scholarly journals Countering the classical renin–angiotensin system

2021 ◽  
Vol 135 (23) ◽  
pp. 2619-2623
Author(s):  
Natalia M. Noto ◽  
Yazmin M. Restrepo ◽  
Robert C. Speth
Keyword(s):  
Fusion Protein ◽  
Rat Model ◽  
Renin Angiotensin System ◽  
Transgenic Rat ◽  
Ang Ii ◽  
Vasopressin Release ◽  
Angiotensin System ◽  
The Brain ◽  
Therapeutic Administration ◽  
Transgenic Rat Model

Abstract It is well-established that Ang-(1-7) counteracts the effects of Ang II in the periphery, while stimulating vasopressin release and mimicking the activity of Ang II in the brain, through interactions with various receptors. The rapid metabolic inactivation of Ang-(1-7) has proven to be a limitation to therapeutic administration of the peptide. To circumvent this problem, Alves et al. (Clinical Science (2021) 135(18), https://doi.org/10.1042/CS20210599) developed a new transgenic rat model that overexpresses an Ang-(1-7)-producing fusion protein. In this commentary, we discuss potential concerns with this model while also highlighting advances that can ensue from this significant technical feat.

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.

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.

Influence of brain renin-angiotensin system on renal sympathetic and cardiac baroreflexes in conscious rabbits

1991 ◽  
Vol 260 (3) ◽  
pp. H770-H778 ◽  
Author(s):  
P. K. Dorward ◽  
C. D. Rudd
Keyword(s):  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Transient Pressure ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Before And After ◽  
Conscious Rabbits ◽  
The Brain ◽  
Renal Sympathetic

The role of the brain renin-angiotensin system (RAS) in the baroreflex regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR) was studied in conscious rabbits. RSNA and HR were recorded during slow ramp changes in mean arterial pressure (MAP) before and after intraventricular infusion of 1) angiotensin II (ANG II), 2) ANG II receptor antagonist, [Sar1,Ile8]ANG II, or 3) converting enzyme inhibitor (CEI, enalaprilat). Central ANG II increased resting MAP and RSNA by 10.6 +/- 0.9 mmHg and 21 +/- 7%, respectively, but did not alter HR. There was a marked increase of 107 +/- 15% in the maximum RSNA evoked by slowly lowering MAP. In contrast, maximum reflex tachycardia was only modestly elevated, and baroreflex inhibition of RSNA and HR during MAP rises was unaffected. Central [Sar1,Ile8]ANG II had no effect on RSNA or HR, either at rest or during baroreflex responses, while CEI slightly enhanced maximal reflex responses. Thus exogenous ANG II causes a powerful excitation of renal sympathetic motoneurons, the magnitude of which is revealed when tonic baroreceptor inhibition is removed during transient pressure falls. However, in quietly resting conscious rabbits, we found no evidence for a tonic influence of endogenous ANG II on these neurons, and the physiological stimuli required for their activation by the brain RAS remain to be found.

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 Controlled Hemorrhage Sensitizes Angiotensin II-Elicited Hypertension through Activation of the Brain Renin-Angiotensin System Independently of Endoplasmic Reticulum Stress

2022 ◽  
Vol 2022 ◽  
pp. 1-13
Author(s):  
Guo-Biao Wu ◽  
Hui-Bo Du ◽  
Jia-Yi Zhai ◽  
Si Sun ◽  
Jun-Ling Cui ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Protein Expression ◽  
Plasma Levels ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Phenylbutyric Acid ◽  
The Brain

Hemorrhagic shock is associated with activation of renin-angiotensin system (RAS) and endoplasmic reticulum stress (ERS). Previous studies demonstrated that central RAS activation produced by various challenges sensitizes angiotensin (Ang) II-elicited hypertension and that ERS contributes to the development of neurogenic hypertension. The present study investigated whether controlled hemorrhage could sensitize Ang II-elicited hypertension and whether the brain RAS and ERS mediate this sensitization. Results showed that hemorrhaged (HEM) rats had a significantly enhanced hypertensive response to a slow-pressor infusion of Ang II when compared to sham HEM rats. Treatment with either angiotensin-converting enzyme (ACE) 1 inhibitor, captopril, or ACE2 activator, diminazene, abolished the HEM-induced sensitization of hypertension. Treatment with the ERS agonist, tunicamycin, in sham HEM rats also sensitized Ang II-elicited hypertension. However, blockade of ERS with 4-phenylbutyric acid in HEM rats did not alter HEM-elicited sensitization of hypertension. Either HEM or ERS activation produced a greater reduction in BP after ganglionic blockade, upregulated mRNA and protein expression of ACE1 in the hypothalamic paraventricular nucleus (PVN), and elevated plasma levels of Ang II but reduced mRNA expression of the Ang-(1-7) receptor, Mas-R, and did not alter plasma levels of Ang-(1-7). Treatment with captopril or diminazene, but not phenylbutyric acid, reversed these changes. No treatments had effects on PVN protein expression of the ERS marker glucose-regulated protein 78. The results indicate that controlled hemorrhage sensitizes Ang II-elicited hypertension by augmenting RAS prohypertensive actions and reducing RAS antihypertensive effects in the brain, which is independent of ERS mechanism.

Role of tissue renin angiotensin system in two-kidney, one-clip hypertensive rats

1993 ◽  
Vol 264 (3) ◽  
pp. F510-F514
Author(s):  
R. Morishita ◽  
J. Higaki ◽  
H. Okunishi ◽  
F. Nakamura ◽  
M. Nagano ◽  
...  
Keyword(s):  
Mrna Level ◽  
Renin Angiotensin System ◽  
Mrna Levels ◽  
Ang Ii ◽  
Gene Expressions ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Significant Difference ◽  
Renin Mrna ◽  
The Brain

To investigate the molecular pathology of two-kidney, one-clip (2K-1C) rats, we examined the gene expressions of the renin-angiotensin system (RAS) and angiotensin II (ANG II) concentration in various tissues in the early (4 wk) and chronic (16 wk) phases of hypertension. Four weeks after clipping, the brain renin mRNA level was lower in 2K-1C rats than in control rats (P < 0.05). On the other hand, the levels of brain and renal angiotensinogen mRNA were not significantly different in the two groups. The brain and adrenal ANG II concentrations were significantly higher in 2K-1C rats than in control rats. Sixteen weeks after clipping, there was no significant difference in the brain renin mRNA levels in the two groups, and renal and brain angiotensinogen mRNA levels were normal. Moreover, the ANG II concentrations in the adrenals and brain (except the cortex) of 2K-1C rats were not significantly higher than those in control rats. These results show a differential pattern of tissue RAS gene expression in rats during the development of 2K-1C hypertension, which is regulated in a tissue-specific manner. Furthermore, the data suggest that brain ANG II may be affected by circulating ANG II, but not by the brain renin angiotensin system, and may regulate brain renin, probably by negative feedback through its own receptor.

scholarly journals Evidence for intraventricular secretion of angiotensinogen and angiotensin by the subfornical organ using transgenic mice

2017 ◽  
Vol 312 (6) ◽  
pp. R973-R981 ◽  
Author(s):  
Khristofor Agassandian ◽  
Justin L. Grobe ◽  
Xuebo Liu ◽  
Marianna Agassandian ◽  
Anthony P. Thompson ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Immunohistochemical Localization ◽  
Subfornical Organ ◽  
Ang Ii ◽  
Angiotensin System ◽  
Angiotensin Peptides ◽  
Human Renin ◽  
Brain Measurements ◽  
The Brain ◽  
Large Decline

Direct intracerebroventricular injection of angiotensin II (ANG II) causes increases in blood pressure and salt and water intake, presumably mimicking an effect mediated by an endogenous mechanism. The subfornical organ (SFO) is a potential source of cerebrospinal fluid (CSF), ANG I, and ANG II, and thus we hypothesized that the SFO has a secretory function. Endogenous levels of angiotensinogen (AGT) and renin are very low in the brain. We therefore examined the immunohistochemical localization of angiotensin peptides and AGT in the SFO, and AGT in the CSF in two transgenic models that overexpress either human AGT (A+ mice), or both human AGT (hAGT) and human renin (SRA mice) in the brain. Measurements were made at baseline and following volumetric depletion of CSF. Ultrastructural analysis with immunoelectron microscopy revealed that superficially located ANG I/ANG II and AGT immunoreactive cells in the SFO were vacuolated and opened directly into the ventricle. Withdrawal of CSF produced an increase in AGT in the CSF that was accompanied by a large decline in AGT immunoreactivity within SFO cells. Our data provide support for the hypothesis that the SFO is a secretory organ that releases AGT and possibly ANG I/ANG II into the ventricle at least under conditions when genes that control the renin-angiotensin system are overexpressed in mice.

scholarly journals Exercise training normalizes ACE and ACE2 in the brain of rabbits with pacing-induced heart failure

2010 ◽  
Vol 108 (4) ◽  
pp. 923-932 ◽  
Author(s):  
Sumit Kar ◽  
Lie Gao ◽  
Irving H. Zucker
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Mrna Expression ◽  
Autonomic Function ◽  
Renin Angiotensin System ◽  
Ventrolateral Medulla ◽  
Ang Ii ◽  
Angiotensin System ◽  
New Zealand White Rabbits ◽  
The Brain

Exercise training (EX) normalizes sympathetic outflow and plasma ANG II in chronic heart failure (CHF). The central mechanisms by which EX reduces this sympathoexcitatory state are unclear, but EX may alter components of the brain renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) may mediate an increase in sympathetic nerve activity (SNA). ACE2 metabolizes ANG II to ANG-(1–7), which may have antagonistic effects to ANG II. Little is known concerning the regulation of ACE and ACE2 in the brain and the effect of EX on these enzymes, especially in the CHF state. This study aimed to investigate the effects of EX on the regulation of ACE and ACE2 in the brain in an animal model of CHF. We hypothesized that the ratio of ACE to ACE2 would increase in CHF and would be reduced by EX. Experiments were performed on New Zealand White rabbits divided into the following groups: sham, sham + EX, CHF, and CHF + EX ( n = 5 rabbits/group). The cortex, cerebellum, medulla, hypothalamus, paraventricular nucleus (PVN), nucleus tractus solitarii (NTS), and rostral ventrolateral medulla (RVLM) were analyzed. ACE protein and mRNA expression in the cerebellum, medulla, hypothalamus, PVN, NTS, and RVLM were significantly upregulated in CHF rabbits (ratio of ACE to GAPDH: 0.3 ± 0.03 to 0.8 ± 0.10 in the RVLM, P < 0.05). EX normalized this upregulation compared with CHF (0.8 ± 0.1 to 0.4 ± 0.1 in the RVLM). ACE2 protein and mRNA expression decreased in CHF (ratio of ACE2 to GAPDH: 0.3 ± 0.02 to 0.1 ± 0.01 in the RVLM). EX increased ACE2 expression compared with CHF (0.1 ± 0.01 to 0.8 ± 0.1 in the RVLM). ACE2 was present in the cytoplasm of neurons and ACE in endothelial cells. These data suggest that the activation of the central RAS in animals with CHF involves an imbalance of ACE and ACE2 in regions of the brain that regulate autonomic function and that EX can reverse this imbalance.

scholarly journals The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

2018 ◽  
Vol 98 (1) ◽  
pp. 505-553 ◽  
Author(s):  
Robson Augusto Souza Santos ◽  
Walkyria Oliveira Sampaio ◽  
Andreia C. Alzamora ◽  
Daisy Motta-Santos ◽  
Natalia Alenina ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Renin Angiotensin System ◽  
The Body ◽  
Biologically Active ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Past ◽  
The Brain ◽  
System Focus

The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1–7)/MAS, whose end point is the metabolite ANG-(1–7). ACE2 and other enzymes can form ANG-(1–7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1–7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1–7) in physiology and disease, with particular emphasis on the brain.

scholarly journals The brain renin-angiotensin system and cardiovascular responses to stress: insights from transgenic rats with low brain angiotensinogen

2012 ◽  
Vol 113 (12) ◽  
pp. 1929-1936 ◽  
Author(s):  
Amy C. Arnold ◽  
Atsushi Sakima ◽  
Sherry O. Kasper ◽  
Sherry Vinsant ◽  
Maria Antonia Garcia-Espinosa ◽  
...  
Keyword(s):  
Stress Responses ◽  
Renin Angiotensin System ◽  
Cardiovascular Responses ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Brain Peptides ◽  
The Impact ◽  
The Brain

The renin-angiotensin system (RAS) has been identified as an attractive target for the treatment of stress-induced cardiovascular disorders. The effects of angiotensin (ANG) peptides during stress responses likely result from an integration of actions by circulating peptides and brain peptides derived from neuronal and glial sources. The present review focuses on the contribution of endogenous brain ANG peptides to pathways involved in cardiovascular responses to stressors. During a variety of forms of stress, neuronal pathways in forebrain areas containing ANG II or ANG-(1–7) are activated to stimulate descending angiotensinergic pathways that increase sympathetic outflow to increase blood pressure. We provide evidence that glia-derived ANG peptides influence brain AT1 receptors. This appears to result in modulation of the responsiveness of the neuronal pathways activated during stressors that elevate circulating ANG peptides to activate brain pathways involving descending hypothalamic projections. It is well established that increased cardiovascular reactivity to stress is a significant predictor of hypertension and other cardiovascular diseases. This review highlights the importance of understanding the impact of RAS components from the circulation, neurons, and glia on the integration of cardiovascular responses to stressors.

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