The Improving Effect And Mechanism Of Angiotensin (1-7) On Anxiety-like Behavior And Gastric Mucosal Damage In Stressed Rats

Part 1: Ang(1-7)through modulation of the NMDAR-nNOS-NO pathway and serotonergic metabolism exerted anxiolytic effects in stressed ratsObjective: To investigate the roles of angiotensin(1-7)[Ang(1-7)] in anxiety-like behavior of stressed rats.Methods: In the present study,Ang(1-7)was injected into the ventral hippocampus of stressed rats,or combined with a Fyn kinase inhibitor,an N-Methyl-D-aspartate receptor(NMDAR)antagonist,an neuronal nitric oxide synthase(nNOS)inhibitor or an nitric oxide(NO)scavenger.Anxiety-like behaviors were performed by the open field test and the elevated plus maze test,as well as the alterations in the NMDAR-nNOS-NO signaling and 5-hydroxytryptamine(5-HT)metabolism were analyzed.Results: After 21 days of chronic restraint stress,the rats showed anxiety-like behavior.The levels of phosphorylated NR2B(the critical NMDAR subunit 2B),as well as the activities of Fyn,nNOS and monoamine oxidase(MAO)were significantly decreased in the ventral hippocampus of stressed rats,while the levels of 5-HT were remarkably elevated.Bilateral infusion of Ang(1-7)into the ventral hippocampus restored the NMDAR-nNOS-NO signaling pathway and MAO-mediated 5-HT metabolism,which were accompanied by the attenuation of anxiety-like behavior.Specific blockers were used to block the activity of Fyn kinase,the phosphorylation of NR2B,the activity of nNOS or the production of NO,and the anxiolytic effects of Ang(1-7)was significantly attenuated.Conclusion: Ang(1-7)induced anxiolytic effects by modulating the NMDAR-nNOS-NO signaling and 5-HT metabolism in the ventral hippocampus of stressed rats,implicating Ang(1-7)a promising anxiolytic agent.Future translational research should focus on the relationship among Ang(1-7),glutamatergic neurotransmission,and serotonergic neurotransmission in the ventral hippocampus.Part 2:NMDAR-NO signaling in the ventral hippocampus mediated the gastroprotective effects of angiotensin(1-7)in a vagus-dependent manner during stressObjective: To explore the roles of the NMDAR-NO signaling in the ventral hippocampus in the gastroprotection of Ang(1-7)during stress.Methods:In the present study,gastric mucosal injury was induced by 2h of cold restraint stress,and Ang(1-7)was injected into the bilateral ventral hippocampus of stressed rats.The mechanisms underlying the gastroprotection of Ang(1-7)were further explored by blockade of Fyn kinase and glutamatergic neurotransmission,as well as bilateral cervical vagotomy.The effects of bilateral intra-ventral-hippocampus Ang(1-7)infusion on glutamatergic neurotransmission,vagal activity,and gastric mucosal blood flow(GMBF)were then investigated.Results: The ventral hippocampus levels of glutamate,phosphorylated NR2B(the critical NMDAR unit),and its downstream effector NO in rats were significantly reduced after 2 h of cold-restraint stress,accompanied by a dysregulated GMBF and injured gastric mucosa.Ang(1-7)treatment promoted glutamate biosynthesis,NR2B phosphorylation and NO production in the ventral hippocampus by stimulating glutaminase,Fyn kinase and neuronal NO synthase activity,respectively,and restored the cardiovascular response,GMBF and mucosal integrity.However,the effects of Ang(1-7)were blocked by Fyn kinase blockade,NR2B inhibition,NO removal or bilateral cervical vagotomy.Conclusion: These findings suggest that Ang(1-7)in the ventral hippocampus promotes Fyn-dependent glutamatergic neurotransmission and sequential vagal excitation through NO,thereby providing protection against stress-induced gastric lesions.The therapeutic effects of Ang(1-7)and its brain-permeable mimics on stress-related disorders,e.g.,stress ulcer,deserve more investigation.