Sympathetic neural patterns and transduction in obesity-associated hypertension

项目总结 可归因于高血压的心血管死亡率(HTN)在过去的几年中增加了10%以上 十年，部分原因是肥胖症的流行不断升级。HTN的有效治疗选择有限，而且 尽管多种药物疗法的流行率很高，但超过50%的高血压患者 仍然不受控制。因此，促进对血压基本机制的理解的研究 需要对人类进行调节以确定新的治疗靶点。夸张的交感神经活动 SNA和血管收缩是包括肥胖相关的许多心血管疾病的显著特征 HTN(Ob-HTN)。交感神经血管收缩过度的原因尚不清楚，但最近在 交感神经活动的量化揭示了影响脑电活动的独特动作电位模式 外周血管收缩对压力的反应。在动物模型中，应激时的交感神经放电模式 增加强大的血管收缩神经肽Y(NPY)与去甲肾上腺素的共同释放， 导致血管收缩机制向NPY介导的信号传递转变。NPY原因 通过激活NPY1受体(Y1R)收缩血管，并促进α-肾上腺素能介导的信号传导 过度的交感神经血管收缩。我们假设像肥胖和缺氧这样的生理应激源 改变导致血管收缩的交感神经动作电位模式，使其依赖NPY介导的信号。这个 这项建议的总体目标是1)确定交感神经动作电位模式是如何改变的 化学反射和心理应激2)以评估动作电位模式对以下机制的影响 健康成人和Ob-HTN患者的血管收缩。为了实现这些目标，我们将评估 在药物操作过程中对内源性SNA爆发的逐搏血管收缩反应 用α-肾上腺素能受体和Y1Rs确定交感神经过度收缩的机制 健康成人和Ob-HTN患者在化学反射/精神应激过程中的变化。我们预计这些调查 1)进一步了解神经血管转导的基本信号机制 人类包括动作电位模式、神经传递和血管收缩之间的相互作用2) 确定Ob-HTN过度神经血管转导的新机制，3)提供 在其他以SNA升高和夸大为特征的患者群体中进行研究的途径 血管收缩，包括睡眠呼吸暂停、代谢性疾病和心力衰竭。

PROJECT SUMMARY Cardiovascular mortality attributable to hypertension (HTN) has increased by more than 10 percent in the last decade, due in part to the escalating obesity epidemic. Effective therapeutic options for HTN are limited and despite a high prevalence of multi-pharmacological approaches, more than 50% of hypertensive individuals remain uncontrolled. As such, studies that advance understanding of basic mechanisms of blood pressure regulation in humans are needed to identify novel therapeutic targets. Exaggerated sympathetic nervous activity (SNA) and vasoconstriction are hallmark features of many cardiovascular diseases including obesity-associated HTN (Ob-HTN). Causes of exaggerated sympathetic vasoconstriction are unclear, however recent advances in quantification of sympathetic activity have uncovered unique action potential patterns that influence the peripheral vasoconstrictor response to stress. In animal models, sympathetic firing patterns during stress increase co-release of the potent vasoconstrictor neuropeptide Y (NPY) in conjunction with norepinephrine, causing a shift in the mechanisms of vasoconstriction towards NPY-mediated signaling. NPY causes vasoconstriction via activation of NPY 1 receptors (Y1R), and facilitates α-adrenergic mediated signaling causing exaggerated sympathetic vasoconstriction. We hypothesize that physiological stressors like obesity and hypoxia alter sympathetic action potential patterns that cause vasoconstriction to rely on NPY-mediated signaling. The overall aim of this proposal is to 1) identify how sympathetic action potential patterns change in response to chemoreflex and mental stress 2) to assess the impact of action potential patterns on mechanisms of vasoconstriction in healthy adults and in patients with Ob-HTN. To accomplish these goals, we will we will assess beat-by-beat vasoconstriction in response to endogenous bursts of SNA during pharmacological manipulation of α-adrenergic receptors and Y1Rs to determine the mechanisms of exaggerated sympathetic vasoconstriction during chemoreflex/mental stress in healthy adults and Ob-HTN patients. We anticipate that these investigations will 1) further understanding of the basic signaling mechanisms responsible for neurovascular transduction in humans including the interaction between action potential patterns, neurotransmission and vasoconstriction 2) identify new mechanisms underlying exaggerated neurovascular transduction in Ob-HTN and 3) provide avenues for research in other patient populations characterized by elevated SNA and exaggerated vasoconstriction including sleep apnea, metabolic disease, and heart failure.