Angiotensin II: multitasking in the brain

In addition to controlling systemic blood pressure, angiotensin II (Ang II) has several roles in the brain, including the regulation of cerebrovascular flow and the reaction to stress. In order to clarify the central effects of Ang II and its type 1 (AT,) receptors, we reviewed the literature reporting recent research on the effects of pretreatment with the AT(1)-receptor blocker, candesartan, on experimental ischemia, cerebrovascular remodeling, and inflammation in spontaneously hypertensive rats (SHRs), and the responses to stress induced by isolation and by cold-restraint. Angiotensin II regulates the brain circulation through stimulation of AT(1)-receptors located in the cerebrovascular endothelium and central pathways. SHRs express greater numbers of endothelial AT(1)-receptors and a central sympathetic overdrive, resulting in pathological cerebrovascular growth, inflammation, decreased cerebrovascular compliance, and enhanced vulnerability to brain ischemia. Sustained central AT(1)-receptor antagonism reverses these effects. Sustained reduction of AT(1)-receptor stimulation before stress prevents the hormonal and sympathoadrenal stress responses during isolation and prevents the gastric ulceration stress response to cold-restraint indicating that increased AT(1)-receptor stimulation is essential to enhance the central sympathetic response and the formation and release of corticotropin-releasing factor (CRF) and arginine vasopressin that occur during stress. AT(1)-receptor blocking agents reverse the cortical alterations in CRF, and benzodiazepine receptors characteristic of isolation stress, effects probably related to their anti-anxiety effect in rodents. Sustained reduction of Ang II tone by AT(1)-receptor antagonism could be considered as a preventive and therapeutic approach for brain ischemia and stress-related and mood disorders. Additional preclinical studies and controlled clinical trials are necessary to confirm the efficacy of this novel therapeutic approach.