Moura Santos Danielle, Ribeiro Marins Fernanda, Limborço-Filho Marcelo, de Oliveira Marilene Luzia, Hamamoto Daniele, Xavier Carlos Henrique, Moreira Fabrício Araújo, Santos Robson Augusto Souza, Campagnole-Santos Maria José, Peliky Fontes Marco Antonio
a Department of Physiology and Biophysics , INCT, Institute of Biological Sciences, Federal University of Minas Gerais , Minas Gerais , Brazil.
b Alamantec/LABFAR , Minas Gerais , Brazil.
Stress. 2017 Mar;20(2):189-196. doi: 10.1080/10253890.2017.1296949. Epub 2017 Mar 13.
Angiotensin II (Ang II) acts as a pro-stress hormone, while other evidence indicates that angiotensin-(1-7) [Ang-(1-7)] attenuates physiological responses to emotional stress. To further test this hypothesis, in groups of 5-6 rats we evaluated autonomic, cardiovascular and behavioral parameters in male Sprague-Dawley (SD) and transgenic TGR(A1-7)3292 (TG) rats chronically overexpressing Ang-(1-7). Compared to SD rats, TG rats showed reduced baseline heart rate (HR; SD 380 ± 16 versus TG 329 ± 9 beats per minute (bpm), mean ± standard error of mean, p < .05) and renal sympathetic discharge (SD 138 ± 4 versus TG 117 ± 5 spikes/second, p < .05). TG rats had an attenuated tachycardic response to acute air-puff stress (ΔHR: SD 51 ± 20 versus TG 1 ± 3 bpm; p < .05), which was reversed by intracerebroventricular injection of the Mas receptor antagonist, A-779 (ΔHR: SD 51 ± 20 versus TG 63 ± 15 bpm). TG rats showed less anxious behavior on the elevated plus maze, as revealed by more entries into open arms (SD 2 ± 2 versus TG 47 ± 5% relative to total entries; p < .05), and more time spent in the open arms (SD 5 ± 4 versus TG 53 ± 9% relative to total time, p < .05). By contrast with SD rats, diazepam (1.5 mg/kg, intraperitoneally) did not further reduce anxious behavior in TG rats, indicating a ceiling anxiolytic effect of Ang-(1-7) overexpression. Ang-(1-7) concentrations in hypothalamus and plasma, measured by mass spectrometry were two- and three-fold greater, respectively, in TG rats than in SD rats. Hence, increased endogenous Ang-(1-7) levels in TG rats diminishes renal sympathetic outflow and attenuates cardiac reactivity to emotional stress, which may be via central Mas receptors, and reduces anxious behavior. Lay summaryWe used a genetically modified rat model that produces above normal amounts of a peptide hormone called angiotensin-(1-7) to test whether this peptide can reduce some of the effects of stress. We found that angiotensin-(1-7), acting in the brain, can reduce anxiety and reduce the increase in heart rate associated with emotional stress. These findings may provide a lead for design of new drugs to reduce stress.
血管紧张素II（Ang II）作为一种促应激激素，而其他证据表明血管紧张素 -（1 - 7）[Ang -（1 - 7）]可减弱对情绪应激的生理反应。为进一步验证这一假设，我们将5 - 6只大鼠分为一组，对长期过度表达Ang -（1 - 7）的雄性斯普拉格 - 道利（SD）大鼠和转基因TGR（A1 - 7）3292（TG）大鼠的自主神经、心血管和行为参数进行了评估。与SD大鼠相比，TG大鼠的基线心率（HR；SD为380±16次/分钟，TG为329±9次/分钟，平均值±平均标准误，p < 0.05）和肾交感神经放电（SD为138±4次/秒，TG为117±5次/秒，p < 0.05）降低。TG大鼠对急性吹空气应激的心动过速反应减弱（ΔHR：SD为51±20次/分钟，TG为1±3次/分钟；p < 0.05），脑室内注射Mas受体拮抗剂A - 779可使其逆转（ΔHR：SD为51±20次/分钟，TG为63±15次/分钟）。在高架十字迷宫实验中，TG大鼠表现出的焦虑行为较少，表现为进入开放臂的次数更多（相对于总进入次数，SD为2±2%，TG为47±5%；p < 0.05），且在开放臂中停留的时间更长（相对于总时间，SD为5±4%，TG为53±9%，p < 0.05）。与SD大鼠相反，地西泮（1.5mg/kg，腹腔注射）并未进一步减轻TG大鼠的焦虑行为，这表明Ang -（1 - 7）过表达具有抗焦虑的上限效应。通过质谱法测定，TG大鼠下丘脑和血浆中的Ang -（1 - 7）浓度分别比SD大鼠高2倍和3倍。因此，TG大鼠内源性Ang -（1 - 7）水平升高可减少肾交感神经流出，减弱心脏对情绪应激的反应性，这可能是通过中枢Mas受体实现的，并可减少焦虑行为。简要概述我们使用了一种基因改造的大鼠模型，该模型产生高于正常量的一种名为血管紧张素 -（1 - 7）的肽类激素，以测试这种肽是否可以减轻某些应激效应。我们发现，作用于大脑的血管紧张素 -（1 - 7）可以减轻焦虑，并减少与情绪应激相关的心率增加。这些发现可能为设计减轻应激的新药提供线索。
