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.
Showing the most recent 10 out of 291 publications
