Coronary to Myocyte Signaling

最近的证据表明，由于血管紧张素II型1受体的激活，超氧化物的产生增加，并且超氧化物来自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输注期间高血压的一部分是超氧化物依赖的。高血压对血管紧张素II的影响至少部分是由于超氧化物对一氧化氮的清除。因此，超氧化物的产生与一氧化氮生物效应的降低之间的联系已经确立。我们最近的研究表明，心脏代谢、氧气消耗和底物摄取的调节是NO的重要作用之一，这可能不仅在生理状态下（如运动和怀孕）对心脏效率的调节中起重要作用，而且在NO被超氧化物清除的疾病状态下，NO生物活性的降低可能有助于疾病过程。有趣的是，血管紧张素II最初的生物作用之一是控制血容量，因为血管紧张素II促进钠的再吸收

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 aim3, 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.