Cardiovascular Regulations: Autonomic/Metabolic Mechanisms

项目4：本项目的总体目标仍然是研究自主和 参与心血管调节的代谢机制。在这一资金期内，我们建议确定 自主神经系统在与高血压相关的心血管和代谢异常中的作用 肥胖和代谢综合征。据推测，肥胖会导致体重的补偿性增加 旨在增加能量消耗和脂肪分解的交感神经活动。的确，肌肉交感神经 神经活动是压力感受性反射调节的交感神经流出的直接测量，与 体重和内脏脂肪。然而，我们认为，激活交感神经不仅不能改善 与肥胖相关的代谢异常，但它是有害的，并有助于心血管和 代谢并发症。我们之前已经证明，使用神经节阻滞剂的自主戒断 三甲氧胺可以用来揭示人类交感依赖和独立的形式 高血压。我们使用这一范例的初步数据表明，自主神经系统是 与肥胖相关的血压升高的主要决定因素，但对 增加静息能量消耗或脂肪分解。我们还观察到标记物的增加 肥胖和其他疾病的炎症(CRP)和氧化应激(F2-异前列腺素) 交感神经激活，反之，交感神经功能低下患者的这些标志物降低 功能。基于这些初步观察，我们假设交感神经活动的增加 肥胖会导致高血压、脂解受损、胰岛素抵抗和 与这种疾病相关的炎症/氧化应激。为了检验这一假设，我们建议比较 急性和慢性交感神经抑制对消瘦和肥胖高血压患者的影响 正常对照组。证明与肥胖相关的交感神经激活不会导致 代偿性有益的代谢作用，但却是有害的，因为它有助于心血管 与这种情况相关的炎症/氧化应激异常，可能会导致更有效的 治疗。

Project 4:The overall goal of this project remains to study the interactions between autonomic and metabolic mechanisms involved in cardiovascular regulation. In this funding period we propose to determine the role of the autonomic nervous system in the cardiovascular and metabolic abnormalities associated with obesity and the metabolic syndrome. It is postulated that obesity leads to a compensatory increase in sympathetic activity intended to increase energy expenditure and lipolysis. Indeed, muscle sympathetic nerve activity, a direct measurement of baroreflex-modulated sympathetic outflow, is positively correlated to body weight and visceral fat. We propose, however, that sympathetic activation not only fails to improve the metabolic abnormalities associated with obesity, but it is detrimental and contributes to cardiovascular and metabolic complications. We have previously shown that autonomic withdrawal with the ganglionic blocker trimethaphan can be used to reveal human forms of sympathetically-dependent and -independent hypertension. Our preliminary data using this paradigm suggest that the autonomic nervous system is the primary determinant of the increase in blood pressure associated with obesity, but contributes little, if any, to increasing resting energy expenditure or lipolysis. We have also observed an increase in markers of inflammation (CRP) and oxidative stress (F2-isoprostanes) in obesity and other conditions characterized by sympathetic activation, and, conversely, a decrease in these markers in patients with low sympathetic function. Based on these preliminary observations, we hypothesize that the increased sympathetic activity present in obesity contributes to hypertension, impaired lipolysis, insulin resistance, and inflammation/oxidative stress associated with this disorder. To test this hypothesis we propose to compare the effects of acute and chronic sympathoinhibition, in lean and obese patients with hypertension, and in normal controls. Proving that the sympathetic activation associated with obesity does not result in compensatory beneficial metabolic effects, but is detrimental because it contributes to the cardiovascular and inflammatory/oxidatie stress abnormalities associated with this condition, may lead to a more effective treatment.