Angiotensin II AT₁ receptor antagonists inhibit the angiotensin‐CRF‐AVP axis and are potentially useful for the treatment of stress‐related and mood disorders

Abstract

The corticotropin-releasing factor (CRF), arginine-vasopressin (AVP), atrial natriuretic peptide (ANP), and Angiotensin II (Ang II) interact, regulating the central sympathetic system, the hypothalamic-pituitary-adrenal (HPA) axis, and the central behavioral mechanisms involved in the response to stress and the development of mood disorders. Non-peptidic, orally active AVP V 1 , V 3 , or CRF 1 receptor antagonists reduce anxiety in animals. ANP is anxiolytic when administered to rodents and humans with anxiety disorders. These compounds are being developed for the therapy of anxiety and depression, but their clinical efficacy has not yet been established.Brain Ang II, a physiological ANP antagonist, promotes CRF and AVP release and stimulates the peripheral and central sympathetic systems. The degree of Ang II AT 1 receptor stimulation determines the response to stress. An orally active, non-peptidic Ang II AT 1 receptor antagonist blocks CRF and AVP release during stress, prevents the sympathoadrenal and hormonal stress reaction, the cortical CRF 1 and benzodiazepine receptor alterations, facilitates the effects of ANP, prevents stress-induced gastric ulcerations, and is anxiolytic in rodents. CRF, AVP, ANP, and the sympathetic system are intimately linked parts of a fundamental regulatory mechanism controlled by the brain Ang II system through AT 1 receptor stimulation, and should be studied together. Selective, safe antagonists of Ang II AT 1 receptors, with central effects after oral administration, have been actively used for the treatment of hypertension and should be considered also as potential anti-stress, anti-anxiety, and antidepressant compounds with properties similar or superior to the CRF and AVP antagonists or the ANP agonists under development. Drug Dev. Res. 65:237-269, 2005.

Angiotensin II: multitasking in the brain

“…Angiotensin II regulates the formation and release of CRF and AVP, and the central and peripheral sympathetic systems, and is a physiological antagonist of ANP [1,40]. This explains why a reduction in Ang II tone by long-term inhibition of its physiologically active AT 1 -receptors decreases CRF and AVP overdrive and promotes the effects of ANP [40], explaining the anti-stress and anti-anxiety effects of ARBs.…”

“…This explains why a reduction in Ang II tone by long-term inhibition of its physiologically active AT 1 -receptors decreases CRF and AVP overdrive and promotes the effects of ANP [40], explaining the anti-stress and anti-anxiety effects of ARBs.…”

“…Inhibition of CRF 1 -receptors or AVP V 1 type and V 3 type receptors reduces anxiety in animal models, and a number of CRF 1 , V 1 , and V 3 receptor antagonists are under development for the treatment of mood disorders and stress-related conditions [40]. Conversely, administration of atrial natriuretic peptide (ANP) reduces anxiety in animal models and in humans [40].…”

“…Evidence from the literature indicates that mood disorders are associated with abnormal responses to stress [40]. Inhibition of CRF 1 -receptors or AVP V 1 type and V 3 type receptors reduces anxiety in animal models, and a number of CRF 1 , V 1 , and V 3 receptor antagonists are under development for the treatment of mood disorders and stress-related conditions [40].…”

“…Inhibition of CRF 1 -receptors or AVP V 1 type and V 3 type receptors reduces anxiety in animal models, and a number of CRF 1 , V 1 , and V 3 receptor antagonists are under development for the treatment of mood disorders and stress-related conditions [40]. Conversely, administration of atrial natriuretic peptide (ANP) reduces anxiety in animal models and in humans [40]. All these compounds share the common properties of reducing the CRF and AVP overdrive, decreasing hormonal and sympathetic response to a number of stressors, and reducing stress-induced anxiety, depression, and other behavioral alterations.…”