ENDOTHELIAL DYSFUNCTION AND A LOW SALT DIET

描述（由申请方提供）：最近的证据表明，由于血管紧张素II 1型受体的激活，超氧化物产生增加，超氧化物来自NADPH氧化酶。这种超氧化物有助于血管紧张素II的生物学效应，因为慢性血管紧张素II输注期间的一部分高血压是超氧化物依赖性的。血管紧张素II引起的高血压至少部分是由于超氧化物对一氧化氮的清除。因此，超氧化物的产生和NO的生物效应的减少之间的联系已经建立。我们最近的研究表明，心脏代谢，氧消耗和底物摄取的调节，是NO的重要作用之一，这可能不仅是重要的生理状态下，如运动和怀孕的心脏效率的调节，但在疾病状态下，NO被清除的超氧化物，NO的生物活性降低可能有助于疾病的进程。有趣的是，血管紧张素II最初的生物学作用之一是控制血容量，因为血管紧张素II促进钠重吸收，特别是在盐摄入量有限的情况下。因此，在限盐饮食的患者和实验动物中，血浆血管紧张素II水平增加。如果血浆血管紧张素II的升高增加了超氧化物的产生并使NO失活，如果血浆血管紧张素II水平在低盐饮食期间增加，那么低盐饮食是否会导致迄今未描述的内皮功能障碍和心脏代谢的改变？因此，我们假设低盐饮食导致内皮功能障碍，其特征在于改变心脏代谢和冠状动脉血流调节，随后降低血管紧张素II和超氧化物依赖的NO生物活性。在具体目标1中，我们将使用大鼠确定低盐摄入期间肾功能、血浆血管紧张素II、心脏代谢和NADPH氧化酶的作用的变化。目的二是利用gp 91 phox KO -/-和p47 -/-小鼠心脏进一步阐明血管紧张素II、NADPH氧化酶和NO在心脏代谢调控中的关系。我们将使用长期仪器清醒的狗，以确定时间进程和心脏代谢的变化，具体目标3，并在心脏底物氧化和代谢基因表达，具体目标4，在限制盐摄入量减少NO生物活性的生物学基础。我们将研究使用利尿剂引起急性盐耗竭导致的潜在内皮功能障碍的机制。有趣的是，与正常盐摄入量的患者相比，低盐饮食的患者可能会增加心脏事件。事件与盐的摄入量成反比。几乎与直觉相反，当盐摄入量增加时，低盐饮食的患者似乎心脏事件减少。因此，我们的研究将审查限制盐的摄入量和内皮功能障碍之间的关系，特别是参考的作用，改变NO的生物活性，由于超氧化物生成的NADPH氧化酶。

DESCRIPTION (provided by applicant): Recent evidence suggests that there is an increase in superoxide production due to activation of the angiotensin II type 1 receptor and that the superoxide comes from the NADPH oxidase. This superoxide contributes to the biological effects of angiotensin II in that a portion of the hypertension during chronic angiotensin II infusion is superoxide dependent. The hypertension to angiotensin II is at least in part due to the scavenging of nitric oxide by superoxide. Thus, the link between the generation of superoxide and the reduction in the biological effects of NO has already been established. Our recent studies suggest that the regulation of cardiac metabolism, oxygen consumption and substrate uptake, is one of the important actions of NO and that this may not only be important in the regulation of cardiac efficiency in physiologic states, such as exercise and pregnancy, but that in disease states where NO is scavenged by superoxide, the decreased bioactivity of NO may contribute to the disease process. Interestingly, one of the initial biologic actions of angiotensin II was the control of blood volume, since angiotensin II promotes sodium reabsorption especially in states where salt intake is limited. Thus plasma angiotensin II levels increase in patients and experimental animals on a salt restricted diet. If a rise in plasma angiotensin II increases superoxide production and inactivates NO, and if plasma angiotensin II levels increase during low salt diet, then does a low salt diet result in a hitherto undescribed endothelial dysfunction and to alterations in cardiac metabolism? Thus we hypothesize that low salt diet results in endothelial dysfunction characterized by altered cardiac metabolism and coronary blood flow regulation subsequent to reduced NO bioactivity that is angiotensin II and superoxide dependent. In specific aim 1 we will use rats to determine changes in renal function, plasma angiotensin II, cardiac metabolism and the role of the NADPH oxidase during low salt intake. Aim 2 will use the gp91phox KO -/- and p47 -/- mouse heart to further elucidate the relationship between angiotensin II, the NADPH oxidase and NO in the control of cardiac metabolism. We will use chronically instrumented conscious dogs to determine the time course and biological basis for alterations in cardiac metabolism, specific aim 3, and in cardiac substrate oxidation and metabolic gene expression, specific aim 4, during restricted salt intake reduction in NO bioactivity. We will examine the mechanism of potential endothelial dysfunction due to acute salt depletion using a diuretic. Interestingly, patients on a low salt diet may have an increase in cardiac events compared to those on normal salt intake, ie. events are inversely proportional to salt intake. Almost counter intuitively, it seems that patients on a low salt diet have a reduction in cardiac events when salt intake is increased. Thus our studies will examine the relationship between restricted salt intake and endothelial dysfunction with special reference to the role of altered NO bioactivity due to superoxide generation by the NADPH oxidase.