Angiotensin as stress mediator: role of its receptor and interrelationships among other stress mediators and receptors.

The involvement of renin-angiotensin system (RAS) and its active peptides, particularly angiotensin II (Ang II), has been described not only in hypertension, but also in stress-associated anxiety disorders. Ang II and its two subtypes of receptors, viz. AT1 and AT2, are localized on stress-responsive brain areas including the hypothalamus-adrenal-pituitary (HPA) axis. The different types of stressors increase the levels of Ang II and change the expression of its receptors. Transgenic animals with a centrally inactivated angiotensin system demonstrate increased anxiety-related behavior describing the anxiolytic effects of basal Ang II. However, studies showing the anxiolytic potential of AT1 receptor antagonists have described the anxiogenic effects of endogenously released Ang II. It suggests that the basal Ang II (in low amount) may attenuate anxiety, while stress-released Ang II (in high amount) may produce anxiety. By employing AT2-deficient mice, the functional role of AT2 receptors in attenuating stress-associated anxiety has been described. Moreover, AT1 receptor antagonists-induced anti-anxiety effects are associated with up-regulation of AT2 receptors in the brain suggesting that the centrally acting AT2 receptor agonists may serve as potential anxiolytic agents. The present review discusses the dual role of Ang II and its receptors in the development of stress-associated anxiety along with its interrelationship with benzodiazepines (BZD) receptors, and other stress mediators including corticotrophin releasing hormone (CRH) and serotonin (5-HT).