Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
J Neurosci Res. 2010 Oct;88(13):2889-98. doi: 10.1002/jnr.22441.
Hypertension reduces endothelial nitric oxide synthase (eNOS) expression and leads to endothelial dysfunction. However, few studies have demonstrated the influences of hypertension on eNOS function in the cerebral cortex. The present study investigates the influences of hypertension on endothelial function in the cerebral cortex and the protective effects of antihypertensive agents against brain ischemia through the preservation of endothelial function. Five- and ten-week-old male Wistar rats and spontaneously hypertensive rats (SHR) were used for experiments. Five-week-old SHR received olmesartan, hydralazine, or vehicle for 5 weeks in drinking water. eNOS activation in the cerebral cortex was evaluated by analyzing levels of total and Ser(1177)-phosphorylated eNOS protein by Western blot. Blood pressure of 10-week-old SHR without treatment was clearly high, and the ratio of phospho-eNOS/total eNOS protein was significantly low. Five-week treatment with olmesartan or hydralazine suppressed the elevation of blood pressure and the reduction of phosphorylated eNOS-Ser(1177) in SHR, and olmesartan was more effective in maintaining phosphorylation of eNOS-Ser(1177) than hydralazine. To assess the contribution of eNOS to maintaining cerebral blood flow (CBF), we monitored CBF by laser-Doppler flowmetry after L-N(5)-(1-iminoethyl)ornithine (L-NIO) infusion. CBF response to L-NIO was preserved in olmesartan-treated SHR but not in hydralazine-treated SHR. Furthermore, infarct volume 48 hr after transient focal brain ischemia in olmesartan-treated SHR was significantly reduced compared with vehicle-treated SHR. These findings indicate that chronic prehypertensive treatment with olmesartan could attenuate brain ischemic injury through the maintenance of endothelial function in the cerebral cortex in SHR.
高血压会降低内皮型一氧化氮合酶（eNOS）的表达，导致内皮功能障碍。然而，很少有研究表明高血压对大脑皮质中 eNOS 功能的影响。本研究通过保存内皮功能，探讨高血压对大脑皮质内皮功能的影响，以及抗高血压药物对脑缺血的保护作用。实验采用 5 周龄和 10 周龄雄性 Wistar 大鼠和自发性高血压大鼠（SHR）。5 周龄 SHR 连续 5 周通过饮用含药（奥美沙坦、肼屈嗪或对照溶剂）的水进行干预。通过 Western blot 分析总 eNOS 和 Ser(1177)磷酸化 eNOS 蛋白的水平来评估大脑皮质中 eNOS 的激活情况。未经治疗的 10 周龄 SHR 的血压明显升高，磷酸化 eNOS/总 eNOS 蛋白的比值显著降低。奥美沙坦或肼屈嗪 5 周的治疗可抑制 SHR 血压升高和 eNOS-Ser(1177)磷酸化减少，且奥美沙坦比肼屈嗪更能维持 eNOS-Ser(1177)的磷酸化。为了评估 eNOS 对维持脑血流（CBF）的贡献，我们通过激光多普勒血流仪监测 L-N(5)-(1-亚氨基乙基)鸟氨酸（L-NIO）输注后 CBF 的变化。奥美沙坦治疗的 SHR 中 L-NIO 诱导的 CBF 反应得到了保留，但肼屈嗪治疗的 SHR 中未观察到这种反应。此外，奥美沙坦治疗的 SHR 与溶剂处理的 SHR 相比，短暂性局灶性脑缺血后 48 小时的梗死体积明显减小。这些发现表明，在 SHR 中，慢性高血压前期治疗用奥美沙坦可能通过维持大脑皮质的内皮功能来减轻脑缺血损伤。
