Elsevier

Neuropharmacology

Volume 97, October 2015, Pages 58-66
Neuropharmacology

Activation of angiotensin-(1–7)/Mas axis in the brain lowers blood pressure and attenuates cardiac remodeling in hypertensive transgenic (mRen2)27 rats

https://doi.org/10.1016/j.neuropharm.2015.04.036Get rights and content

Highlights

  • Ang-(1–7) through Mas receptor in the brain of (mRen2)27 rats attenuates hypertension.

  • Brain Ang-(1–7)/Mas activation improved baroreflex and cardiac autonomic control in (mRen2)27 rats.

  • Brain Ang-(1–7) reduced hypertrophy and makers of cardiac stress induced by hypertension.

  • Brain Ang-(1–7)/Mas activation can improve treatment of cardiovascular diseases.

Abstract

Activation of the peripheral angiotensin-(1–7)/Mas axis of the renin–angiotensin system produces important cardioprotective actions, counterbalancing the deleterious actions of an overactivity of Ang II/AT1 axis. In the present study we evaluated whether the chronic increase in Ang-(1–7) levels in the brain could ameliorate cardiac disorders observed in transgenic (mRen2)27 hypertensive rats through actions on Mas receptor. Sprague Dawley (SD) and transgenic (mRen2)27 hypertensive rats, instrumented with telemetry probe for arterial pressure (AP) measurement were subjected to 14 days of ICV infusion of Ang-(1–7) (200 ng/h) or Ang-(1–7) associated with Mas receptor antagonist (A779, 1 μg/h) or 0.9% sterile saline (0.5 μl/h) through osmotic mini-pumps. Ang-(1–7) infusion in (mRen2)27 rats reduced blood pressure, normalized the baroreflex control of HR, restored cardiac autonomic balance, reduced cardiac hypertrophy and pre-fibrotic alterations and decreased the altered imbalance of Ang II/Ang-(1–7) in the heart. In addition, there was an attenuation of the increased levels of atrial natriuretic peptide, brain natriuretic peptide, collagen I, fibronectin and TGF-β in the heart of (mRen2)27 rats. Furthermore, most of these effects were mediated in the brain by Mas receptor, since were blocked by its selective antagonist, A779. These data indicate that increasing Ang-(1–7) levels in the brain can attenuate cardiovascular disorders observed in (mRen2)27 hypertensive rats, probably by improving the autonomic balance to the heart due to centrally-mediated actions on Mas receptor.

Introduction

The renin–angiotensin system (RAS) plays a key role in the control of arterial pressure (AP) and hydroelectrolytic balance (Hall, 1991). However, the inappropriate overactivity of the angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/AT1 receptor axis is critically involved in the pathogenesis of cardiovascular diseases. On the other hand, the ACE2/Ang-(1–7)/Mas receptor axis can counterbalance and attenuate the deleterious actions of Ang II (Ferrario et al., 2010, Santos, 2014). It is well known that increase in circulating levels of Ang-(1–7) induces important cardioprotective actions mediated by Mas receptor (Ferrario et al., 2010, Santos, 2014). Ang-(1–7) is capable to induce antiarrhythmogenic effect against ischemia/reperfusion injuries in rats (Ferreira et al., 2001, Santos, 2014), as well as, to prevent atrial tachycardia and fibrillation in rats and dogs (Ferreira et al., 2011, Liu et al., 2011), cardiac hypertrophy and Ang II-induced pathological cardiac remodeling (Santos, 2014).

In the brain, Ang-(1–7) is a powerful facilitator of the bradycardic component of the baroreflex control of heart rate (HR) in normotensive (Campagnole-Santos et al., 1992, Santos, 2014) or hypertensive animals (Benter et al., 1995, Britto et al., 1997, Heringer-Walther et al., 2001, Oliveira et al., 1996). ICV infusion of Ang-(1–7) inhibits sympathetic outflow and increases vagal outflow in rabbits with chronic heart failure, thus contributing to enhanced baroreflex gain in this condition (Kar et al., 2011). In addition, ICV infusion of Ang-(1–7) for 4 weeks significantly reduces the expression of Ang II and AT1 receptors in the brain of spontaneous hypertensive rats (Jiang et al., 2013).

We have previously shown that chronic ICV infusion of Ang-(1–7) attenuated hypertension and prevented the increase in collagen type I mRNA expression, normalized the baroreflex control of the AP and the autonomic tone to the heart in DOCA-salt rats (Guimaraes et al., 2012). Similarly, selective overexpression of ACE2 throughout the brain attenuated neurogenic hypertension (Feng et al., 2010). Moreover, ACE2 gene therapy in the paraventricular nucleus of the hypothalamus in mice prevented Ang II mediated oxidative stress in the brain and restored autonomic dysfunction (Xia et al., 2011). The actions of Ang-(1–7) in the brain seems to be mostly mediated by Mas receptor (Santos et al., 2005) which was shown to be expressed in cardiovascular-related areas in the central nervous system (Becker et al., 2007, Freund et al., 2012).

More recently, Xue et al. (2013) showed that ICV infusion of A779, a selective Mas receptor antagonist (Santos et al., 1994) significantly augmented the blood pressure of DOCA-salt induced hypertension in female rats. Moreover these authors showed that ICV Ang-(1–7) infusion attenuated the increased blood pressure observed after ovariectomy in female DOCA-salt rats (Xue et al., 2013).

Transgenic model of renin-dependent hypertension created by insertion of the mouse Ren-2 gene into the rat genome, the transgenic (mRen2)27 hypertensive rats (Mullins et al., 1990), exhibit high levels of Ang II in the brain and develop hypertension at early age (Mullins et al., 1990). Elevated Ang II/Ang-(1–7) ratio in the medulla of transgenic (mRen2)27 hypertensive rats (Senanayake et al., 1994) is accompanied by impaired baroreflex function (Diz et al., 2008). Furthermore, these rats exhibit cardiac fibrosis, remodeling, hypertrophy and cardiac dysfunction (Langheinrich et al., 1996). Previous studies showed that ICV administration (Dobruch et al., 2003) of Ang-(1–7) or the delivery of an Ang-(1–7) fusion protein in the cisterna magna (Garcia-Espinosa et al., 2012) attenuated the hypertension of (mRen2)27 hypertensive rats.

Considering that Ang-(1–7) lowers blood pressure, we hypothesized that chronic increase in Ang-(1–7) levels in the brain could ameliorate cardiac disorders observed in transgenic (mRen2)27 hypertensive rats through actions on Mas receptor. To address this hypothesis, we evaluated the cardiovascular parameters in (mRen2)27 rats subjected to chronic intracerebroventricular (ICV) infusion of Ang-(1–7) or Ang-(1–7) with the selective Mas receptor antagonist.

Section snippets

Material and methods

The procedures used for: blood pressure monitoring, ICV infusion, baroreflex test, cardiac autonomic tone evaluation, echocardiography, histological analysis, measurement of ACE and ACE2 activity, angiotensin levels, AT1 and Mas receptor protein expression, ANP, BNP, TGF-β levels and mRNA expression of components of the extracellular matrix are described only in the online Data Supplement.

Baseline systolic, diastolic, mean arterial pressure and heart rate

As shown in Fig. 1, conscious freely moving (mRen-2)27rats presented higher baseline SBP, DBP and HR compared to SD rats (n = 5). As expected, (mRen2)27-A7 showed a significant attenuation of hypertension [SBP = 168 ± 10 mmHg vs. 201 ± 3 mmHg in (mRen-2)27; or ΔMAP = −26 ± 4 mmHg in comparison to baseline, n = 6 each, Fig. 1A–C] and normalized baseline HR (372 ± 6 beats/min vs. 392 ± 6 beats/min, mmHg in (mRen-2)27; Fig. 1D). Furthermore, the co-infusion with A779 reversed the beneficial

Discussion

In the present study we showed that ICV infusion of Ang-(1–7) in transgenic (mRen-2)27 hypertensive rats reduced blood pressure, normalized the baroreflex control of HR, restored cardiac autonomic balance, reduced cardiac hypertrophy and pre-fibrotic lesions and decreased the altered imbalance of Ang II/Ang-(1–7) in the heart. Furthermore, most of these effects were mediated by Mas receptor in the brain, since were blocked by its selective antagonist, A779. Our data extended previous

Funding

This study was funded by Conselho Nacional de Ciência e Tecnologia (CNPq) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) through the following grants: PRONEX–CBB-APQ-04758-10 and INCT-NanoBiofar. LMK was a recipient of a fellowship from CAPES.

Conflicts of interest

The authors declare to have no conflicts of interest.

Acknowledgments

We are thankful to Marilene L. Oliveira, José Roberto da Silva, Bônia Alves and Mônica Alves for skillful technical assistance. This study is part of L. M. Kangussu doctoral thesis at the Graduate Program in Biological Sciences: Physiology and Pharmacology of the Federal University of Minas Gerais (UFMG).

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