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Since ARBs strongly reduce inflammation it was
Since ARBs strongly reduce inflammation, it was hypothesized that the protective effects on cognition were the result of reduction of inflammation and amelioration of neurogenic decrease. However, ARB treatment did not normalize increased inflammation and neurogenic loss. For this reason, the protective effect of ARB on cognition is probably the consequence of early mechanisms of injury common to other methylphenol synthesis disorders that immediately follow radiation injury [133]. The principal mechanism to consider is initial damage and precipitated senescence to the vascular endothelium [136], [137], [138].
Radiation-induced damage to vascular endothelium is not confined to the brain, because radiation increases senescence in pulmonary artery endothelial cells [138] . This mechanism may explain the significant protection offered by ARBs, since it is well-known that these compounds protect the cerebrovascular endothelium and the blood-brain barrier from injury [26], [29], [33], [46], [72].
Stress and mood disorders
Stress enhances hormonal (ACTH, aldosterone, glucocorticoid, vasopressin) production and release and peripheral as well as central sympathetic activity. While intended to protect homeostasis during stress, failure to control these responses to acceptable levels is associated with multiple disorders, including but not limited to cardiovascular, gastrointestinal and brain disease [31], [32] .
Dysregulated hormonal and sympathetic responses to stress are causally associated with enhanced central and peripheral AT1 receptor hyper activity [26], [31], [32]. It is therefore not surprising that AT1 receptor blockade decreases the central and peripheral response to many types of stress, including isolation, restraint and peripheral and brain inflammation [26], [31], [32] . The beneficial effects of ARB administration can be demonstrated, in pre-clinical studies, by their amelioration of stress-induced disorders. ARB administration protects from gastric ulcerations resulting from cold- restraint [139].
There are indications that ARB beneficial effects extend to mood disorders. AT1 receptor blockade reduces anxiety in cold-restraint and isolation stress [31], [140], [141] . Additionally, AT1 receptor expression is enhanced [142] in the brain of a rodent model with increased anxiety responses, the AT2 receptor −/− mouse [143].
The antianxiety effect of AT1 receptor blockade is associated with decreased corticotropin- releasing factor response to isolation stress [144]. These was confirmed by the finding that AT1A receptors in neurons expressing corticotropin-releasing factor enhance expression of conditioned fear, while AT1 receptor blockade enhances extinction of fear memory [145], [146]]. More importantly, reduction of stress and mood disorders after ARB treatment has been demonstrated in humans. There is convincing evidence of a significant association of depression with neurological disorders including stroke, Alzheimer’s and Parkinson’s disease and chronic emotional stress, [147], [148], [149], [150], [151], [152], [153], [154]. Observational studies reveal that treatment with ARBs reduces stress, anxiety and depression, improving the quality of life not only in hypertensive but also in normotensive subjects suffering from diabetes [29]. An epidemiological study revealed that ARBs ameliorate post-traumatic stress disorder [155] and treatment with antihypertensive drugs reducing AT1 receptor activity, but not with other types of antihypertensive medications, significantly decrease the risk of hospital admissions for mood disorders [156].
Selected ongoing and recruitment clinical trials on the effects of ARB administration on stress conditions and mood disorders are listed in Table 1.
Reduced AT1 receptor activity increases the lifespan
Reduction of the hormonal and sympathetic responses to stress and heart and kidney injury are proposed mechanisms for the very significant increase in lifespan observed after life-long ARB treatment of genetically hypertensive rats [157], [158].