An Angiotensin II Type 1 Receptor Blocker Can Preserve Endothelial Function and Attenuate Brain Ischemic Damage in Spontaneously Hypertensive Rats
An Angiotensin II Type 1 Receptor Blocker Can Preserve Endothelial Function and Attenuate Brain Ischemic Damage in Spontaneously Hypertensive Rats
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DOI：
10.1002/jnr.22441
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发表时间：
2010-10-01
影响因子：
4.2
通讯作者：
Kitagawa, Kazuo
中科院分区：
文献类型：
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作者：
Oyama, Naoki;Yagita, Yoshiki;Kitagawa, Kazuo
高血压降低内皮一氧化氮合酶（eNOS）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层eNOS功能的影响。本研究探讨高血压对大脑皮层内皮功能的影响，以及降压药通过维持内皮功能对脑缺血的保护作用。实验采用5、10周龄雄性Wistar大鼠和自发性高血压大鼠（SHR）。5周大的SHR在饮用水中给予奥美沙坦、肼嗪或载药5周。Western blot分析eNOS总磷酸化蛋白和丝氨酸（1177）磷酸化蛋白水平，评价eNOS在大脑皮层的激活情况。未经治疗的10周龄SHR血压明显偏高，磷酸化eNOS/总eNOS蛋白比值明显偏低。奥美沙坦或肼嗪治疗5周可抑制SHR患者血压升高和eNOS-Ser（1177）磷酸化水平的降低，且奥美沙坦在维持eNOS-Ser（1177）磷酸化水平方面比肼嗪更有效。为了评估eNOS对维持脑血流（CBF）的贡献，我们用激光多普勒血流仪监测L-N-5-（1-亚氨基乙基）鸟氨酸（L-NIO）输注后的脑血流（CBF）。奥美沙坦处理的SHR保留了对L-NIO的CBF反应，而肼处理的SHR则没有。此外，奥美沙坦治疗的SHR在短暂局灶性脑缺血48小时后的梗死体积明显低于药物治疗的SHR。这些结果表明，慢性高血压前期治疗奥美沙坦可以通过维持SHR大脑皮层内皮功能来减轻脑缺血损伤。(C) 2010 Wiley-Liss, Inc。
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. (C) 2010 Wiley-Liss, Inc.