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 (AT1) receptors, we reviewed the literature reporting recent research on the effects of pretreatment with the AT1-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 AT1-receptors located in the cerebrovascular endothelium and central pathways. SHRs express greater numbers of endothelial AT1-receptors and a central sympathetic overdrive, resulting in pathological cerebrovascular growth, inflammation, decreased cerebrovascular compliance, and enhanced vulnerability to brain ischemia. Sustained central AT1-receptor antagonism reverses these effects. Sustained reduction of AT1-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 AT1-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. AT1-receptor blocking agents reverse the cortical alterations in CRF1 and benzodiazepine receptors characteristic of isolation stress, effects probably related to their anti-anxiety effect in rodents. Sustained reduction of Ang II tone by AT1-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.
Saavedra
Juan M
JM
Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA. Saavedrj@mail.nih.gov
Benicky
Julius
J
Zhou
Jin
J
D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism; D001921:Brain / Q000502:physiology*; D002545:Brain Ischemia / Q000188:drug therapy; D002560:Cerebrovascular Circulation; D003071:Cognition; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D006801:Humans; D019964:Mood Disorders / Q000209:etiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D013315:Stress, Psychological / Q000209:etiology
D047228:Angiotensin II Type 1 Receptor Blockers; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D001127:Arginine Vasopressin; D003346:Corticotropin-Releasing Hormone; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III