Development of methods of clinical experiment and biomarkers for the assessment of cardiovascular drugs

1. 我们评估了通过血流介导的血管舒张测量内皮功能和通过脉搏波速度测量主动脉硬度的方法。我们还标准化了血流介导的血管舒张方法，这在研究人员之间存在差异。我们估计了葡萄糖钳技术测量的胰岛素敏感性与血清代谢标志物（如脂联素）的相关性。建立了评估游离脂肪酸升高对白细胞血管紧张素II形成活性、内皮功能、胰岛素敏感性和白细胞活化影响的人体实验方法。我们在这个模拟内脏脂肪肥胖的脂质负荷实验中测试了几种心血管药物的作用。我们发现FFA升高部分通过白细胞肾素-血管紧张素系统引起内皮功能障碍、微循环功能障碍（白细胞激活）和胰岛素抵抗。该实验方案可用于抗动脉粥样硬化药物的评估。白细胞血管紧张素II形成活性可能是与血管功能障碍相关的内脏脂肪肥胖的生物标志物。

1. We assessed methods of the measurement of endothelial function by flow-mediated vasodilatation and of aortic stiffness by pulse wave velocity. We also standardized the method of flow-mediated vasodilatation, which had varied among researchers.2. We estimated the association of insulin sensitivity measured by glucose clamp technique and serum metabolic marker such as adiponectin.3. The methods of experiments in humans for the assessment of effects of elevated free fatty acids on angiotensin II forming activity in leukocytes, endothelial function, insulin sensitivity, and leukocyte activation was established. We tested effects of several cardiovascular drugs in this lipid loading experiment mimicking visceral fat obesity. We found that elevated FFA caused endothelial dysfunction, microcirculatory dysfunction (leukocyte activation), insulin resistance partly via leukocyte renin-angiotensin system. This experimental protocol may be useful for the assessment of anti-atherosclerotic drugs. Leukocyte angiotensin II forming activity could be a biomarker for visceral fat obesity linking to vascular dysfunction.