Pharmacology Division, ISF College of Pharmacy, Moga, 142 001, Punjab, India.
Cardiovasc Toxicol. 2010 Sep;10(3):227-38. doi: 10.1007/s12012-010-9086-7.
The present study investigated the effect of fenofibrate, an agonist of PPAR-alpha, in nicotine- and sodium arsenite-induced vascular endothelial dysfunction (VED) in rats. Nicotine (2 mg/kg/day, i.p., 4 weeks) and sodium arsenite (1.5 mg/kg/day, i.p., 2 weeks) were administered to produce VED in rats. The scanning electron microscopy study in thoracic aorta revealed that administration of nicotine or sodium arsenite impaired the integrity of vascular endothelium. Further, administration of nicotine or sodium arsenite significantly decreased serum and aortic concentrations of nitrite/nitrate and subsequently reduced acetylcholine-induced endothelium-dependent relaxation. Moreover, nicotine or sodium arsenite produced oxidative stress by increasing serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide generation. However, treatment with fenofibrate (30 mg/kg/day, p.o.) or atorvastatin (30 mg/kg/day p.o., a standard agent) significantly prevented nicotine- and sodium arsenite-induced VED and oxidative stress by improving the integrity of vascular endothelium, increasing the concentrations of serum and aortic nitrite/nitrate, enhancing the acetylcholine-induced endothelium-dependent relaxation and decreasing serum TBARS and aortic superoxide anion generation. Conversely, co-administration of L-NAME (25 mg/kg/day, i.p.), an inhibitor of nitric oxide synthase, markedly attenuated these vascular protective effects of fenofibrate. The administration of nicotine or sodium arsenite altered the lipid profile by increasing serum cholesterol and triglycerides and consequently decreasing high-density lipoprotein levels, which were significantly prevented by treatment with fenofibrate or atorvastatin. It may be concluded that fenofibrate improves the integrity and function of vascular endothelium, and the vascular protecting potential of fenofibrate in preventing the development of nicotine- and sodium arsenite-induced VED may be attributed to its additional properties (other than lipid lowering effect) such as activation of eNOS and generation of NO and consequent reduction in oxidative stress.
本研究探讨了 PPAR-α激动剂非诺贝特对尼古丁和亚砷酸钠诱导的大鼠血管内皮功能障碍（VED）的影响。给予尼古丁（2 mg/kg/天，腹腔注射，4 周）和亚砷酸钠（1.5 mg/kg/天，腹腔注射，2 周）以在大鼠中产生 VED。胸主动脉扫描电子显微镜研究显示，给予尼古丁或亚砷酸钠可损害血管内皮的完整性。此外，给予尼古丁或亚砷酸钠可显著降低血清和主动脉中亚硝酸盐/硝酸盐的浓度，随后降低乙酰胆碱诱导的内皮依赖性舒张。此外，尼古丁或亚砷酸钠通过增加血清硫代巴比妥酸反应物质（TBARS）和主动脉超氧化物生成来产生氧化应激。然而，用非诺贝特（30 mg/kg/天，口服）或阿托伐他汀（30 mg/kg/天，口服，标准药物）治疗可显著预防尼古丁和亚砷酸钠引起的 VED 和氧化应激，方法是改善血管内皮的完整性，增加血清和主动脉中亚硝酸盐/硝酸盐的浓度，增强乙酰胆碱诱导的内皮依赖性舒张，并降低血清 TBARS 和主动脉超氧阴离子生成。相反，给予一氧化氮合酶抑制剂 L-NAME（25 mg/kg/天，腹腔注射）可显著减弱非诺贝特的这些血管保护作用。给予尼古丁或亚砷酸钠会通过增加血清胆固醇和甘油三酯并降低高密度脂蛋白水平来改变脂质谱，用非诺贝特或阿托伐他汀治疗可显著预防这种变化。可以得出结论，非诺贝特可改善血管内皮的完整性和功能，非诺贝特预防尼古丁和亚砷酸钠引起的 VED 的血管保护潜力可能归因于其额外的特性（除了降低血脂作用之外），如 eNOS 的激活、NO 的产生和随后的氧化应激减少。
