Angiotensin-converting enzyme 2 activator, DIZE in the basolateral amygdala attenuates the tachycardic response to acute stress by modulating glutamatergic tone.

The basolateral amygdala (BLA) is critical in the control of the sympathetic output during stress. Studies demonstrated the involvement of the renin-angiotensin system components in the BLA. Angiotensin-(1-7) [Ang-(1-7)], acting through Mas receptors, reduces stress effects. Considering that angiotensin-converting enzyme 2 (ACE2) is the principal enzyme for the production of Ang-(1-7), here we evaluate the cardiovascular reactivity to acute stress after administration of the ACE2 activator, diminazene aceturate (DIZE) into the BLA. We also tested whether systemic treatment with DIZE could modify synaptic activity in the BLA and its effect directly on the expression of the N-methyl-d-aspartate receptors (NMDARs) in NG108 neurons in-vitro. Administration of DIZE into the BLA (200 pmol/100 nL) attenuated the tachycardia to stress (ΔHR, bpm: vehicle = 103 ± 17 vs DIZE = 49 ± 7 p = 0.018); this effect was inhibited by Ang-(1-7) antagonist, A-779 (ΔHR, bpm: DIZE = 49 ± 7 vs A-779 + DIZE = 100 ± 15 p = 0.04). Systemic treatment with DIZE attenuated the excitatory synaptic activity in the BLA (Frequency (Hz): vehicle = 2.9 ± 0.4 vs. DIZE =1.8 ± 0.3 p < 0.04). NG108 cells treated with DIZE demonstrated decreased expression of l subunit NMDAR-NR1 (NR1 expression (a.u): control = 0.534 ± 0.0593 vs. DIZE = 0.254 ± 0.0260) of NMDAR and increases of Mas receptors expression. These data demonstrate that DIZE attenuates the tachycardia evoked by acute stress. This effect results from a central action in the BLA involving activation of Mas receptors. The ACE2 activation via DIZE treatment attenuated the frequency of excitatory synaptic activity in the basolateral amygdala and this effect can be related with the decreases of the NMDAR-NR1 receptor expression.

Mas receptor contributes to pregnancy-induced cardiac remodelling.

Previous studies have demonstrated a protective effect of the Ang-(1-7)/Mas receptor axis on pathological cardiac hypertrophy. Also, the involvement of Mas receptor in exercise-induced cardiac hypertrophy has been suggested. However, the role of the Ang-(1-7)/Mas receptor on pregnancy-induced cardiac remodelling remains unknown. The objective of the present study was to evaluate the participation of the Mas receptor in the development of the cardiac hypertrophy and fibrosis induced by gestation. Female Wistar rats were divided in three groups: control, pregnant and pregnant treated with Mas receptor antagonist A-779. Wild-type (WT) and Mas-knockout (KO) mice were distributed in non-pregnant and pregnant groups. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography. The medial part of the left ventricle (LV) was collected for histological analysis. Echocardiographic analysis was used to evaluate cardiac function. SBP was not changed by pregnancy or A-779 treatment in the Wistar rats. Pharmacological blockade or genetic deletion of Mas receptor attenuates the pregnancy-induced myocyte hypertrophy. The treatment with A-779 or genetic deletion of the Mas receptor increased the collagen III deposition in LV from pregnant animals without changing fibroblast proliferation. KO mice presented a lower ejection fraction (EF), fractional shortening (FS) and stroke volume (SV) and higher end systolic volume (ESV) compared with WT. Interestingly, pregnancy restored these parameters. In conclusion, these data show that although Mas receptor blockade or deletion decreases physiological hypertrophy of pregnancy, it is associated with more extracellular matrix deposition. These alterations are associated with improvement of cardiac function through a Mas-independent mechanism.