title: Chronic overexpression of angiotensin-(1-7) in rats reduces cardiac reactivity to acute stress and dampens anxious behavior.
abstract: 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.
authors.affiliation: a Department of Physiology and Biophysics , INCT, Institute of Biological Sciences, Federal University of Minas Gerais , Minas Gerais , Brazil.
authors.forename: Danielle
authors.initials: D
authors.lastname: Moura Santos
authors.affiliation: a Department of Physiology and Biophysics , INCT, Institute of Biological Sciences, Federal University of Minas Gerais , Minas Gerais , Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ribeiro Marins
authors.affiliation: a Department of Physiology and Biophysics , INCT, Institute of Biological Sciences, Federal University of Minas Gerais , Minas Gerais , Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Limborço-Filho
authors.affiliation: a Department of Physiology and Biophysics , INCT, Institute of Biological Sciences, Federal University of Minas Gerais , Minas Gerais , Brazil.
authors.forename: Marilene Luzia
authors.initials: ML
authors.lastname: de Oliveira
authors.affiliation: b Alamantec/LABFAR , Minas Gerais , Brazil.
authors.forename: Daniele
authors.initials: D
authors.lastname: Hamamoto
authors.affiliation: c Department of Physiology , Institute of Biological Sciences, Federal University of Goiás , Goiás , Brazil Goiânia.
authors.forename: Carlos Henrique
authors.initials: CH
authors.lastname: Xavier
authors.affiliation: d Department of Pharmacology , Institute of Biological Sciences, Federal University of Minas Gerais , Minas Gerais , Brazil.
authors.forename: Fabrício Araújo
authors.initials: FA
authors.lastname: Moreira
authors.affiliation: 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.|e Institute of Cardiology , University Foundation of Cardiology , Rio Grande do Sul , Brazil.
authors.forename: Robson Augusto Souza
authors.initials: RA
authors.lastname: Santos
authors.affiliation: a Department of Physiology and Biophysics , INCT, Institute of Biological Sciences, Federal University of Minas Gerais , Minas Gerais , Brazil.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Campagnole-Santos
authors.affiliation: a Department of Physiology and Biophysics , INCT, Institute of Biological Sciences, Federal University of Minas Gerais , Minas Gerais , Brazil.
authors.forename: Marco Antonio
authors.initials: MA
authors.lastname: Peliky Fontes
mesh_terms: D000803:Angiotensin I / Q000235:genetics*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D001007:Anxiety / Q000235:genetics*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010446:Peptide Fragments / Q000235:genetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: C092006:7-Ala-angiotensin (1-7); D010446:Peptide Fragments; D000804:Angiotensin II; D000803:Angiotensin I; C118790:angiotensin I (1-7)
keywords: Angiotensin-(1-7); anxiety; emotional stressor; heart rate; renal sympathetic activity; transgenic