PRESSOR EFFECTS OF FATTY ACIDS

本项目将检验肝细胞游离脂肪酸 水平是血压的重要决定因素。 的假设 预测内脏或腹部肥胖与 高血压是因为内脏脂肪细胞释放脂肪酸， 门脉循环，导致肝脂肪酸显著增加 内容 相比之下，下半身肥胖的人， 对于低血压者，应具有较低的肝脂肪酸水平。 我们实验室的初步数据表明， 链游离脂肪酸进入大鼠导致血压升高， 肝脏游离脂肪酸水平升高。 该项目将以 高血压与脂肪酸输注相关， 肝脂肪酸含量是否是血液中 压力 将对清醒的、装有仪器的大鼠进行研究。 脂肪酸输注 溶液或载体进入全身和门静脉循环将是 评估其对血压的影响。 全身 以及对脂肪酸高血压的局部血流动力学反应， 确定和相关的肾脏和激素的变化将是 测定了 剂量反应曲线，以建立 将确定脂肪酸输注量和升压反应， 全身和门静脉输注。 在单独的实验中，血浆和 与高血压反应相关的脂肪酸组织水平 将被确定。 不同长链和中链脂肪酸的输液 酸将进行评估是否饱和或链长的 注入的脂肪酸影响升压反应。 长期 然后进行脂肪酸输注以确定是否 可诱发慢性高血压。 为了确定脂肪酸和胰岛素之间的关系 使用胰岛素最小模型的体内研究 敏感性将得到加强。 胰岛素敏感性在脂肪酸 输注期间的灵敏度将与溶媒输注期间的灵敏度进行比较。 在 将进行体外研究以评估脂肪酸对 血管反应性 此外，来自体内处理的动物的血管 将脂肪酸输注的血管与对照血管进行比较 动物 禁食对瘦型和肥胖型动物肝脏的影响 将测定脂肪酸含量和血压。 脂肪酸 输注和依托莫西将用于维持肝脏脂肪酸水平 在三天禁食期间喂食动物中观察到的范围内。 这些研究 将决定维持肝脏脂肪酸水平是否能防止 降低血压和增加胰岛素敏感性， 通常发生在禁食时。 烟酸将用于减少 肥胖、高血压大鼠肝脏游离脂肪酸含量及其对血液的影响 将测定压力和肝脏FFA含量。 这些研究应该描述脂肪酸和 深入了解脂肪酸在高血压中的作用， 腹部肥胖

This project will test the hypothesis that hepatocellular free fatty acid levels are an important determinant of blood pressure. The hypothesis predicts that visceral or abdominal obesity is strongly associated with hypertension because visceral fat cells release their fatty acids into the portal circulation, causing a marked increase in hepatic fatty acid content. By contrast, individuals with lower body obesity, whose risk for hypertension is low, should have lower hepatic fatty acid levels. Preliminary data from our laboratory demonstrate that infusion of long chain free fatty acids into rats results in elevated blood pressure and increased hepatic free fatty acid levels. This project will characterize the hypertension associated with fatty acid infusion and determine whether hepatic fatty acid content is a significant determinant of blood pressure. Conscious, instrumented rats will be studies. Infusions of fatty acid solution or vehicle into the systemic and portal circulations will be assessed with regard to their effects on blood pressure. The systemic and regional hemodynamic responses to fatty acid hypertension will be determined and the associated renal and hormonal changes will be measured. Dose response curves to establish the relationship between amount of fatty acid infused and pressor response will be determined for both systemic and portal infusions. In separate experiments, plasma and tissue levels of fatty acids associated with the hypertensive response will be determined. Infusions of different long and medium chain fatty acids will be performed to assess whether saturation or chain length of the infused fatty acid influences the pressor response. Long term infusions of fatty acids will then be performed to ascertain whether chronic hypertension can be induced. In order to determine the relationship between fatty acids and insulin resistance, in vivo studies using the minimal model of insulin sensitivity will be undertaken. Insulin sensitivity during fatty acid infusion will be compared with sensitivity during vehicle infusion. In vitro studies will be performed to assess the effects of fatty acids on vascular reactivity. In addition, vessels from animals treated in vivo with fatty acid infusion will be compared to vessels from control animals. The effect of fasting in lean and obese animals on hepatic fatty acid content and blood pressure will be determined. Fatty acid infusions and etomoxir will be used to maintain hepatic fatty acid levels in the range seen in fed animals during a three day fast. These studies will determine whether maintaining hepatic fatty acid levels prevents the decrease in blood pressure and the increase in insulin sensitivity which normally occurs with fasting. Nicotinin acid will be used to decrease hepatic FFA content in obese, hypertensive rats, and its effects on blood pressure and hepatic FFA content will be determined. These studies should characterize the pressor effects fatty acids and provide insight into the role of fatty acids in the hypertension of abdominal obesity.