Renal control of sodium excretion is a critical factor in determining long-term regulation of blood pressure.The Dahl salt sensitive (DS) rat is a well-established animal model of salt-sensitivity that has many of thecharacteristics of human hypertension that is common in African Americans. We have observed that DS ratshave an exaggerated blood pressure response to an acute stress and this is exacerbated by a high fat diet.Studies from Project 1 investigators have shown that African Americans have a shift in the relationshipbetween arterial pressure and natriuresis during an acute stress protocol such that blood pressure isinappropriately high relative to the sodium excretion. When given a high salt diet, the DS rat developshypertension due to its inability to appropriately excrete a salt load. In recent years, our laboratory hasgenerated considerable evidence that the renal endothelin B (ETB) receptor plays a critical role in promotingthe excretion of an acute and chronic salt load by activation of nitric oxide synthase 1 (NOS1). Lack of ETBreceptor function leads to endothelial dysfunction and salt sensitive hypertension in various animal models.To the contrary, treatment with an ETA receptor antagonist will lower blood pressure in salt-dependentmodels of hypertension such as the DS rat. We have hypothesized that an imbalance between ETA andETB mediated actions contributes to salt-dependent hypertension and associated changes in renal andvascular function. We further hypothesize that the endothelin and renin-angiotensin-aldosterone systemsplay a role in modulating renal excretory function following stress-induced changes in blood pressure.Surprisingly little is known about the influence of obesity on the ability of the kidney to excrete salt especiallyin the context of environmental stress. The overall hypothesis of the current proposal is that an imbalance ofETA/ETB receptor function and over activity of the renin-angiotensin-aldosterone system contributes to areduced ability to excrete salt in the Dahl salt-sensitive rat and that moderate obesity exacerbates this effect.The following aims will address more specific hypotheses.
Specific Aim 1 : To test the hypothesis that stressinducedpressure natriuresis is facilitated by activation of the ETB/NOS1 pathway and that the ETA andrenin-angiotensin-aldosterone pathways attenuate the response in genetically salt-sensitive rats;
SpecificAim 2 : To test the hypothesis moderate obesity attenuates stress-induced pressure natriuresis in geneticallysalt-sensitive rats;
Specific Aim 3 : To test the hypothesis that moderate obesity interferes with the ability ofthe ETB/NOS1 pathway to promote sodium excretion by increasing oxidative stress. Relevance: A shift inthe relationship between arterial pressure and sodium excretion is a well-established hallmark of every formof hypertension. Understanding the mechanisms responsible for pressure-natriuresis in the setting of majorrisk factors, such as environmental stress and obesity, will be critically important for developing newapproaches towards the prevention and treatment of hypertension and related disorders.
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