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.

项目概要： 肥胖的存在会增加患高血压和糖尿病的风险，部分原因是 胰岛素抵抗。肥胖还与交感神经激活和我们的总体假设有关 交感神经的激活会导致胰岛素抵抗，并损害其血管和神经系统 代谢作用。我们的初步研究表明 1) 血压可以通过自主神经恢复正常 肥胖高血压患者的阻断，2) 交感神经激活不会带来代谢益处，因为 与肥胖相关的静息能量消耗的增加是由于去脂质量的增加 而不是交感神经的激活。相反，自主神经阻滞：3）提高胰岛素敏感性 肥胖高血压，4) 逆转其受损的一氧化氮介导的扩张，以及 5) 减少血浆 异前列烷，氧化应激的衡量标准。此外，这些异常是相互关联的 负反馈循环，炎症/氧化应激会损害一氧化氮机制， 这反过来又减少了对底物输送很重要的胰岛素介导的血管舒张，从而有助于 胰岛素抵抗；胰岛素抵抗会导致胰岛素水平代偿性增加，从而导致 进一步激活交感神经。 目前的治疗指南并未专门针对肥胖高血压的治疗，但确实 不将交感神经激活作为一线方法。因此，确定是否或 与治疗肥胖高血压相比，不针对交感神经激活具有独特的优势 目前的方法。我们提出了一项概念验证机制研究，比较代谢、血管、 交感神经抑制、钙通道阻断和血管紧张素受体的抗炎作用 封锁肥胖高血压。我们将测试交感神经激活有助于 1) 的假设 代谢性胰岛素抵抗，损害内源性葡萄糖产生的抑制和 通常由胰岛素提供的葡萄糖摄取刺激，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) 炎症和氧化应激会导致胰岛素抵抗和高血压。 拟议的研究将衡量交感神经激活对心血管的贡献 和肥胖的代谢并发症，并提供机制见解来确定我们是否 应促进目前正在努力开发针对交感神经的新疗法 激活高血压。