MECHANISMS OF ENDOTHELIAL DYSFUNCTION IN OBESITY

肥胖症是一个独立的危险因素， 心血管疾病，肥胖症的患病率正在增加， 这个国家肥胖如何导致心血管疾病尚不清楚。 肥胖与内皮功能受损有关， 在心血管疾病的发病机制中起关键作用。那个女人 本提案的长期目标是调查 肥胖/胰岛素抵抗和内皮依赖性血管舒张之间的关系。 我们建议的具体目标是研究内皮细胞的变化， 响应于1）提高游离脂肪酸水平，2）抑制 交感神经系统活动，和3）改善胰岛素 阻力将通过评估腿部来确定内皮功能 响应于股动脉内输注 内皮依赖性血管扩张剂氯化乙酰甲胆碱， 非依赖性血管扩张剂硝普钠和 内皮源性一氧化氮NG-单甲基-L-精氨酸（L-NMMA）。免费 脂肪酸水平将通过全身输注脂内脂来提高， 肝素交感神经系统的活动将受到抑制， 股动脉注射酚妥拉明一种α肾上腺素受体阻滞剂 胰岛素抵抗将通过减肥或给药来改善 胰岛素增敏剂曲格列酮。这些研究将有助于更好地 了解肥胖/胰岛素抵抗对内皮细胞的影响 功能，并可能有助于设计治疗策略，以降低风险 心血管疾病的风险。

Obesity is an independent risk factor for the development of cardiovascular disease, and the prevalence of obesity is increasing in this country. How obesity causes cardiovascular disease is not understood. Obesity is associated with impaired endothelial function which may play a crucial role in the pathogenesis of cardiovascular disease. The broad, long term objective of this proposal is to investigate the relationship between obesity/insulin resistance and endothelium dependent vasodilation. The specific aims of our proposal are to study changes in endothelial function in response to 1) raising free fatty acid levels, 2) inhibition of sympathetic nervous system activity, and 3) amelioration of insulin resistance. Endothelial function will be determined by assessing the leg blood flow increments in response to intrafemoral artery infusion of the endothelium dependent vasodilator methacholine chloride, the endothelium independent vasodilator sodium nitroprusside, and the inhibitor of endothelium derived nitric oxide NG-monomethyl-L-arginine (L-NMMA). Free fatty acid levels will be raised by systemic infusion of intralipids with heparin. The sympathetic nervous system activity will be inhibited by a femoral artery infusion of phentolamine, an alpha adrenoreceptor blocker. Insulin resistance will be ameliorated by weight loss or by administration of the insulin sensitizer troglitazone. These studies will help to better understand the effect of obesity/insulin resistance on endothelial function and may help to design treatment strategies to decrease the risk for cardiovascular diseases in this population.