Ying Chen-Jiang, Noguchi Takanori, Aso Hiroaki, Ikeda Katsumi, Yamori Yukio, Nara Yasuo
Department of Pharmacy, School of Pharmacy, Shujitsu University, Okayama, Japan.
Hypertens Res. 2008 Sep;31(9):1821-7. doi: 10.1291/hypres.31.1821.
Stroke-prone spontaneously hypertensive rats (SHRSP/Izm) are salt sensitive: they develop severe hypertension and die of stroke within a short time after salt loading. We studied the role of cytochrome P-450 (CYP) isoforms in the brain and the effect of clofibrate to investigate the mechanism of salt sensitive stroke-proneness in SHRSP/Izm. Male SHRSP/Izm at 9 weeks of age were fed a regular diet with or without 0.25% clofibrate and given a 1% NaCl solution for drinking water for 10 d. The expression levels of CYP4A1, 2C11, and 2C23 were measured by Western blotting. Cerebral blood flow was measured with a laser Doppler method and blood vessel diameters were measured under microscopic observation. SHRSP/Izm died within 60 d after salt loading; however, clofibrate prolonged the survival (mean life span, 33+/-7 vs. 215+/-23 d, p<0.0001) without significant attenuation of the severe hypertension. CYP4A1 and CYP2C11 expression levels were lower in SHRSP/Izm than those in age-matched male spontaneously hypertensive rats (SHR/Izm) in the cerebral cortex (p<0.05). Salt loading down-regulated CYP2C11 expression in the cerebral cortex of SHRSP/Izm (p<0.05). No obvious change in cerebral CYP4A1 was observed in either salt-loaded SHRSP/Izm or SHR/Izm. Clofibrate significantly up-regulated the expression of cerebral CYP2C11 and significantly attenuated its salt-induced suppression (p<0.05). Additionally, clofibrate significantly increased blood vessel diameters (p<0.01) and cerebral blood flow (p<0.0001). CYP2C11 plays an important role in regulating cerebral blood flow and, as a result, in preventing stroke in the salt-sensitive stroke-prone SHRSP/Izm.
易患中风的自发性高血压大鼠（SHRSP/Izm）对盐敏感：它们会发展为严重高血压，并在高盐饮食后短时间内死于中风。我们研究了细胞色素P-450（CYP）同工型在大脑中的作用以及氯贝丁酯的影响，以探讨SHRSP/Izm中盐敏感性中风易感性的机制。9周龄的雄性SHRSP/Izm大鼠分别喂食含或不含0.25%氯贝丁酯的常规饮食，并给予1%氯化钠溶液作为饮用水，持续10天。通过蛋白质免疫印迹法测量CYP4A1、2C11和2C23的表达水平。用激光多普勒法测量脑血流量，并在显微镜下观察测量血管直径。SHRSP/Izm大鼠在高盐饮食后60天内死亡；然而，氯贝丁酯延长了其存活时间（平均寿命，33±7天对215±23天，p<0.0001），且未显著减轻严重高血压。在大脑皮层中，SHRSP/Izm大鼠的CYP4A1和CYP2C11表达水平低于年龄匹配的雄性自发性高血压大鼠（SHR/Izm）（p<0.05）。高盐饮食下调了SHRSP/Izm大鼠大脑皮层中CYP2C11的表达（p<0.05）。在高盐饮食的SHRSP/Izm大鼠或SHR/Izm大鼠中，均未观察到大脑CYP4A1有明显变化。氯贝丁酯显著上调了大脑CYP2C11的表达，并显著减轻了其盐诱导的抑制作用（p<0.05）。此外，氯贝丁酯显著增加了血管直径（p<0.01）和脑血流量（p<0.0001）。CYP2C11在调节脑血流量中起重要作用，因此在预防盐敏感性中风易感性的SHRSP/Izm大鼠中风方面发挥作用。
