Temporary Pretreatment With the Angiotensin II Type 1 Receptor Blocker, Valsartan, Prevents Ischemic Brain Damage Through an Increase in Capillary Density

Li, Jianmei; Mogi, Masaki; Iwanami, Jun; Min, Li‐Juan; Tsukuda, Kana; Sakamoto, Akiko; Fujita, Toshio; Iwai, Masaru; Horiuchi, Masatsugu

doi:10.1161/strokeaha.107.503458

Cited by 40 publications

(32 citation statements)

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“…Another important downstream effect of endothelial nitric oxide is angiogenesis, and brain capillary density determines stroke outcome in mice. 28 Here, ivabradine significantly increased capillary density both in naive and in stressed mice, consistent with the importance of vascular nitric oxide for the ivabradine effects. In summary, these findings support the concept of heart rate reduction as an intervention to conserve endothelial integrity.…”

Section: Custodis Et Alsupporting

confidence: 78%

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Heart Rate Contributes to the Vascular Effects of Chronic Mental Stress

Custodis

Gertz

Balkaya

et al. 2011

Stroke

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Background and Purpose-Vascular effects of mental stress are only partially understood. Therefore, we studied effects of chronic stress and heart rate (HR) on endothelial function and cerebral ischemia. Methods-129S6/SvEv mice were randomized to the I(f)-channel inhibitor ivabradine (10 mg/kg per day) or vehicle and underwent a chronic stress protocol for 28 days. Results-Stress increased HR from 514Ϯ10 bpm to 570Ϯ14 bpm, this was prevented by ivabradine (485Ϯ7 bpm).Endothelium-dependent relaxation of aortic rings was impaired in mice exposed to stress. HR reduction restored endothelial function to the level of naive controls. Vascular lipid hydroperoxides were increased to 333%Ϯ24% and vascular NADPH oxidase activity was upregulated to 223Ϯ38% in stressed mice, which was prevented by ivabradine. Stress reduced aortic endothelial nitric oxide synthase mRNA expression to 84%Ϯ3% and increased AT1 receptor mRNA to 168%Ϯ18%. Both effects were attenuated by HR reduction. In brain tissue, stress resulted in an upregulation of lipid hydroperoxides to 140%Ϯ11%, which was attenuated by HR reduction. Ivabradine increased brain capillary density in naive and in stressed mice.

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Section: Custodis Et Alsupporting

confidence: 78%

“…28 Chronic stress did not affect density of CD31-positive cells in the brain. Heart rate reduction with ivabradine increased the number of CD31-expressing cells in naive mice from 4503Ϯ501/mm 2 to 6794Ϯ485/mm 2 (PϽ0.05).…”

Section: Brain Capillary Densitymentioning

confidence: 86%

Heart Rate Contributes to the Vascular Effects of Chronic Mental Stress

Custodis

Gertz

Balkaya

et al. 2011

Stroke

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“…31,32 Moreover, we have reported previously that capillary density in the brain was increased by treatment with an ARB. 33 These results suggest that these beneficial effects on cerebral vessels by blockade of the AT 1 receptor could contribute to suppression of the decrease in CBF.…”

Section: Discussionmentioning

confidence: 90%

Continuous Activation of Renin-Angiotensin System Impairs Cognitive Function in Renin/Angiotensinogen Transgenic Mice

et al. 2009

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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. Key Words: angiotensin II receptors Ⅲ cognitive function Ⅲ blood flow Ⅲ oxidative stress Ⅲ transgenic mice D ementia is a common serious health problem that impairs quality of life. A continuous decline in cognitive function occurs as the natural aging course in both humans and animal models. Hypertension is a major risk factor for cerebrovascular disease, including stroke, and contributes to the development of vascular dementia. 1 Several clinical studies, such as Perindopril Protection Against Recurrent Stroke Study, Systolic Hypertension in Europe, and Study on Cognition and Prognosis in the Elderly, have shown that antihypertensive drug treatment is associated with reduced cognitive decline. 2-4 However, it is not still clear which classes of antihypertensive drugs provide greater benefits than others.Activation of the renin-angiotensin system (RAS) plays major roles in elevated blood pressure and the development of cerebrovascular disorders. All of the components of the classic RAS have been identified in the brain. 5,6 Recent clinical trials, such as the Losartan Intervention for Endpoint Reduction in Hypertensive Study, Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention, and...

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“…31 Furthermore, our previous report demonstrated that treatment with an ARB, valsartan, increased capillary density in the brain. 32 Therefore, we speculated that treatment with an even lower dose of telmisartan would increase CBF, with PPAR-␥ activation as well as AT 1 receptor blockade.…”

Section: Discussionmentioning

confidence: 99%