We have utilized an established model of behavioral stress in Dahl salt-sensitive (DS) ratsthat indicates reactive oxygen species (ROS) mediate the stress-induced increase in blood pressure. Wehave hypothesized that stress triggers ROS production via mechanisms involving the endothelin (ET) and/orangiotensin II pathways through activation of NADPH oxidase and uncoupled NOS. Project 2's BPStressCohort of young adults has shown that the response to stress was significantly greater in obese individualsor ones at a lower socioeconomic status that carry a specific ET polymorphism. Data in DS rats indicatesthat a high fat diet augments the stress-induced blood pressure response when compared to DS rats on anormal fat diet. Given the epidemic of childhood obesity that has contributed to the risk of hypertension, it isimportant to determine the mechanisms responsible for the augmented stress response. Lower childhoodsocioeconomic status is recognized to be associated with increased cardiovascular disease morbidity andmortality. We initiated preliminary studies with an established model of early life stress in rats. Pups areseparated from their mothers for 3 hr/day from day 2-14 of life. The early life stress (separated) rats display agreater response to stress when compared to the non-separated rats. Rats with an impaired ET signalingpathway that are exposed to early life stress do not have an augmented response to stress in adulthood.These data have led us to predict that early life stress activates a component of the ET pathway thatpotentiates the stress response. We propose the following specific aims:
Specific Aim 1 : To test thehypothesis that air jet stress activates the ET and/or Ang II pathways, which stimulates NADPH oxidaseand/or uncoupled NOS as the enzymatic source of ROS, increasing blood pressure;
Specific Aim 2 : To testthe hypothesis that high fat diet augments the air jet stress induced increase in blood pressure via productionof ROS;
Specific Aim 3 : To test the hypothesis that early life stress potentiates the air jet stress inducedincrease in blood pressure via the ET pathway. Relevance: The chronic stressors (high fat diet and early lifestress) are models of established stressors that are known to sensitize humans to stress and increase therisk for hypertension. A complete understanding of the mechanisms involved in the blood pressure responseto stress may disclose approaches for minimizing the risk of hypertension.
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