Critical role of angiotensin II in excess salt-induced brain oxidative stress of stroke-prone spontaneously hypertensive rats.
OBJECTIVE
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/mm2; 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.


CONCLUSIONS
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.
Kim-Mitsuyama
Shokei
S
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Yamamoto
Eiichiro
E
Tanaka
Tomoko
T
Zhan
Yumei
Y
Izumi
Yasukatsu
Y
Izumiya
Yasuhiro
Y
Ioroi
Takeshi
T
Wanibuchi
Hideki
H
Iwao
Hiroshi
H
D017311:Amlodipine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001812:Blood-Brain Barrier; D002121:Calcium Channel Blockers / Q000494:pharmacology; D049109:Cell Proliferation; D002536:Cerebral Arteries / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000166:cytology; D020343:Hypertensive Encephalopathy / Q000150:complications* / Q000473:pathology; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018384:Oxidative Stress; D051381:Rats; D011918:Rats, Inbred SHR; D012965:Sodium Chloride / Q000633:toxicity*; D020521:Stroke / Q000209:etiology* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D013777:Tetrazoles; D013481:Superoxides; D000804:Angiotensin II; D017311:Amlodipine; D012965:Sodium Chloride; C081643:candesartan