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

项目概要/摘要-项目1 本项目先前的动物实验主要关注血管电容的影响 （血液储存）对心血管调节的影响。因为内脏血管在 决定总的血管容量，交感神经系统是主要的调节器 内脏血管电容，我们调查了内脏交感神经的想法， 可能对高血压很重要。肥胖是目前已知的人类的主要原因 高血压及其伴随的发病率、死亡率和增加的卫生保健费用。 此外，增加的交感神经系统活动被认为是与神经系统的一个关键环节。 肥胖和高血压。虽然交感神经对肾脏的控制是一个确定的因素， 肥胖相关的高血压，有大量的证据表明，交感神经活动的其他目标 也是一部分。考虑到与肥胖相关的交感神经过度活跃和 高血压伴内脏区炎症性脂肪组织蓄积 （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- 相关高血压。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， 促进和加速血液周围内脏脂肪组织的炎症 船舶.在这种情况下，内脏交感神经活动不仅指交感神经的作用， 神经和循环的儿茶酚胺，但也释放去甲肾上腺素从一个新发现的 肾上腺素能系统固有的内脏脂肪本身（在项目3中描述）。为了测试这些假设， 实验将在大鼠中进行，通过给它们喂食高脂肪（HF）饮食长达26 从3周龄开始。大鼠会出现葡萄糖耐受不良、内脏肥胖和 高血压在饮食的12-18周之间开始。在HF喂养的第6、18和26周，我们将 用去甲肾上腺素溢出估计内脏神经活动;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性;以及 评估内脏血管和内脏脂肪组织的慢性去神经支配对 高血压发展最后，我们将确定大脑中的前列腺素D2是否有助于 交感神经兴奋在我们的肥胖大鼠模型。预计这些研究可以产生新的 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.