Aminopeptidase A, generating one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, plays a key role in the central control of blood pressure

2000 ◽  
Vol 28 (3) ◽  
pp. A60-A60
Author(s):  
A. REAUX ◽  
X. ITURRIOZ ◽  
M-C. FOURNIE-ZALUSKI ◽  
C. DAVID ◽  
B. P. ROQUES ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renin Angiotensin System ◽  
Central Control ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Angiotensin Iii ◽  
Aminopeptidase A ◽  
The Brain

Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, has a key role in central control of arterial blood pressure

2000 ◽  
Vol 28 (4) ◽  
pp. 435-440 ◽  
Author(s):  
A. Reaux ◽  
X. Iturrioz ◽  
G. Vazeux ◽  
M.-C. Fournie-Zaluski ◽  
C. David ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Renin Angiotensin System ◽  
Central Control ◽  
Angiotensin System ◽  
Arterial Blood ◽  
Angiotensin Iii ◽  
Aminopeptidase A ◽  
The Brain

Overactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental animal models. We have recently reported that, in the murine brain RAS, angiotensin II (AngII) is converted by aminopeptidase A (APA) into angiotensin III (AngIII), which is itself degraded by aminopeptidase N (APN), both peptides being equipotent to increase vasopressin release and arterial blood pressure when injected by the intracerebroventricular (i.c.v.) route. Because AngII is converted in vivo into AngIII, the exact nature of the active peptide is not precisely known. To delineate their respective roles in the central control of cardiovascular functions, specific and selective APA and APN inhibitors are needed to block the metabolic pathways of AngII and AngIII respectively. In the absence of such compounds for APA, we first explored the organization of the APA active site by site-directed mutagenesis. This led us to propose a molecular mechanism of action for APA similar to that proposed for the bacterial enzyme thermolysin deduced from X-ray diffraction studies. Secondly, we developed a specific and selective APA inhibitor, compound EC33 [(S)-3-amino-4-mercaptobutylsulphonic acid], as well as a potent and selective APN inhibitor, PC18 (2-amino-4-methylsulphonylbutane thiol). With these new tools we examined the respective roles of AngII and AngIII in the central control of arterial blood pressure. A central blockade of APA with the APA inhibitor EC33 suppressed the pressor effect of exogenous AngII, suggesting that brain AngII must be converted into AngIII to increase arterial blood pressure. Furthermore, EC33, injected alone i.c.v. but not intravenously, caused a dose-dependent decrease in arterial blood pressure by blocking the formation of brain AngIII but not systemic AngIII. This is corroborated by the fact that the selective APN inhibitor PC 18 administered alone via the i.c.v. route increased arterial blood pressure. This pressor response was blocked by prior treatment with the angiotensin type 1 receptor antagonist losartan, showing that blocking the action of APN on AngIII metabolism leads to an increase in endogenous AngIII levels, resulting in arterial blood pressure increase through an interaction with angiotensin type 1 receptors. These results demonstrate that AngIII is a major effector peptide of the brain RAS, exerting a tonic stimulatory control over arterial blood pressure. Thus APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors, crossing the blood-brain barrier, as central anti-hypertensive agents.

scholarly journals Divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system

2012 ◽  
Vol 302 (3) ◽  
pp. R313-R320 ◽  
Author(s):  
Curt D. Sigmund
Keyword(s):  
Blood Pressure ◽  
Fluid Intake ◽  
Renin Angiotensin System ◽  
Metabolic Effects ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Intracellular Form ◽  
Efferent Pathways ◽  
The Brain ◽  
Pituitary Adrenal Axis

The purpose of this review is two-fold. First, I will highlight recent advances in our understanding of the mechanisms regulating angiotensin II (ANG II) synthesis in the brain, focusing on evidence that renin is expressed in the brain and is expressed in two forms: a secreted form, which may catalyze extracellular ANG I generation from glial or neuronal angiotensinogen (AGT), and an intracellular form, which may generate intracellular ANG in neurons that may act as a neurotransmitter. Second, I will discuss recent studies that advance the concept that the renin-angiotensin system (RAS) in the brain not only is a potent regulator of blood pressure and fluid intake but may also regulate metabolism. The efferent pathways regulating the blood pressure/dipsogenic effects and the metabolic effects of elevated central RAS activity appear different, with the former being dependent upon the hypothalamic-pituitary-adrenal axis, and the latter being dependent upon an interaction between the brain and the systemic (or adipose) RAS.

The renin-angiotensin system in the central control of blood pressure

1987 ◽  
Vol 8 (suppl B) ◽  
pp. 129-132 ◽  
Author(s):  
R. Rettig ◽  
D. Ganten ◽  
R. E. Lang ◽  
TH. Unger
Keyword(s):  
Blood Pressure ◽  
Renin Angiotensin System ◽  
Central Control ◽  
Angiotensin System ◽  
Renin Angiotensin

Role of the Brain Renin-angiotensin System in Blood Pressure Regulation

2007 ◽  
Vol 31 (S1) ◽  
pp. 343-346
Author(s):  
M. V. Varoni ◽  
D. Palomba ◽  
M. P. Demontis ◽  
S. Gianorso ◽  
G. L. Pais ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renin Angiotensin System ◽  
Blood Pressure Regulation ◽  
Pressure Regulation ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain

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.

scholarly journals Increased (pro)renin receptor expression in the subfornical organ of hypertensive humans

2018 ◽  
Vol 314 (4) ◽  
pp. H796-H804 ◽  
Author(s):  
Silvana G. Cooper ◽  
Darshan P. Trivedi ◽  
Rieko Yamamoto ◽  
Caleb J. Worker ◽  
Cheng-Yuan Feng ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Animal Models ◽  
Systolic Blood Pressure ◽  
Renin Angiotensin System ◽  
Subfornical Organ ◽  
Antihypertensive Drug Therapy ◽  
Angiotensin System ◽  
Human Hypertension ◽  
Renin Angiotensin ◽  
The Brain

The central nervous system plays an important role in essential hypertension in humans and in animal models of hypertension through modulation of sympathetic activity and Na+ and body fluid homeostasis. Data from animal models of hypertension suggest that the renin-angiotensin system in the subfornical organ (SFO) of the brain is critical for hypertension development. We recently reported that the brain (pro)renin receptor (PRR) is a novel component of the brain renin-angiotensin system and could be a key initiator of the pathogenesis of hypertension. Here, we examined the expression level and cellular distribution of PRR in the SFO of postmortem human brains to assess its association with the pathogenesis of human hypertension. Postmortem SFO tissues were collected from hypertensive and normotensive human subjects. Immunolabeling for the PRR and a retrospective analysis of clinical data were performed. We found that human PRR was prominently expressed in most neurons and microglia, but not in astrocytes, in the SFO. Importantly, PRR levels in the SFO were elevated in hypertensive subjects. Moreover, PRR immunoreactivity was significantly correlated with systolic blood pressure but not body weight, age, or diastolic blood pressure. Interestingly, this correlation was independent of antihypertensive drug therapy. Our data indicate that PRR in the SFO may be a key molecular player in the pathogenesis of human hypertension and, as such, could be an important focus of efforts to understand the neurogenic origin of hypertension. NEW & NOTEWORTHY This study provides evidence that, in the subfornical organ of the human brain, the (pro)renin receptor is expressed in neurons and microglia cells but not in astrocytes. More importantly, (pro)renin receptor immunoreactivity in the subfornical organ is increased in hypertensive humans and is significantly correlated with systolic blood pressure.

Abstract P061: Selective Deletion of Intracellular Renin in the Brain Causes Hypertension and Elevated Sympathetic Nervous System Activity

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Keisuke Shinohara ◽  
Benjamin J Weidemann ◽  
Matthew D Folchert ◽  
Xuebo Liu ◽  
Donald A Morgan ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Metabolic Rate ◽  
Systolic Blood Pressure ◽  
Neural Circuit ◽  
Resting Metabolic Rate ◽  
Renin Angiotensin System ◽  
Power Spectral Analysis ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain

Renin expression is regulated by two distinct promoter-1st exon combinations that target renin either for secretion (exon 1a for secreted renin) or cytoplasmic retention (exon 1b for intracellular renin, icREN). We developed icREN knockout (KO) mice by selectively deleting exon 1b. icREN KO mice are essentially brain-specific knockouts of icREN because icREN is predominantly expressed in the brain. Notably, systolic blood pressure measured by telemetry was increased in icREN KO mice (130±2 mmHg, n=8 vs 122±2 mmHg in controls, n=7, P<0.01). The low- to high-frequency ratio (LF/HF) derived from power spectral analysis of heart rate variability, a parameter of sympathetic nerve activity (SNA), was increased in icREN KO mice (KO: 1.24±0.21, n=7 vs control: 0.70±0.11, n=7, P<0.05). Body weight (BW) was normal in icREN KO mice compared to controls, but the BW gain and fat accumulation induced by high fat diet (HFD) were attenuated in male icREN KO mice (BW at 16 wks of HFD- KO: 36.8±1.2 g, n=8 vs control: 41.9±1.4 g, n=9; relative fat mass at 14 wks of HFD- KO: 27.7±1.7%, n=8 vs control: 34.4±2.3%, n=9, both P<0.05). The resting metabolic rate measured by respirometry was increased in icREN KO mice (0.156±0.005 kcal/h, n=46, P<0.05) vs controls (0.145±0.003 kcal/h, n=53), whereas food consumption and absorbed calories were not different. We previously reported that the brain renin-angiotensin system facilitates renal SNA (RSNA) response to acute intracerebroventricular (ICV) injection of leptin. Interestingly, the RSNA response to ICV leptin was greater in icREN KO mice (KO: 214±40 % baseline, n=5 vs control: 114±18 % baseline, n=10, P<0.01). AT1a receptor mRNA was upregulated in the paraventricular nucleus of icREN KO mice (P<0.05). Chronic ICV injection of losartan not only abolished the elevated blood pressure in icREN KO mice, but reduced it to below baseline in controls (systolic blood pressure, 111±3 mmHg in KO, n=5; 124±4 mmHg in controls, n=6). These data suggest that icREN deletion increases the activity of brain renin-angiotensin system and elevates blood pressure and metabolic rate through sympathetic activation. We conclude that this novel icREN isoform contributes to cardiovascular and metabolic control possibly as part of an inhibitory neural circuit.

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.

Sign in / Sign up

Export Citation Format

Share Document