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: 10619649
• 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/10619649
• 关键词: 20 year old; 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; Hyperinsulinism; 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; Titrations; Ultrasonography; Vasodilation; Vision; Work; 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

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： 肥胖的存在增加了患高血压和糖尿病的风险，部分原因是 胰岛素抵抗肥胖也与交感神经激活有关， 交感神经激活导致胰岛素抵抗， 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 2）交感神经激活不提供代谢益处，因为 与肥胖相关的静息能量消耗的增加是由于无脂肪质量的增加 而不是交感神经激活。相反，自主神经阻滞：3）改善胰岛素敏感性， 肥胖高血压患者，4）逆转其受损的NO介导的扩张，和5）降低血浆 异前列腺素，氧化应激的一种量度。此外，这些异常是相互关联的， 负反馈回路，炎症/氧化应激由此损害一氧化氮机制， 这又减少了对底物递送重要的胰岛素介导的血管舒张，因此有助于 胰岛素抵抗;胰岛素抵抗导致胰岛素水平的代偿性增加， 进一步激活交感神经 目前的治疗指南并没有专门针对肥胖高血压的治疗， 而不是将交感神经激活作为一线治疗方法。因此，重要的是确定是否或 不靶向交感神经激活在治疗肥胖高血压方面提供了独特的优势， 目前的做法。我们提出了一个概念验证机制的研究比较代谢，血管， 交感神经抑制、钙通道阻滞和血管紧张素受体的抗炎作用 阻断肥胖高血压。我们将测试交感神经激活有助于1） 代谢性胰岛素抵抗，其损害内源性葡萄糖产生的抑制， 胰岛素正常提供的葡萄糖摄取的刺激，2）血管胰岛素抵抗，其损害 胰岛素介导的血管舒张和微血管募集，其通常促进葡萄糖摄取，以及3） 炎症和氧化应激，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疾病的贡献。 和肥胖的代谢并发症，并提供了机制的见解，以确定我们是否 应该促进目前正在进行的努力，开发针对交感神经的新疗法， 高血压的激活。

项目成果

Symptom Presentation and Access to Medical Care in Patients With Postural Orthostatic Tachycardia Syndrome: Role of Sex.

• DOI: 10.1016/j.cjco.2021.08.014
• 发表时间: 2021-12
• 期刊: CJC open
• 作者: Bourne KM;Hall J;Stiles LE;Sheldon RS;Shibao CA;Okamoto LE;Garland EM;Gamboa AC;Peltier A;Diedrich A;Biaggioni I;Robertson D;Raj SR
• 通讯作者: Raj SR

Transdermal auricular vagus stimulation for the treatment of postural tachycardia syndrome.

• DOI: 10.1016/j.autneu.2021.102886
• 发表时间: 2021-12
• 期刊: Autonomic neuroscience : basic & clinical
• 作者: Diedrich A;Urechie V;Shiffer D;Rigo S;Minonzio M;Cairo B;Smith EC;Okamoto LE;Barbic F;Bisoglio A;Porta A;Biaggioni I;Furlan R
• 通讯作者: Furlan R

Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial.

• DOI: 10.1007/s10286-021-00827-0
• 发表时间: 2021-12
• 期刊: Clinical autonomic research : official journal of the Clinical Autonomic Research Society
• 作者: Kaufmann H;Vickery R;Wang W;Kanodia J;Shibao CA;Norcliffe-Kaufmann L;Haumann B;Biaggioni I
• 通讯作者: Biaggioni I