Neurohumoral regulation of splanchnic arteries and veins in the pathophysiology of hypertension

项目摘要/摘要-项目1 本项目以前的动物实验主要集中在血管电容的影响上 (血液储存)对心血管调节的影响。因为内脏血管系统在 决定整个血管的电容，交感神经系统是主要的调节器 内脏血管电容，我们研究了内脏交感神经 可能在高血压中起重要作用。肥胖症现在已被认为是人类 高血压及其伴随的发病率、死亡率和增加的医疗费用。 此外，交感神经系统活动的增加被认为是 肥胖和高血压。尽管对肾脏的交感神经控制是一个既定的因素 与肥胖相关的高血压，有大量证据表明，交感神经活动对其他靶点 也起到了一定作用。考虑到与肥胖相关的交感神经过度活动和 高血压伴内脏区域炎性脂肪组织聚集 (内脏脂肪组织)，我们假设内脏交感神经活动在肥胖中很重要- 伴发高血压。我们进一步提出内脏交感神经活动调节动脉 肥胖的压力不仅通过影响内脏血管的功能，而且还通过 促进和加速血液周围内脏脂肪组织的炎症 船只。在此背景下，内脏交感活动不仅指交感神经的影响 神经和循环中的儿茶酚胺，也是从去甲肾上腺素释放出来的一种新发现 内脏脂肪本身固有的肾上腺素能系统(在项目3中描述)。为了检验这些假设， 实验将在肥胖的大鼠身上进行，方法是给它们喂高脂肪(HF)食物，最多26次 3周，从3周大开始。这些大鼠会患上葡萄糖耐量减低、内脏肥胖和 高血压从饮食的12-18周开始。在6周、18周和26周的HF喂养时，我们将 用去甲肾上腺素溢出法估计内脏神经活动；测量血管电容 (主要是内脏)、内脏血管阻力及其对肾上腺素能输入的依赖； 评价内脏血管和内脏脂肪组织慢性失神经对心脏功能的影响 高血压的发展。最后，我们将确定大脑中的前列腺素D2是否有助于 我们的肥胖大鼠模型中的交感神经兴奋。预计这些研究可能会产生新的 管理肥胖相关高血压的方法。

Project Summary/Abstract – Project 1 Previous animal-based experiments in this Project focused on the impact of vascular capacitance (blood storage) on cardiovascular regulation. Because the splanchnic vasculature plays a large role in determining overall vascular capacitance, and the sympathetic nervous system is the major regulator of splanchnic vascular capacitance, we investigated the idea that the splanchnic sympathetic nerves may be important in hypertension. Obesity is now known to be the major cause of human hypertension and its accompanying morbidities, mortalities and increased health care costs. Furthermore, increased sympathetic nervous system activity is accepted as one critical link between obesity and hypertension. Although sympathetic control of the kidney is an established factor in obesity-related hypertension, there is substantial evidence that sympathetic activity to other targets also plays a part. Given the close association of obesity-related sympathetic overactivity and hypertension with accumulation of inflammed adipose tissue specifically in the splanchnic region (visceral adipose tissue), we hypothesize that splanchnic sympathetic activity is important in obesity- associated hypertension. We further propose that splanchnic sympathetic activity regulates arterial pressure in obesity not only by affecting the function of splanchnic blood vessels, but also by promoting and accelerating inflammation of the visceral adipose tissue surrounding those blood vessels. In this context, splanchnic sympathetic activity refers not only to effects of sympathetic nerves and circulating catecholamines, but also to norepinephrine released from a newly discovered adrenergic system intrinsic to visceral fat itself (described in Project 3).To test these hypotheses, experiments will be conducted in rats made obese by feeding them a high fat (HF) diet for up to 26 weeks, starting at 3 weeks of age. The rats will develop glucose intolerance, visceral obesity and hypertension starting between 12-18 weeks of the diet. At 6, 18 and 26 weeks of HF feeding we will estimate splanchnic nerve activity using norepinephrine spillover; measure vascular capacitance (mainly splanchnic), splanchnic vascular resistance and their dependence on adrenergic input; and evaluate the impact of chronic denervation of splanchnic blood vessels and visceral adipose tissue on hypertension development. Finally, we will determine if prostaglandin D2 in the brain contributes to sympathoexcitation in our rat model of obesity. It is anticipated that these studies could produce new approaches to managing obesity-related hypertension.