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

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.

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Sympathoexcitation Associated with Renin-Angiotensin System in Metabolic Syndrome

International Journal of Hypertension ◽

10.1155/2013/406897 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 13

Author(s):

Takuya Kishi ◽

Yoshitaka Hirooka

Keyword(s):

Metabolic Syndrome ◽

Animal Studies ◽

Renin Angiotensin System ◽

Hypertensive Rats ◽

Angiotensin System ◽

Renin Angiotensin ◽

Ras Activation ◽

Sympathetic Nervous ◽

The Brain

Renin-angiotensin system (RAS) is activated in metabolic syndrome (MetS), and RAS inhibitors are preferred for the treatments of hypertension with MetS. Although RAS activation is important for the therapeutic target, underlying sympathetic nervous system (SNS) activation is critically involved and should not be neglected in the pathogenesis of hypertension with MetS. In fact, previous studies have suggested that SNS activation has the interaction with RAS activation and/or insulin resistance. As a novel aspect connecting the importance of SNS and RAS activation, we and other investigators have recently demonstrated that angiotensin II type 1 receptor (AT1R) blockers (ARBs) improve SNS activation in patients with MetS. In the animal studies, SNS activation is regulated by the AT1R-induced oxidative stress in the brain. We have also demonstrated that orally administered ARBs cause sympathoinhibition independent of the depressor effects in dietary-induced hypertensive rats. Interestingly, these benefits on SNS activation of ARBs in clinical and animal studies are not class effects of ARBs. In conclusion, SNS activation associated with RAS activation in the brain should be the target of the treatment, and ARBs could have the potential benefit on SNS activation in patients with MetS.

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The role of the renin-angiotensin system and oxidative stress in spontaneously hypertensive rat mesenteric collateral growth impairment

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01296.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. H2523-H2531 ◽

Cited By ~ 21

Author(s):

Steven J. Miller ◽

Laura E. Norton ◽

Michael P. Murphy ◽

Michael C. Dalsing ◽

Joseph L. Unthank

Keyword(s):

Renin Angiotensin System ◽

Ang Ii ◽

Hypertensive Rats ◽

Angiotensin System ◽

Spontaneously Hypertensive ◽

Renin Angiotensin ◽

Growth Impairment ◽

Collateral Growth ◽

Collateral Artery

Recent clinical and animal studies have shown that collateral artery growth is impaired in the presence of vascular risk factors, including hypertension. Available evidence suggests that angiotensin-converting enzyme inhibitors (ACEI) promote collateral growth in both hypertensive humans and animals; however, the specific mechanisms are not established. This study evaluated the hypothesis that collateral growth impairment in hypertension is mediated by excess superoxide produced by NAD(P)H oxidase in response to stimulation of the ANG II type 1 receptor. After ileal artery ligation, mesenteric collateral growth did not occur in untreated, young, spontaneously hypertensive rats. Significant luminal expansion occurred in collaterals of spontaneously hypertensive rats treated with the superoxide dismutase mimetic tempol, the NAD(P)H oxidase inhibitor apocynin, and the ACEI captopril, but not ANG II type 1 (losartan) or type 2 (PD-123319) receptor blockers. The ACEI enalapril produced equivalent reduction of arterial pressure as captopril but did not promote luminal expansion. This suggests the effects of captopril on collateral growth might result from its antioxidant properties. RT-PCR demonstrated that ANG II type 1 receptor and angiotensinogen expression was reduced in collaterals of untreated rats. This local suppression of the renin angiotensin system provides a potential explanation for the lack of effect of enalapril and losartan on collateral growth. The results demonstrate the capability of antioxidant therapies, including captopril, to reverse impaired collateral artery growth and the novel finding that components of the local renin angiotensin system are naturally suppressed in collaterals.

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Protective axis of the renin–angiotensin system in the brain

Clinical Science ◽

10.1042/cs20130450 ◽

2014 ◽

Vol 127 (5) ◽

pp. 295-306 ◽

Cited By ~ 36

Author(s):

Mariela M. Gironacci ◽

Flavia M. Cerniello ◽

Nadia A. Longo Carbajosa ◽

Jorge Goldstein ◽

Bruno D. Cerrato

Keyword(s):

Neuronal Apoptosis ◽

Baroreflex Sensitivity ◽

Potential Role ◽

Renin Angiotensin System ◽

Ventrolateral Medulla ◽

Hypothalamic Area ◽

Angiotensin System ◽

Renin Angiotensin ◽

The Brain

The RAS (renin–angiotensin system) is composed of two arms: the pressor arm containing AngII (angiotensin II)/ACE (angiotensin-converting enzyme)/AT1Rs (AngII type 1 receptors), and the depressor arm represented by Ang-(1–7) [angiotensin-(1–7)]/ACE2/Mas receptors. All of the components of the RAS are present in the brain. Within the brain, Ang-(1–7) contributes to the regulation of BP (blood pressure) by acting at regions that control cardiovascular function such that, when Ang-(1–7) is injected into the nucleus of the solitary tract, caudal ventrolateral medulla, paraventricular nucleus or anterior hypothalamic area, a reduction in BP occurs; however, when injected into the rostral ventrolateral medulla, Ang-(1–7) stimulates an increase in BP. In contrast with AngII, Ang-(1–7) improves baroreflex sensitivity and has an inhibitory neuromodulatory role in hypothalamic noradrenergic neurotransmission. Ang-(1–7) not only exerts effects related to BP regulation, but also acts as a cerebroprotective component of the RAS by reducing cerebral infarct size and neuronal apoptosis. In the present review, we provide an overview of effects elicited by Ang-(1–7) in the brain, which suggest a potential role for Ang-(1–7) in controlling the central development of hypertension.

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

Clinical Science ◽

10.1042/cs20130396 ◽

2014 ◽

Vol 127 (3) ◽

pp. 135-148 ◽

Cited By ~ 47

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.

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