Obesity, salt-sensitivity, and the natriuretic peptides

肥胖、盐敏感性和利钠肽

• 批准号: 8310943
• 负责人: Thomas J. Wang
• 金额: $ 39.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310943
• 关键词: Acute; Atrial Fibrillation; Behavioral; Biological Markers; Blood Plasma Volume; Blood Pressure; Body Weight decreased; Body mass index; Cardiac; Chronic; Clinical; Clinical Trials; Coronary heart disease; Development; Diet; Echocardiography; Enrollment; Excretory function; Heart; Heart failure; High Prevalence; Hormones; Hypertension; Individual; Infusion procedures; Kidney; Left Ventricular Mass; Measures; Mediator of activation protein; Morbidity - disease rate; Natriuretic Peptides; Obesity; Obesity Related Hypertension; Obesity associated cardiovascular disease; Organ; Physiological; Physiology; Prevention; Relative (related person); Renal Blood Flow; Renin-Angiotensin-Aldosterone System; Research; Research Personnel; Rest; Risk; Risk Factors; Role; Saline; Sodium; Sodium Chloride; Stimulus; Stress; Stroke; System; Testing; Therapeutic; Work; bariatric surgery; blood flow measurement; blood pressure regulation; cardiovascular risk factor; comparative; insight; modifiable risk; mortality; novel; novel strategies; post intervention; programs; response; salt balance; saluretic; urinary

DESCRIPTION (provided by applicant): One of the key mediators of cardiovascular risk in obesity is the development of hypertension. Obesity is the principal modifiable risk factor for hypertension, and one of the major contributors to its very high prevalence. Nonetheless, the mechanisms underlying the dysregulation of blood pressure in obesity are incompletely understood. An impaired ability to handle a salt load, or salt-sensitivity, is regarded as an important mechanism for obesity-related hypertension. Salt-sensitivity is determined by the balance of salt-retaining and salt-excreting systems. One of the best-studied salt-retaining systems is the renin-angiotensin-aldosterone system (RAAS). Excess RAAS activation in obesity is well-established. The principal counter-regulatory system to the RAAS is the natriuretic peptide (NP) system. The NPs are natriuretic and vasodilatory molecules produced by the heart in response to increased chamber stress. However, little is known regarding changes in the NP axis in obesity. In preliminary work, we have shown that obese individuals have decreased circulating NP concentrations, which reverse with weight loss. However, resting NP levels may not adequately reflect the ability of the NP axis to respond to stimuli, emphasizing the need for more detailed physiologic studies, under controlled salt conditions and with standardized assessment of the NP and RAAS axes, and related target organs (kidney, heart, and vasculature). We postulate that obesity promotes a state of relative "NP deficiency," which leads to impaired NP responses to salt loading, increased salt-sensitivity and elevated blood pressure. In Specific Aim 1, we will assess the NP and target organ responses to acute and chronic salt loading, in lean versus obese individuals. In Aim 2, we will examine the effect of weight loss on the NP and target organ responses to acute and chronic salt loading. The proposed research represents a systematic effort to build upon the investigators' prior clinical investigations into the novel interactions between the NP axis, obesity, and cardiometabolic risk. These studies have the potential to provide important insight into the causes of hypertension in obesity. Furthermore, because the NP system is easily accessible to pharmacologic manipulation, establishing that "NP deficiency" exists and defining its physiologic consequences could suggest novel approaches to the treatment and prevention of obesity-related cardiovascular disease.

描述（由申请人提供）：肥胖症心血管风险的关键介质之一是高血压的发展。肥胖是高血压的主要可改变的危险因素，也是其非常高的患病率的主要原因之一。尽管如此，肥胖患者血压失调的机制还不完全清楚。处理盐负荷的能力受损或盐敏感性被认为是肥胖相关高血压的重要机制。盐敏感性是由植物体内的排盐系统和贮盐系统的平衡决定的。研究得最好的盐保留系统之一是肾素-血管紧张素-醛固酮系统（RAAS）。肥胖症中RAAS的过度激活是公认的。RAAS的主要反调节系统是利钠肽（NP）系统。NP是由心脏响应于增加的腔室应激而产生的利钠和血管舒张分子。然而，很少有人知道在肥胖症的NP轴的变化。在初步的工作中，我们已经表明，肥胖的人已经降低了循环NP浓度，这与体重减轻逆转。然而，静息NP水平可能不能充分反映NP轴对刺激的反应能力，强调需要在受控盐条件下进行更详细的生理学研究，并对NP和RAAS轴以及相关靶器官（肾脏、心脏和血管系统）进行标准化评估。我们推测，肥胖促进了一种相对的“NP缺乏”状态，这导致NP对盐负荷的反应受损，盐敏感性增加和血压升高。在具体目标1中，我们将评估瘦与肥胖个体对急性和慢性盐负荷的NP和靶器官反应。在目标2中，我们将研究体重减轻对急性和慢性盐负荷的NP和靶器官反应的影响。拟议的研究代表了一项系统性的努力，以建立在研究人员先前的临床研究，NP轴，肥胖和心脏代谢风险之间的新的相互作用。这些研究有可能为肥胖者高血压的病因提供重要的见解。此外，由于NP系统很容易获得药理学操作，建立“NP缺乏症”的存在和定义其生理后果可能会提出新的方法来治疗和预防肥胖相关的心血管疾病。