Sympathetic Mechanisms in the Cardiovascular and Metabolic Alterations of Obesity

肥胖心血管和代谢改变中的交感机制

• 批准号: 10192815
• 负责人: Italo Biaggioni
• 金额: $ 60.2万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192815
• 关键词: Address; Agonist; Amlodipine; Angiotensin Receptor; Antihypertensive Agents; Antiinflammatory Effect; Blood Pressure; Blood Vessels; Body mass index; Calcium Channel; Calcium Channel Blockers; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical; Control Groups; Development; Diabetes Mellitus; Dose; Energy Metabolism; Enrollment; Epidemic; Event; Fatty acid glycerol esters; Feedback; Fluorescence-Activated Cell Sorting; Fostering; Glucose Clamp; Guidelines; Health Care Costs; Hypertension; Imidazolines; Impairment; Inflammation; Inflammatory; Insulin; Insulin Resistance; Isoprostanes; Laboratories; Life Expectancy; Literature; Measures; Mediating; Metabolic; Metabolic syndrome; Metabolism; Nitric Oxide; Obesity; Organ; Outcome; Oxidative Stress; Pathway interactions; Patients; Plasma; Prevalence; Public Health; Recommendation; Resistance; Rest; Risk; Risk Factors; Role; Side; Stress; Sympatholytics; Testing; Therapeutic; Thinness; Ultrasonography; Vasodilation; Vision; Work; base; cardiovascular risk factor; contrast enhanced; fighting; glucose production; glucose uptake; hypertension treatment; improved; innovation; insight; insulin sensitivity; new therapeutic target; novel; obesity treatment; recruit; side effect; stable isotope; tool; treatment guidelines; valsartan

Project Summary: The presence of obesity increases the risk for hypertension and diabetes, in part due to the development of insulin resistance. Obesity is also associated with sympathetic activation and our overarching hypothesis is that sympathetic activation contributes to insulin resistance with impairment of its vascular and metabolic actions. Our preliminary studies suggest that 1) Blood pressure can be normalized by autonomic blockade in obese hypertensives, 2) Sympathetic activation provides no metabolic benefit because the increase in resting energy expenditure associated with obesity is due to an increase in fat free mass rather than sympathetic activation. On the contrary, autonomic blockade: 3) Improves insulin sensitivity in obese hypertensives, 4) Reverses their impaired NO-mediated dilation, and 5) Reduces plasma isoprostanes, a measure of oxidative stress. Furthermore, these abnormalities are interrelated in negative feedback loops, whereby inflammation/oxidative stress impairs nitric oxide mechanisms, which in turn reduces insulin-mediated vasodilation important for substrate delivery, thus contributing to insulin resistance; insulin resistance leads to compensatory increases in insulin levels, which contributes to further sympathetic activation. Current treatment guidelines do not specifically address the treatment of obesity hypertension, and do not target sympathetic activation as a first line approach. It is important, therefore, to determine whether or not targeting sympathetic activation offers unique advantages in the treatment of obesity hypertension over current approaches. We propose a proof-of-concept mechanistic study comparing the metabolic, vascular, and anti-inflammatory effects of sympathetic inhibition, calcium channel blockade and angiotensin receptor blockade in obesity hypertension. We will test the hypotheses that sympathetic activation contributes to 1) metabolic insulin resistance, which impairs the suppression of endogenous glucose production and the stimulation of glucose uptake normally provided by insulin, 2) vascular insulin resistance, which impairs insulin-mediated vasodilation and microvascular recruitment that normally promote glucose uptake, and 3) inflammation and oxidative stress, which contribute to insulin resistance and hypertension. The proposed studies will gauge the contribution of sympathetic activation to the cardiovascular and metabolic complications of obesity, and provide the mechanistic insight to determine whether or not we should foster the efforts currently under way to develop novel therapies targeting sympathetic activation for hypertension.

项目摘要： 肥胖的存在增加了高血压和糖尿病的风险，部分原因是 胰岛素抵抗。肥胖还与同情激活和我们的总体假设有关 是同情激活有助于胰岛素耐药性，其血管损害和 代谢作用。我们的初步研究表明1）血压可以通过自主神经归一化 肥胖高血压中的封锁，2）交感神经激活没有代谢益处，因为 与肥胖相关的静息能量消耗增加是由于无脂肪质量增加 而不是同情激活。相反，自主封锁：3）提高胰岛素灵敏度 肥胖高血压，4）逆转其无介导的扩张，5）减少等离子体 异丙烷，一种氧化应激的度量。此外，这些异常是相互关联的 负反馈回路，炎症/氧化应激会损害一氧化氮机制 这反过 胰岛素抵抗；胰岛素抵抗会导致胰岛素水平的补偿性增加，这有助于 进一步的交感神经激活。 当前的治疗指南并未具体解决肥胖高血压的治疗 不是目标交感激活作为第一行方法。因此，重要的是要确定是否或 不针对同情激活在治疗肥胖高血压方面具有独特的优势 当前的方法。我们提出了一项概念验证机械研究，以比较代谢，血管， 以及交感神经抑制，钙通道阻滞和血管紧张素受体的抗炎作用 肥胖高血压的封锁。我们将测试同情激活有助于1）的假设 代谢胰岛素抵抗，会损害内源性葡萄糖的抑制和 刺激通常由胰岛素提供的葡萄糖摄取，2）血管胰岛素抵抗，这会损害 胰岛素介导的血管舒张和微血管募集通常会促进葡萄糖摄取，3） 炎症和氧化应激，有助于胰岛素抵抗和高血压。 拟议的研究将衡量交感神经对心血管的贡献 和肥胖的代谢并发症，并提供机械见解，以确定我们是否是否 应促进目前正在开发针对同情的新型疗法的努力 高血压激活。