arm of RAS components in the brain as well as their physiological and pathophysiological significance. It then focus on the (pro)renin receptor (PRR), a newly discovered component of the RAS which has a high level in the brain. We review the role of prorenin and PRR in peripheral organs and emphasize the involvement of brain PRR in the pathogenesis of hypertension. Some future perspectives in PRR research are heighted with respect to novel therapeutic target for the treatment of hypertension and other cardiovascular diseases.

scholarly journals Regulation of brain renin-angiotensin system by benzamil-blockable sodium channels

1999 ◽  
Vol 276 (5) ◽  
pp. R1416-R1424 ◽  
Author(s):  
Masato Nishimura ◽  
Ken Ohtsuka ◽  
Naoharu Iwai ◽  
Hakuo Takahashi ◽  
Manabu Yoshimura
Keyword(s):  
Sodium Channels ◽  
Renin Angiotensin System ◽  
Hypertensive Rats ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Intracerebroventricular Infusion ◽  
Pcr Method ◽  
The Brain ◽  
Renal Hypertensive Rats

Changes in the renin-angiotensin system (RAS) mRNAs in the brain and the kidney of rats after administration of DOCA and/or sodium chloride were assessed by use of a competitive PCR method. Benzamil, a blocker of amiloride-sensitive sodium channels, was infused intracerebroventricularly or intravenously for 7 days in DOCA-salt or renal hypertensive rats, and the effects of benzamil on the brain RAS mRNAs were determined. Renin and ANG I-converting enzyme (ACE) mRNAs were not downregulated in the brain of rats administered DOCA and/or salt; however, these mRNAs were decreased in the kidney. Intracerebroventricular infusion of benzamil decreased renin, ACE, and ANG II type 1 receptor mRNAs in the brain of DOCA-salt hypertensive rats but not in the brain of renal hypertensive rats. The gene expression of the brain RAS, particularly renin and ACE, is regulated differently between the brain and the kidney in DOCA-salt hypertensive rats, and benzamil-blockable brain sodium channels may participate in the regulation of the brain RAS mRNAs.

scholarly journals EXPRESSION OF COMPONENTS OF THE RENIN‐ANGIOTENSIN SYSTEM IN THE BRAIN OF 2K1C HYPERTENSIVE RATS AFTER EXERCISE TRAINING

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
Luiza Michelle Cangussu ◽  
Robson AS Santos ◽  
Almir Martins ◽  
Andreia Carvalho Alzamora ◽  
Maria Jose Campagnole‐Santos
Keyword(s):  
Exercise Training ◽  
Renin Angiotensin System ◽  
Hypertensive Rats ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain

Role of the Brain Iso-Renin-Angiotensin System in Experimental Hypertension in Rats

1981 ◽  
Vol 61 (2) ◽  
pp. 175-180 ◽  
Author(s):  
Hiromichi Suzuki ◽  
Kazuoki Kondo ◽  
Michiko Handa ◽  
Takao Saruta
Keyword(s):  
Blood Pressure ◽  
Plasma Renin Activity ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Renin Activity ◽  
Cerebral Ventricles ◽  
Hypertensive Rats ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain

1. To examine the possible participation of the brain iso-renin-angiotensin system in the control of blood pressure, as well as in the regulation of plasma renin activity, saralasin and captopril were injected into the cerebral ventricles of three types of experimental hypertensive rats with different plasma renin profiles. 2. Injection of saralasin and captopril into the cerebral ventricles resulted in a significant decrease in blood pressure of two-kidney, one-clip Goldblatt hypertensive rats (11 ± 2 and 9 ± 3 mmHg respectively) and that of spontaneously hypertensive rats (13 ± 2 and 12 ± 2 mmHg respectively), but in deoxycorticosterone (DOC)-salt hypertensive rats injection of these two agents showed a significant increase in blood pressure (13 ± 2 and 12 ± 3 mmHg respectively). 3. The plasma renin activity was markedly decreased after injection of saralasin and captopril into the cerebral ventricles of two-kidney, one-clip Goldblatt hypertensive rats. Conversely, in DOC-salt hypertensive rats, the plasma renin activity was markedly increased after injection of these two agents. In spontaneously hypertensive rats these agents caused no significant change in plasma renin activity. 4. These findings suggest that the brain iso-renin-angiotensin system participates in the central regulation of blood pressure and may be responsible for modulation of the peripheral renin-angiotensin system.

scholarly journals Brain ACE2 activation following brain aminopeptidase A blockade by firibastat in salt-dependent hypertension

2021 ◽  
Vol 135 (6) ◽  
pp. 775-791
Author(s):  
Reda Hmazzou ◽  
Yannick Marc ◽  
Adrien Flahault ◽  
Romain Gerbier ◽  
Nadia De Mota ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Vasopressin Release ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Zinc Metalloprotease ◽  
Angiotensin Iii ◽  
Membrane Bound ◽  
Aminopeptidase A ◽  
The Brain

Abstract In the brain, aminopeptidase A (APA), a membrane-bound zinc metalloprotease, generates angiotensin III from angiotensin II. Brain angiotensin III exerts a tonic stimulatory effect on the control of blood pressure (BP) in hypertensive rats and increases vasopressin release. Blocking brain angiotensin III formation by the APA inhibitor prodrug RB150/firibastat normalizes arterial BP in hypertensive deoxycorticosterone acetate (DOCA)-salt rats without inducing angiotensin II accumulation. We therefore hypothesized that another metabolic pathway of brain angiotensin II, such as the conversion of angiotensin II into angiotensin 1-7 (Ang 1-7) by angiotensin-converting enzyme 2 (ACE2) might be activated following brain APA inhibition. We found that the intracerebroventricular (icv) administration of RB150/firibastat in conscious DOCA-salt rats both inhibited brain APA activity and induced an increase in brain ACE2 activity. Then, we showed that the decreases in BP and vasopressin release resulting from brain APA inhibition with RB150/firibastat were reduced if ACE2 was concomitantly inhibited by MLN4760, a potent ACE2 inhibitor, or if the Mas receptor (MasR) was blocked by A779, a MasR antagonist. Our findings suggest that in the brain, the increase in ACE2 activity resulting from APA inhibition by RB150/firibastat treatment, subsequently increasing Ang 1-7 and activating the MasR while blocking angiotensin III formation, contributes to the antihypertensive effect and the decrease in vasopressin release induced by RB150/firibastat. RB150/firibastat treatment constitutes an interesting therapeutic approach to improve BP control in hypertensive patients by inducing in the brain renin–angiotensin system, hyperactivity of the beneficial ACE2/Ang 1-7/MasR axis while decreasing that of the deleterious APA/Ang II/Ang III/ATI receptor axis.

Lack of interaction between a hypertonic NaCl stimulus and the brain renin-angiotensin system

1983 ◽  
Vol 244 (4) ◽  
pp. H471-H478 ◽  
Author(s):  
S. Takishita ◽  
C. M. Ferrario
Keyword(s):  
Renin Angiotensin System ◽  
Ang Ii ◽  
Central Administration ◽  
Nerve Activity ◽  
Renal Nerve ◽  
Vasopressin Release ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Before And After ◽  
The Brain

Sodium and the renin-angiotensin system (RAS) participate in the regulation of cardiovascular function, in part via activation of central nervous system (CNS) mechanisms. Because intraventricular (IVT) administration of either hypertonic sodium chloride (NaCl) or angiotensin II (ANG II) elicits similar effects (i.e., natriuresis, hypertension, increased drinking, and enhanced vasopressin release) a common and final pathway may be involved. With this in mind, we measured the effect of an IVT injection (third or lateral ventricle) of 0.6 M NaCl on postganglionic renal nerve activity (RNA) and blood pressure in morphine-pentobarbital-anesthetized dogs before and after blockade of the brain RAS with either captopril or [Sar1,Ile8]ANG II. Both vagus and carotid sinus nerves were cut to avoid impingement of the baroreceptor reflex on the measured variables. IVT injection of 0.6 M NaCl produced a prominent hypertensive response and tachycardia associated with a 59 +/- 9% increase in RNA. These changes were statistically significant (P less than 0.001), correlated with each other, and were abolished by administration of hexamethonium chloride (10 mg/kg iv). Blockade of central ANG II receptors with [Sar1,Ile8]ANG II was without effect. However, in dogs given IVT SQ 14,225, there was a slight increase in baseline RNA before injection of 0.6 M NaCl; in addition, both the pressor and heart rate responses to the stimulus of hypertonic NaCl were further augmented. These results demonstrate that central administration of hypertonic NaCl in baroreceptor-denervated dogs produces marked activation of sympathetic nerve activity via mechanisms other than activation of the brain RAS.

Significance of the Brain Renin—Angiotensin System in Spontaneously Hypertensive Rats

1982 ◽  
Vol 63 (s8) ◽  
pp. 159s-161s ◽  
Author(s):  
Jeroen A. D. M. Tonnaer ◽  
Joke J. van Put ◽  
Victor M. Wiegant ◽  
Wybren de Jong
Keyword(s):  
Spontaneously Hypertensive Rats ◽  
Spontaneously Hypertensive Rat ◽  
Renin Angiotensin System ◽  
Hypotensive Effect ◽  
Sympathetic Outflow ◽  
Hypertensive Rats ◽  
Angiotensin System ◽  
Spontaneously Hypertensive ◽  
Renin Angiotensin ◽  
The Brain

1. The renin inhibitor N-acetyl-pepstatin was infused for 14 days or 5 days into the cerebral ventricular system of young and adult spontaneously hypertensive rats respectively. 2. The blood pressure and heart rate of the young animals was significantly lower as a result of this treatment, whereas the pressure of the adult animals tended to decrease. 3. The mechanism involved in the hypotensive effect of N-acetyl-pepstatin appeared to be independent of the peripheral renin-angiotensin system. The possible involvement of a decreased sympathetic outflow is suggested. 4. The present data indicate that the brain renin-angiotensin system contributes to the development of hypertension in the spontaneously hypertensive rat.

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