Obesity, salt-sensitivity, and the natriuretic peptides

描述(由申请人提供)：肥胖心血管风险的关键因素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，也是其高患病率的主要因素之一。尽管如此，肥胖症患者血压调节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。盐敏性是由保盐和排盐系统的平衡决定的。其中研究最深入的是肾素-血管紧张素-醛固酮系统(RAAS)。过度激活RAAS在肥胖症中的作用是公认的。RAAS的主要逆调节系统是利钠肽(NP)系统。NPs是心脏对增加的室内压力做出反应时产生的利钠和扩张血管的分子。然而，关于肥胖症中NP轴的变化知之甚少。在初步工作中，我们已经表明肥胖个体循环中的NP浓度降低，这与体重减轻的情况相反。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缺乏症”状态，这会导致NP对盐负荷的反应受损，对盐的敏感性增加，血压升高。在具体目标1中，我们将评估瘦人和肥胖者的NP和靶器官对急性和慢性盐负荷的反应。在目标2中，我们将研究体重减轻对急性和慢性盐负荷对NP和靶器官反应的影响。这项拟议的研究代表了一项系统性的努力，旨在建立在研究人员先前对NP轴、肥胖和心脏代谢风险之间的新交互作用的临床调查的基础上。这些研究有可能为肥胖症中高血压的原因提供重要的见解。此外，由于NP系统很容易被药物操纵，证实“NP缺乏症”的存在并确定其生理后果可能会为肥胖相关心血管疾病的治疗和预防提供新的方法。

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.