Beneficial Effects of Long-Term Administration of an Oral Formulation of Angiotensin-(1–7) in Infarcted Rats

Marques, Fúlvia D.; Melo, Marcos Barrouin; Souza, Leandro Franco de; Irigoyen, Maria Cláudia; Sinisterra, Rubén D.; Sousa, Frederico B. De; Savergnini, Silvia Q; Braga, Vinícius B.A.; Ferreira, Anderson J.; Santos, Robson A.S.

doi:10.1155/2012/795452

Cited by 56 publications

(44 citation statements)

References 45 publications

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“…Taking advantage of this formulation, Marques et al (2011Marques et al ( , 2012 found that chronic oral administration of HPbCD/Ang-(1-7) significantly attenuated the impairment of heart function and cardiac remodeling induced by isoproterenol treatment and myocardial infarction in rats. Furthermore, CGEN-856S, a Mas agonist, promoted antiarrhythmic effects and produced a small dosedependent decrease in arterial pressure in conscious SHR (Savergnini et al 2010).…”

Section: Figurementioning

confidence: 99%

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

Santos

Ferreira

Verano‐Braga

et al. 2012

Journal of Endocrinology

432

369

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Angiotensin (Ang)-(1-7) is now recognized as a biologically active component of the reninangiotensin system (RAS). Ang-(1-7) appears to play a central role in the RAS because it exerts a vast array of actions, many of them opposite to those attributed to the main effector peptide of the RAS, Ang II. The discovery of the Ang-converting enzyme (ACE) homolog ACE2 brought to light an important metabolic pathway responsible for Ang-(1-7) synthesis. This enzyme can form Ang-(1-7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1-9) with subsequent Ang-(1-7) formation by ACE. In addition, it is now well established that the G protein-coupled receptor Mas is a functional binding site for Ang-(1-7). Thus, the axis formed by ACE2/Ang-(1-7)/Mas appears to represent an endogenous counterregulatory pathway within the RAS, the actions of which are in opposition to the vasoconstrictor/ proliferative arm of the RAS consisting of ACE, Ang II, and AT 1 receptor. In this brief review, we will discuss recent findings related to the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular and renal systems, as well as in metabolism. In addition, we will highlight the potential interactions of Ang-(1-7) and Mas with AT 1 and AT 2 receptors.

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Section: Figurementioning

confidence: 99%

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

Santos

Ferreira

Verano‐Braga

et al. 2012

Journal of Endocrinology

432

369

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“…59,60 These studies were limited in scope, and native Ang(1-7) has not been developed further because of its abbreviated half-life in vivo. A cyclic Ang(1-7) analog containing a thioether bridge that makes it resistant to enzymatic digestion and a hydroxypropyl-β-cyclodextrin incorporated Ang(1-7) formulation (HP-β-CD/Ang1-7) have been synthesized and shown to be cardioprotective in animal models of myocardial infarction and insulin resistance/type 2 diabetes [61][62][63] (Table). As an alternative to Ang(1-7), nonpeptide agonists of the Mas receptor, for example, the imidazole compound AVE0991, 64 and novel G-protein-coupled receptor activating peptides, for example, CGEN-856S that have high specificity for the Mas receptor, 65 have been shown to lower BP and protect the vasculature and kidneys in animal models of hypertension and CVD (Table).…”

Section: Activators Of the Angiotensin-converting Enzyme2/angiotensinmentioning

confidence: 99%

New Approaches in the Treatment of Hypertension

Oparil

Schmieder

2015

Circulation Research

237

137

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Hypertension is the most common modifiable risk factor for cardiovascular disease and death, and lowering blood pressure with antihypertensive drugs reduces target organ damage and prevents cardiovascular disease outcomes. Despite a plethora of available treatment options, a substantial portion of the hypertensive population has uncontrolled blood pressure. The unmet need of controlling blood pressure in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its comorbidities. In this Compendium Review, we discuss new drugs and interventional treatments that are undergoing preclinical or clinical testing for hypertension treatment. New drug classes, eg, inhibitors of vasopeptidases, aldosterone synthase and soluble epoxide hydrolase, agonists of natriuretic peptide A and vasoactive intestinal peptide receptor 2, and a novel mineralocorticoid receptor antagonist are in phase II/III of development, while inhibitors of aminopeptidase A, dopamine β-hydroxylase, and the intestinal Na + /H + exchanger 3, agonists of components of the angiotensin-converting enzyme 2/angiotensin(1–7)/Mas receptor axis and vaccines directed toward angiotensin II and its type 1 receptor are in phase I or preclinical development. The two main interventional approaches, transcatheter renal denervation and baroreflex activation therapy, are used in clinical practice for severe treatment resistant hypertension in some countries. Renal denervation is also being evaluated for treatment of various comorbidities, eg, chronic heart failure, cardiac arrhythmias and chronic renal failure. Novel interventional approaches in early development include carotid body ablation and arteriovenous fistula placement. Importantly, none of these novel drug or device treatments has been shown to prevent cardiovascular disease outcomes or death in hypertensive patients.

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“…The fact that LVH is an independent risk factor for the development of HF reinforces the importance of this finding. In addition, others 7,8,21 have demonstrated that Ang-(1-7) prevents extracellular matrix deposition, a key event in the transition from LVH to symptomatic HF that may also contribute to Ang-(1-7) protection in TG-DOCA.…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Angiotensin-(1–7) Against Deoxycorticosterone Acetate–Induced Diastolic Dysfunction Occur Independently of Changes in Blood Pressure

et al. 2015

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Abstract-Mineralocorticoids have been implicated in the pathogenesis of diastolic heart failure. On the contrary, angiotensin (Ang)-(1-7) has emerged as a potential strategy for treatment of cardiac dysfunction induced by excessive mineralocorticoid receptor activation. A critical question about the cardioprotective effect of Ang-(1-7) in hypertensive models is its dependence on blood pressure (BP) reduction. Here, we addressed this question by investigating the mechanisms involved in Ang-(1-7) cardioprotection against mineralocorticoid receptor activation. Sprague-Dawley (SD) and transgenic (TG) rats that overexpress an Ang-(1-7) producing fusion protein (TG(A1-7)3292) were treated with deoxycorticosterone acetate (DOCA) for 6 weeks. After treatment, SD rats became hypertensive and developed ventricular hypertrophy. These parameters were attenuated in TG-DOCA. SD-DOCA rats developed diastolic dysfunction which was associated at the cellular level with reduced Ca 2+ transient. Oppositely, TG-DOCA myocytes presented enhanced Ca 2+ transient. Moreover, higher extracellular signal-regulated kinase phosphorylation, type 1 phosphatase, and protein kinase Cα levels were found in SD-DOCA cells. In vivo, pressor effects of DOCA can contribute to the diastolic dysfunction, raising the question of whether protection in TG was a consequence of reduced BP. To address this issue, BP in SD-DOCA was kept at TG-DOCA level by giving hydralazine or by reducing the DOCA amount given to rats (Low-DOCA). Under similar BP, diastolic dysfunction and molecular changes were still evident in DOCA-hydralazine and SD-low-DOCA, but not in TG-DOCA. In conclusion, Ang-(1-7) protective signaling against DOCA-induced diastolic dysfunction occurs independently of BP attenuation and is mediated by the activation of pathways involved in Ca 2+ handling, hypertrophy, and survival.

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Beneficial Effects of Long-Term Administration of an Oral Formulation of Angiotensin-(1–7) in Infarcted Rats

Cited by 56 publications

References 45 publications

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

New Approaches in the Treatment of Hypertension

Beneficial Effects of Angiotensin-(1–7) Against Deoxycorticosterone Acetate–Induced Diastolic Dysfunction Occur Independently of Changes in Blood Pressure

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