Critical role of angiotensin II in excess salt-induced brain oxidative stress of stroke-prone spontaneously hypertensive rats

Background and Purpose - The detailed role of angiotensin II in salt-exacerbated stroke is unclear. We examined the role of angiotensin II in salt-accelerated stroke of stroke-prone spontaneously hypertensive rats (SHRSP). Methods - Salt- loaded SHRSP were orally given the angiotensin II type 1 (AT1) receptor blocker candesartan ( 0.3 to 3 mg/kg per day) and calcium channel blocker amlodipine ( 1 mg/kg per day), and the effects on stroke ( n = 61) and brain superoxide were compared between them. We also examined the effect of angiotensin II infusion ( 200 ng/kg per min) on brain superoxide production and blood - brain barrier. Results - Despite the comparable hypotensive effect between candesartan and amlodipine, candesartan prolonged survival of salt-loaded SHRSP much more than amlodipine ( P < 0.01), being associated with more improvement of cerebral arteriolar thickening, cerebral arteriolar cell proliferation, and hippocampal CA1 neuronal cell reduction (1024.9 +/- 20.6 versus 724.9 +/- 22.8 cells/mm(2); P < 0.01; n = 7 to 10 in each group) in SHRSP by candesartan ( P < 0.05) than amlodipine. Salt loading increased superoxide and NADPH oxidase activity in brain cortex and hippocampus of SHRSP, and this increase was prevented by candesartan ( P < 0.01) but not amlodipine. Angiotensin II infusion, via AT1 receptor, directly increased brain superoxide by 1.8-fold ( P < 0.05; n = 6 to 7 in each group) and impaired blood - brain barrier in salt-loaded SHRSP by 1.7-fold ( P < 0.05), and this increase in brain superoxide and blood - brain barrier impairment was prevented by tempol as well as candesartan. Conclusion - Excess salt, via oxidative stress, accelerates stroke, and angiotensin II, via AT1 receptor, plays a pivotal role in brain superoxide production of SHRSP by excess salt.