Nagae Ai, Fujita Megumi, Kawarazaki Hiroo, Matsui Hiromitsu, Ando Katsuyuki, Fujita Toshiro
Department of Nephrology and Endocrinology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Circulation. 2009 Feb 24;119(7):978-86. doi: 10.1161/CIRCULATIONAHA.108.824730. Epub 2009 Feb 9.
Obesity is one of the major risk factors for cardiovascular disease and is often associated with increased oxidative stress and sympathoexcitation. We have already suggested that increased oxidative stress in the brain modulates the sympathetic regulation of arterial pressure in salt-sensitive hypertension, which is often associated with obesity. The present study was performed to determine whether oxidative stress could mediate central sympathoexcitation in the initial stage of obesity-induced hypertension.
Four-week-old male Sprague-Dawley rats were fed a high-fat (45% kcal as fat) or low-fat (10% kcal as fat) diet for 6 weeks. Fat loading elicited hypertension and sympathoexcitation, along with visceral obesity. In urethane-anesthetized and artificially ventilated rats, arterial pressure and renal sympathetic nerve activity decreased in a dose-dependent fashion when 53 or 105 mumol/kg tempol, a membrane-permeable superoxide dismutase mimetic, was infused into the lateral cerebral ventricle. Central tempol reduced arterial pressure and renal sympathetic nerve activity to a significantly greater extent in high-fat diet-fed hypertensive rats than in low-fat diet-fed normotensive rats. Intracerebroventricular apocynin or diphenyleneiodonium, a reduced NADPH oxidase inhibitor, also elicited markedly greater reductions in arterial pressure and renal sympathetic nerve activity in the high-fat diet-fed rats. In addition, fat loading increased NADPH oxidase activity and NADPH oxidase subunit p22(phox), p47(phox), and gp91(phox) mRNA expression in the hypothalamus.
In obesity-induced hypertension, increased oxidative stress in the brain, possibly via activation of NADPH oxidase, may contribute to the progression of hypertension through central sympathoexcitation.
肥胖是心血管疾病的主要危险因素之一，常与氧化应激增加和交感神经兴奋有关。我们已经提出，脑内氧化应激增加会调节盐敏感性高血压患者的动脉压力交感神经调节，而盐敏感性高血压常与肥胖相关。本研究旨在确定氧化应激是否能在肥胖诱导的高血压初期介导中枢交感神经兴奋。
给4周龄雄性Sprague-Dawley大鼠喂食高脂（脂肪占45%千卡）或低脂（脂肪占10%千卡）饮食6周。脂肪负荷导致高血压、交感神经兴奋以及内脏肥胖。在氨基甲酸乙酯麻醉并人工通气的大鼠中，当向侧脑室注入53或105 μmol/kg tempol（一种可透过细胞膜的超氧化物歧化酶模拟物）时，动脉血压和肾交感神经活动呈剂量依赖性降低。与低脂饮食喂养的正常血压大鼠相比，中枢tempol在高脂饮食喂养的高血压大鼠中能更显著地降低动脉血压和肾交感神经活动。脑室内注射阿朴吗啡或二苯基碘鎓（一种还原型NADPH氧化酶抑制剂），在高脂饮食喂养的大鼠中也能更显著地降低动脉血压和肾交感神经活动。此外，脂肪负荷增加了下丘脑NADPH氧化酶活性以及NADPH氧化酶亚基p22(phox)、p47(phox)和gp91(phox)的mRNA表达。
在肥胖诱导的高血压中，脑内氧化应激增加，可能通过激活NADPH氧化酶，可能通过中枢交感神经兴奋促进高血压的进展。
