Anxiolytic- and antidepressant-like effects of angiotensin-(1–7) in hypertensive transgenic (mRen2)27 rats

Abstract

Angiotensin-(1-7) [Ang-(1-7)], a counter-regulatory peptide of the renin-angiotensin system (RAS) exerts its effects through the G-protein-coupled receptor Mas, which is expressed in different tissues, including the brain. Ang-(1-7) has a broad range of effects beyond the well-described cardiovascular and renal actions, including the modulation of emotional and behavioural responses. In the present study we tested the hypothesis that Ang-(1-7) could attenuate the anxiety- and depression-like behaviours observed in transgenic hypertensive (mRen2)27 rats (TGRs). We also hypothesized that Ang-(1-7) could be involved in the anxiolytic-like effect induced by ACE (angiotensin-converting enzyme) treatment in these hypertensive rats. Therefore, TGRs and Sprague-Dawley rats were subjected to the Elevated Plus Maze (EPM) test, Forced Swimming Test (FST) and Novelty Suppressed Feeding (NSF). TGRs presented a decreased percentage of entries in the open arms of the EPM test, a phenotype reversed by systemic treatment with enalapril or intracerebroventricular infusion of Ang-(1-7). It is interesting that pre-treatment with A779, a selective Mas receptor antagonist, prevented the anxiolytic-like effect induced by the ACE inhibitor. In the NSF test, TGRs showed increased latency to eating, an indicative of a higher aversion in response to a new environment. These animals also showed increased immobility in the FST. Again, Ang-(1-7) reversed this phenotype. Thus, our data showed that Ang-(1-7) can modulate anxiety- and depression-like behaviours in TGRs and warrant further investigation as a new therapy for certain psychiatric disorders.

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

“…Accordingly, years later Bild and Ciobica (43) showed an anxiolytic-like effect after chronic ICV infusions of ANG-(1-7), accompanied by a reduction in oxidative stress in the amygdala. More recently, using two different transgenic rat lines, we showed that ANG-(1-7) ICV infusions could attenuate anxiety-like behavior (11,272). In addition, we showed that ANG-(1-7) was also effective in attenuating a depression-like phenotype (11).…”

“…More recently, using two different transgenic rat lines, we showed that ANG-(1-7) ICV infusions could attenuate anxiety-like behavior (11,272). In addition, we showed that ANG-(1-7) was also effective in attenuating a depression-like phenotype (11). Interestingly, hypertensive patients who suffer from depression exhibit mood improvements after treatment with the ACE inhibitor captopril, which increases levels of ANG-(1-7) (50).…”

“…Interestingly, hypertensive patients who suffer from depression exhibit mood improvements after treatment with the ACE inhibitor captopril, which increases levels of ANG-(1-7) (50). Recently, we showed that the anxiety-like behavior of hypertensive rats was rescued in enalapril-treated animals after blockade, unveiling an anti-aversive role for endogenous ANG-(1-7), at least in hypertensive rats (11). More recently, similar findings have been obtained in mice by increasing ACE2 activity (583).…”

The renin–angiotensin system: a possible new target for depression

“…Administering Ang-(1-7) was associated with decreased oxidative stress markers in the amygdala [ 180 ]. The same Mas antagonism also prevented the anxiolytic/antidepressant effect of enalapril in transgenic hypertensive rats [ 181 , 182 ].…”

Significance of angiotensin 1–7 coupling with MAS1 receptor and other GPCRs to the renin‐angiotensin system: IUPHAR Review 22

“…Central Ang(1–7) treatment of hypertensive (mRen2)27 transgenic rats attenuates the anxiety and depression‐like behaviour in these animals (Almeida‐Santos et al, ; Wang et al, ). In a chronic constriction injury rat model, intrathecal administration of Ang(1–7) relieves, whereas A‐779 aggravates injury‐induced neuropathic pain (Zhao et al, ).…”