Sympathetic neural patterns and transduction in obesity-associated hypertension

肥胖相关高血压的交感神经模式和转导

基本信息

批准号：
10877436
负责人：
Christopher M Hearon
金额：
$ 24.9万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10877436
关键词：
Action Potentials Adrenergic Agents Adrenergic alpha-Antagonists Adult Age Animal Model Cardiovascular Diseases Cardiovascular system Chronic Data Goals Heart failure High Prevalence Human Hypertension Hypoxia Individual Investigation Measures Mediating Metabolic Diseases National Heart, Lung, and Blood Institute Norepinephrine Obesity Obesity Epidemic Participant Patients Pattern Peripheral Physiological Psyche structure Recommendation Reflex action Research Rest Rodent Model Signal Transduction Sleep Apnea Syndromes Stress Testing Vasoconstrictor Agents adult obesity alpha-adrenergic receptor attributable mortality blood pressure regulation hypertensive neural patterning neuropeptide Y neurotransmission neurovascular new therapeutic target novel therapeutic intervention obese patients patient population pharmacologic physiologic stressor receptor recruit response therapeutically effective vasoconstriction working group

项目摘要

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.

项目概要去年，高血压 (HTN) 导致的心血管死亡率增加了 10% 以上十年来，部分原因是肥胖流行病不断升级，有效的治疗选择有限且有限。尽管多种药物治疗方法的普及率很高，但超过 50% 的高血压患者因此，促进对血压基本机制的理解的研究仍然不受控制。需要对人类进行调节来确定新的治疗靶标。 (SNA) 和血管收缩是许多心血管疾病的标志特征，包括与肥胖相关的疾病 HTN (Ob-HTN) 交感血管过度收缩的原因尚不清楚，但最近在这方面取得了进展。交感神经活动的量化揭示了影响交感神经活动的独特动作电位模式在动物模型中，应激期间的外周血管收缩反应。增加强效血管收缩神经肽 Y (NPY) 与去甲肾上腺素的共同释放，导致血管收缩机制转向 NPY 介导的信号传导。通过激活 NPY 1 受体 (Y1R) 来收缩血管，并促进 α-肾上腺素能介导的信号传导，从而导致我们夸大了肥胖和缺氧等生理压力。改变交感神经动作电位模式，导致血管收缩依赖于 NPY 介导的信号传导。该提案的总体目标是 1）确定交感神经动作电位模式如何响应变化化学反射和精神压力 2) 评估动作电位模式对化学反射机制的影响为了实现这些目标，我们将评估健康成人和 Ob-HTN 患者的血管收缩。药物操作过程中响应内源性 SNA 爆发的逐次血管收缩 α-肾上腺素能受体和 Y1R 以确定过度交感血管收缩的机制我们预计这些研究将在健康成人和 Ob-HTN 患者的化学反射/精神压力期间进行。 1）进一步了解负责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 中神经血管转导过度的新机制，并且 3) 提供对其他以 SNA 升高和夸大为特征的患者群体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。