RRC ID |
11801
|
著者 |
Inaba S, Iwai M, Furuno M, Tomono Y, Kanno H, Senba I, Okayama H, Mogi M, Higaki J, Horiuchi M.
|
タイトル |
Continuous activation of renin-angiotensin system impairs cognitive function in renin/angiotensinogen transgenic mice.
|
ジャーナル |
Hypertension
|
Abstract |
We examined the possibility that continuous activation of the human brain renin-angiotensin system causes cognitive impairment, using human renin (hRN) and human angiotensinogen (hANG) gene chimeric transgenic (Tg) mice. Cognitive function was evaluated by the shuttle avoidance test once a week from 10 to 20 weeks of age. The avoidance rate in wild-type mice gradually increased. In contrast, the avoidance rate in chimeric hRN/hANG-Tg mice also increased; however, no further increase in avoidance rate was observed from 14 weeks of age, and it decreased thereafter. Cerebral surface blood flow was markedly reduced in 20-week-old hRN/hANG-Tg mice. Superoxide anion production in the brain was already higher in 10-week-old hRN/hANG-Tg mice and further increased thereafter with an increase in NADPH oxidase activity. Moreover, expression of p47(phox) and Nox4 in the brain of hRN/hANG-Tg mice also increased. Administration of an angiotensin II type 1 receptor blocker, olmesartan (5.0 mg/kg per day), attenuated the increase in blood pressure and ameliorated cognitive decline with enhancement of cerebral surface blood flow and a reduction of oxidative stress in hRN/hANG-Tg mice. On the other hand, hydralazine (0.5 mg/kg per day) did not improve the decrease in avoidance rate, and did not influence cerebral surface blood flow or oxidative stress in hRN/hANG-Tg mice, in spite of a similar reduction of blood pressure to that by olmesartan. Moreover, we observed that treatment with Tempol improved impaired cognitive function in hRN/hANG-Tg mice. These results suggest that continuous activation of the brain renin-angiotensin system impairs cognitive function via stimulation of the angiotensin II type 1 receptor with a decrease in cerebral surface blood flow and an increase in oxidative stress.
|
巻・号 |
53(2)
|
ページ |
356-62
|
公開日 |
2009-2-1
|
DOI |
10.1161/HYPERTENSIONAHA.108.123612
|
PII |
HYPERTENSIONAHA.108.123612
|
PMID |
19047580
|
MeSH |
Angiotensin II Type 1 Receptor Blockers / pharmacology
Angiotensinogen / genetics
Angiotensinogen / metabolism*
Animals
Antioxidants / pharmacology
Blood Pressure / physiology
Brain / blood supply*
Brain / metabolism*
Cognition / physiology*
Cyclic N-Oxides / pharmacology
Imidazoles / pharmacology
Male
Mice
Mice, Transgenic
NADPH Oxidase 4
NADPH Oxidases / metabolism
Oxidative Stress / physiology
Receptor, Angiotensin, Type 1 / metabolism
Regional Blood Flow / physiology
Renin / genetics
Renin / metabolism*
Renin-Angiotensin System / physiology*
Spin Labels
Superoxides / metabolism
Tetrazoles / pharmacology
|
IF |
7.713
|
引用数 |
79
|
WOS 分野
|
PERIPHERAL VASCULAR DISEASE
|
リソース情報 |
実験動物マウス |
RBRC01122
RBRC01123 |