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

• 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
• 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

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.

项目摘要 归因于高血压（HTN）的心血管死亡率上升超过10％ 十年，部分原因是肥胖的流行。 HTN的有效治疗选择有限，并且 尽管多种药理学方法的流行率很高，但超过50％的高血压个体 保持不受控制。因此，研究提高对血压基本机制的理解的研究 需要在人类中进行调节以识别新的治疗靶标。夸张的交感神经活动 （SNA）和血管收缩是许多心血管疾病（包括肥胖相关）的标志性特征 HTN（OB-HTN）。夸张的同情血管收缩的原因尚不清楚，但是最近的进步 数量的交感神经活动已经发现了影响该影响的独特动作潜力模式 外周血管收缩对应激的反应。在动物模型中，压力期间的交感神经射击模式 增加潜在血管收缩剂神经肽Y（NPY）的共释放，并与去甲肾上腺素结合使用， 引起血管收缩机制向NPY介导的信号传导的转移。 npy原因 通过激活NPY 1受体（Y1R）的血管收缩，并促进引起α-肾上腺素能介导的信号传导 夸张的交感神经收缩。我们假设肥胖和缺氧等身体压力源 改变交感神经的电势模式，导致血管收缩依赖于NPY介导的信号传导。这 该提案的总体目的是1）确定同情行动潜在模式如何改变 化学反射和精神压力2）评估动作电位模式对机制的影响 健康成年人和OB-HTN患者的血管收缩。为了实现这些目标，我们将评估 在药物操纵过程中，响应内源性SNA爆发的血管收缩跳动血管收缩 α-肾上腺素受体和Y1R，以确定夸张的交感神经血管收缩的机制 在健康的成年人和OB-HTN患者的化学反射/精神压力期间。我们预计这些调查 1）进一步了解负责神经血管转导的基本信号传导机制 人类包括动作潜在模式之间的相互作用，神经传递和血管收缩2） 确定OB-HTN中夸张的神经血管转导的新机制，3） 在其他患者人群中进行研究的途径，其特征是SNA升高和夸张 血管收缩，包括睡眠呼吸暂停，代谢疾病和心力衰竭。