Sorrogate biomarker for evaluation of cardiovascular drugs

1. 在模拟代谢综合征/胰岛素敏感性的人类实验模型中，FFA诱导内皮功能障碍及其在评估药物抗动脉粥样硬化作用中的可能作用。游离脂肪酸（FFA）水平升高会损害人类内皮依赖性血管舒张，这可能与胰岛素抵抗患者内皮功能障碍的发生有病理生理上的关系。我们研究了抑制肾素-血管紧张素系统（RAS）对ffa诱导的内皮功能障碍的影响。在没有L-NMMA的情况下，FFA升高显著降低了对乙酰胆碱的反应。但对L-NMMA的反应没有影响，而FFA对硝普塞的反应没有影响。单剂量氯沙坦或培哚普利完全预防ffa诱导的内皮功能障碍。维生素C还能预防脂肪酸诱导的内皮功能障碍。脂质/肝素输注导致的FFA水平升高，可能在一定程度上模拟胰岛素抵抗患者的异常脂质谱……更重要的是，通过RAS激活和可能导致的氧化应激，在人类中引起内皮功能障碍。我们的研究结果提示了在高FFA水平患者中抑制RAS的治疗原理。我们在大鼠和离体血管中的另一项研究表明，ffa诱导的NADPH氧化酶亚基过表达和ROS的产生可能参与肥胖ZDF大鼠的内皮功能障碍，这可能受到pitavastate或NADPH氧化酶抑制剂的保护。我们评估了阿卡波糖对餐后糖脂代谢和内皮功能的影响。糖耐量受损的患者在试验餐前接受单剂量100mg阿卡波糖或安慰剂的交叉设计。测量代谢参数，包括血清葡萄糖、甘油三酯和残余脂蛋白，并通过测量试验餐前后反应性充血期间前臂血流的变化来评估内皮功能。糖耐量受损的患者代谢参数显著升高，内皮功能显著受损，而健康受试者则无此现象。单剂量阿卡波糖显著抑制代谢参数升高，防止糖耐量受损患者餐后内皮功能障碍。我们的研究结果表明，阿卡波糖可以改善餐后代谢异常，从而改善糖耐量受损受试者的内皮功能。另一方面，正常志愿者的餐后内皮功能仅在高脂肪饮食后受损，而在高碳水化合物和标准测试餐后则没有受损。由于高脂肪餐后的内皮功能障碍与游离脂肪酸浓度密切相关，健康受试者的餐后状态可能主要通过急性高脂血症发生。少

1. FFA induced endothelial dysfunction in humans experimental model mimicking metabolic syndrome/insulin sensitivity and possible roles in evaluating anti atherosclerotic effect of drugs. An elevated free fatty acid (FFA) level impairs endothelium-dependent vasodilation in humans, which may be pathophysiologically relevant to the development of endothelial dysfunction in patients with insulin resistance. We investigated the effect of inhibition of the renin-angiotensin system (RAS) on FFA-induced endothelial dysfunction. Elevated FFA significantly reduced the response to acetylcholine without L-NMMA., but not the response with L-NMMA, whereas FFA did not affect the response to nitroprusside. The single dose of either losartan or perindopril completely prevented FFA-induced endothelial dysfunction. Vitamin C also prevented FFA-induced endothelial dysfunction. Elevated FFA levels by lipid/heparin infusion, which may partly mimic the abnormal lipid profile in patients with insulin resista … More nce, caused endothelial dysfunction via RAS activation and the presumably resultant oxidative stress in humans. Our results suggest the therapeutic rationale for RAS inhibition inpatients with high FFA levels. Our other study in rats and isolated vessels suggest that FFA-induced NADPH oxidase subunit overexpression and ROS production could be involved in the endothelial dysfunction seen in obese ZDF rats, and this could be protected by pitavastatia or NADPH oxidase inhibitors.2. Postprandial endothelial dysfunction and alpha glucosidase inhibitor We evaluated effect of acarbose on post-prandial glucose and lipid metabolism and endothelial function. Patients with impaired glucose tolerance received the single dose of 100mg of acarbose or placebo in cross-over design before test meal. Metabolic parameters including serum glucose, triglyceride, and remnant lipoprotein were measured and endothelial function was evaluated by the measurement of changes in forearm blood flow during reactive hyperemia before and after the test meal. There were significant elevation in metabolic parameters and endothelial function was significantly impaired in patients with impaired glucose tolerance but not in healthy subjects. The single dose acarbose significantly inhibited the elevation in metabolic parameters and prevented post-prandial endothelial dysfunction in patients with impaired-glucose tolerance. Our results suggest that acarbose may improve post--prandial metabolic abnormalities and, consequently, improve endothelial function in subjects with impaired glucose tolerance. On the other hand, Postprandial endothelial function in normal volunteers was impaired only after high-fat diet, but not after high-carbohydrate and standard test meal. Since such endothelial dysfunction after high-fat meal was closely correlated with FFA concentrations, postprandial 'state could be hazardous mostly through acute hyperlipacidenia in healthy subjects. Less