|Nitric oxide (NO) plays an essential role in the regulation of numerous biological processes. Its bioavailability is assured by a well regulated balance between NO generation and NO removal. Disruptions in this balance contribute to the pathogenesis of various diseases, including hypertension, Alzheimer? disease, diabetes mellitus and arthritis. Many factors contribute to the maintenance of NO bioavailability by controlling nitric oxide synthase (NOS) expression, NOS activity, the availability of substrates and cofactors involved in the generation of NO by NOS, levels of reactive oxygen species (ROS), and the formation and mobilization of NO reservoirs. Dietary factors have a significant impact on NO bioavailability. Of the major dietary constituents, fats have been the most extensively studied. The long-term consumption of high fat diets decreases NO bioavailability and induces some irreversible pathological changes in various organs of experimental animal models. The effect of the short-term consumption of excessive dietary fat is still unclear. The primary objective of the studies presented in this dissertation was to investigate the impact of the short-term consumption of a moderately high fat diet (MHFD) on NO generation and the mechanisms involved in the maintenance of NO bioavailability. The consumption of the MHFD markedly reduced urinary excretion of stable NO metabolites and levels of these metabolites in the plasma within a week of the onset of dietary treatment. eNOS expression was suppressed in a tissue-specific and time-dependent manner. The earliest decrease in expression occurred in the liver at week one. In addition, hepatic NOS activity was depressed and nitrotyrosine levels were elevated; increased nitrotyrosine formation is indicative of the increased production of ROS. Other tissues in which NOS expression was suppressed in rats on the MHFD included the heart and kidney medulla.
In addition to affecting NO bioavailability, the ingestion of a MHFD also caused a decrease in drinking behavior. A portion of this reduction in drinking behavior may be attributable to the physical properties of the diet whereas the remainder is probably due to variations in the nutrient composition of the diet. The rats adapted to reduced drinking behavior by decreasing urine output and increasing urine osmolality. Nitric oxide synthase expression in the supraoptic and paraventricular nuclei did not change.
In conclusion, the short-term consumption of a MHFD has profound effects on circulating NO levels by affecting mechanisms that regulate NO availability in specific tissues. In addition, the ingestion of a MHFD may affect other biological functions such as drinking behavior.