Neurohumoral control of arteries and veins in obesity-associated hypertension

描述（由申请人提供）：总体高血压是美国过早死亡和残疾的主要风险因素。需要新的治疗方法来改善临床管理并降低死亡率和发病率。我们的计划项目是基于这样的假设，即通过血管容量的变化向心脏重新分配外周储存的血液是高血压病理生理学的一个重要因素。由于大多数外周储存的血液是在内脏静脉，再分布主要是由减少内脏静脉电容驱动。这可以由内脏动脉的主动收缩或内脏静脉的主动或被动收缩引起。在过去的五年里，我们的计划项目一直专注于表征交感神经机制，调节静脉电容，重点是动脉和静脉功能的差异控制。我们的大部分工作是在盐皮质激素盐性高血压的啮齿动物中进行的。然而，临床高血压越来越多地与肥胖相关，特别是与内脏区域的炎症内脏脂肪堆积相关。结合肥胖者交感神经过度活跃的证据，这使我们假设内脏动脉和静脉的交感神经控制改变可能是肥胖和高血压之间的关键联系。因此，最近，我们已经开始重新集中我们的工作在高脂肪喂养模型的肥胖相关的高血压的啮齿动物和补充研究内脏血管和脂肪从人类患者。在接下来的五年里，我们计划：1）在我们的啮齿动物模型中进行体内生理学研究，以确定肥胖相关高血压中内脏交感神经驱动的数量、来源和对动脉压的影响; 2）在大鼠和人类血管中检查发炎的内脏脂肪如何影响交感神经传递;和3）在大鼠和人血管中建立a）对血管周围脂肪组织的交感神经驱动和B）新发现的对血管周围脂肪组织本身内源的肾上腺素能系统两者的重要性。

DESCRIPTION (provided by applicant): Overall Hypertension is a major risk factor for premature death and disability in the United States. New approaches to therapy are needed to improve clinical management and reduce mortality and morbidity. Our Program Project is based on the assumption that redistribution of peripherally stored blood toward the heart via changes in vascular capacitance is an important factor in the pathophysiology of hypertension. Since most peripherally stored blood is in the splanchnic veins, redistribution is driven largely by reduced splanchnic venous capacitance. This can be caused by active constriction of splanchnic arteries, or active or passive constriction of splanchnic veins. Over the past five years our Program Project has focused on characterizing sympathetic neural mechanisms that regulate venous capacitance, with emphasis on differential control of arterial and venous function. Most of our work has been conducted in rodents with mineralocorticoid-salt hypertension. However, clinical hypertension is increasingly associated with obesity and especially with accumulation of inflamed visceral fat in the splanchnic region. Combined with evidence of sympathetic overactivity in obesity, this led us to hypothesize that altered sympathetic control of splanchnic arteries and veins could be a critical link between obesity and hypertension. Therefore, recently we have begun to refocus our work on a high fat feeding model of obesity-related hypertension in rodents and on complementary studies in splanchnic blood vessels and fat obtained from human patients. Over the next five years we propose to: 1) perform in vivo physiological studies in our rodent model to determine the amount, source and impact on arterial pressure of splanchnic sympathetic drive in obesity-related hypertension; 2) examine in rat and human blood vessels how inflamed visceral fat impacts sympathetic neurotransmission; and 3) establish in rat and human blood vessels the importance of both a) sympathetic drive to perivascular adipose tissue and b) a newly discovered adrenergic system endogenous to perivascular adipose tissue itself.