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

基本信息

批准号：
10417218
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
项目类别：
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/10417218
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 hypertensive hypertensives improved innovation insight insulin sensitivity new therapeutic target novel obesity treatment recruit side effect stable isotope tool treatment guidelines valsartan

项目摘要

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。