Inoue N, Ohara Y, Fukai T, Harrison D G, Nishida K
Cardiology Division, Emory University School of Medicine, Atlanta, Georgia, USA.
Am J Med Sci. 1998 Apr;315(4):242-7. doi: 10.1097/00000441-199804000-00005.
Recent data indicate that hypercholesterolemia increases endothelial superoxide anion (.O2-) production, and that this diminishes the bioactivity of nitric oxide produced in the endothelium. Probucol, a drug commonly employed for treatment of hypercholesterolemia, has antioxidant properties and inhibits oxidation of low density lipoproteins in vitro. We tested the hypothesis that probucol would decrease vascular .O2- production and improve endothelium-dependent relaxations in cholesterol-fed rabbits. Rabbits were divided into four groups: 1) a control group fed a standard diet; 2) a probucol group fed a standard diet containing 0.3% probucol; 3) a hypercholesterolemic group fed a diet containing 0.5% cholesterol; 4) a hypercholesterolemia-probucol group fed a diet containing 0.5% cholesterol and 0.3% probucol. The cholesterol-rich diet markedly increased plasma total cholesterol level and lipid peroxidation in the plasma, as reflected by thiobarbituric acid-reactive substances (TBARS). This concentration of probucol did not lower plasma cholesterol, but markedly reduced TBARS in the plasma of cholesterol-fed rabbits. Aortic segments from cholesterol-fed rabbits produced 1.8-fold more .O2- (assessed by lucigenin-enhanced chemiluminescence) and decreased endothelium-dependent vascular relaxations to acetylcholine compared to vessels from normal rabbits. In cholesterol-fed rabbits, probucol treatment normalized both .O2- production and endothelium-dependent relaxations to acetylcholine. In control rabbits, probucol had no effect on either of these parameters. We conclude that probucol treatment may prevent .O2(-)-induced inactivation of endothelium-derived nitric oxide and reduce vascular oxidant stress via reducing the level of .O2-.
近期数据表明，高胆固醇血症会增加内皮超氧阴离子（·O₂⁻）的生成，进而降低内皮产生的一氧化氮的生物活性。普罗布考是一种常用于治疗高胆固醇血症的药物，具有抗氧化特性，在体外可抑制低密度脂蛋白的氧化。我们检验了这样一个假说：普罗布考会减少胆固醇喂养兔的血管·O₂⁻生成，并改善内皮依赖性舒张功能。将兔子分为四组：1）喂食标准饮食的对照组；2）喂食含0.3%普罗布考标准饮食的普罗布考组；3）喂食含0.5%胆固醇饮食的高胆固醇血症组；4）喂食含0.5%胆固醇和0.3%普罗布考饮食的高胆固醇血症 - 普罗布考组。富含胆固醇的饮食显著提高了血浆总胆固醇水平以及血浆中的脂质过氧化，这可通过硫代巴比妥酸反应性物质（TBARS）反映出来。这种浓度的普罗布考并未降低血浆胆固醇，但显著降低了胆固醇喂养兔血浆中的TBARS。与正常兔的血管相比，胆固醇喂养兔的主动脉段产生的·O₂⁻（通过光泽精增强化学发光评估）多1.8倍，且对乙酰胆碱的内皮依赖性血管舒张功能降低。在胆固醇喂养兔中，普罗布考治疗使·O₂⁻生成以及对乙酰胆碱的内皮依赖性舒张功能均恢复正常。在对照兔中，普罗布考对这两个参数均无影响。我们得出结论，普罗布考治疗可能通过降低·O₂⁻水平来预防·O₂⁻诱导的内皮源性一氧化氮失活，并减轻血管氧化应激。
