Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Stroke. 2011 Sep;42(9):2571-7. doi: 10.1161/STROKEAHA.110.609834. Epub 2011 Jul 28.
It is well-established that hypertension leads to endothelial dysfunction in the cerebral artery. Recently, cilostazol has been used for the secondary prevention of ischemic stroke. Among antiplatelet drugs, phosphodiesterase inhibitors including cilostazol have been shown to have protective effects on endothelial cells. The aim of the present study is to investigate the effects of cilostazol and aspirin on endothelial nitric oxide synthase (eNOS) phosphorylation in the cerebral cortex, endothelial function, and infarct size after brain ischemia in spontaneously hypertensive rats (SHR).
Five-week-old male SHR received a 5-week regimen of chow containing 0.1% aspirin, 0.1% cilostazol, 0.3% cilostazol, or the vehicle control. The levels of total and Ser(1177)-phosphorylated eNOS protein in the cerebral cortex were evaluated by Western blot. To assess the contribution of eNOS in maintaining cerebral blood flow, we monitored cerebral blood flow by laser-Doppler flowmetry after L-N(5)-(1-iminoethyl)ornithine infusion. Additionally, we evaluated residual microperfusion using fluorescence-labeled serum protein and infarct size after transient focal brain ischemia.
In SHR, the blood pressure and heart rate were similar among the groups. Cilostazol-treated SHR had a significantly higher ratio of phospho-eNOS/total eNOS protein than vehicle-treated and aspirin-treated SHR. Treating with cilostazol, but not aspirin, significantly improved cerebral blood flow response to L-N(5)-(1-iminoethyl)ornithine. Cilostazol also increased residual perfusion of the microcirculation and reduced brain damage after ischemia compared to vehicle control and aspirin.
These findings indicate that cilostazol, but not aspirin, can attenuate ischemic brain injury by maintaining endothelial function in the cerebral cortex of SHR.
高血压可导致脑动脉内皮功能障碍，这一点已得到充分证实。最近，西洛他唑已被用于缺血性脑卒中的二级预防。在抗血小板药物中，磷酸二酯酶抑制剂（包括西洛他唑）已被证明对内皮细胞具有保护作用。本研究旨在探讨西洛他唑和阿司匹林对自发性高血压大鼠（SHR）脑缺血后大脑皮质内皮型一氧化氮合酶（eNOS）磷酸化、内皮功能和梗死面积的影响。
5 周龄雄性 SHR 给予含 0.1%阿司匹林、0.1%西洛他唑、0.3%西洛他唑或载体对照的饲料 5 周。采用 Western blot 法检测大脑皮质总 eNOS 和 Ser(1177)磷酸化 eNOS 蛋白水平。通过激光多普勒血流仪监测 L-N（5）-（1-亚氨基乙基）鸟氨酸输注后大脑血流，评估 eNOS 在维持脑血流中的作用。此外，通过荧光标记血清蛋白评估残余微血管灌注，通过短暂局灶性脑缺血评估梗死面积。
SHR 各组间血压和心率相似。与 vehicle 组和阿司匹林组相比，西洛他唑治疗的 SHR 磷酸化 eNOS/总 eNOS 蛋白比值显著升高。与 vehicle 组和阿司匹林组相比，西洛他唑治疗显著改善了 L-N（5）-（1-亚氨基乙基）鸟氨酸引起的大脑血流反应。与 vehicle 对照组和阿司匹林组相比，西洛他唑还增加了微循环的残余灌注，并减少了缺血后的脑损伤。
这些发现表明，西洛他唑而非阿司匹林可通过维持 SHR 大脑皮质内皮功能来减轻缺血性脑损伤。
