The association between the renin-angiotensin system and the hypothalamic-pituitary-adrenal axis in anxiety disorders: A systematic review of animal studies

Anxiety is characterized as the emotional response in anticipation of a future threat. This hypervigilant state comprehends a cascade of neuroendocrine and physiological processes, involving the renin-angiotensin system (RAS) and hypothalamic-pituitary-adrenal axis (HPA). Excessive and chronic anxiety may ultimately lead to the development of anxiety disorders. This systematic review aimed to investigate experimental studies using animal models that explored the relationship between RAS and the HPA axis in anxiety disorders. A systematic search was conducted in MEDLINE/PubMed, Embase and Web of Science, and was performed according to PRISMA guidelines. The inclusion criteria was mainly the mention of RAS, HPA axis, and an anxiety disorder in the same study. Quality of studies was evaluated according to the table of risk of bias from SYRCLE. From 12 eligible studies, 7 were included. Research in rats and mice shows that the overactivation of the RAS and HPA axis triggers several neuroendocrine reactions, mainly mediated by AT1 receptors, which promote anxiety-like behaviors and positive feedback for its hyperactivation. On the contrary, the administration of antihypertensive drugs, such as angiotensin AT1 receptor blocker, propitiated the regulation of the RAS and HPA axis, maintaining homeostasis even amid aversive situations. Assessment of risk of bias revealed a pronounced unclear to high risk in several categories, which thus jeopardize the comparability and reproducibility of the results. Nonetheless, the preclinical evidence indicates that the hyperactivation of both RAS and HPA axis during stress exerts deleterious consequences, inducing anxiogenic responses. Moreover, the compiled results show that the modulation of both systems by the administration of AT1 receptor blockers produce anxiolytic effects in animal models and may constitute a new venue for the treatment of anxiety-like disorders.