Mechanisms of Vasovagal Syncope

血管迷走性晕厥的机制

• 批准号: 8606885
• 负责人: JULIAN M STEWART
• 金额: $ 52.17万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606885
• 关键词: Acute; Adenosine; Adrenergic Agents; Age; Agonist; American; Arginine; Baroreflex; Biopsy; Blood; Blood Volume; Blood flow; Cardiac Output; Cerebrum; Chronic; Cutaneous; Data; Diagnosis; Dietary intake; Disodium Salt Nitroprusside; Dose; Gene Expression; Gene Proteins; Heart Rate; Heating; Hemoglobin; High Pressure Liquid Chromatography; Hour; Human; Hyperpnea; Hypovolemia; Individual; Injection of therapeutic agent; Intervention; Intravenous; Knowledge; Laser-Doppler Flowmetry; Lead; Lightheadedness; Lower Body Negative Pressure; Measurement; Measures; Medical; Methods; Microdialysis; Modeling; Molecular; Muscle; Nerve; Neurocognitive; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Noble Gases; Norepinephrine; Patients; Perfusion; Phenylephrine; Physiology; Plasma; Posture; Production; Protein Isoforms; Punch Biopsy; Questionnaires; Recording of previous events; Recruitment Activity; Reflex action; Regional Blood Flow; Research; Rest; Schools; Signs and Symptoms; Site; Skin; Specificity; Stress; Subgroup; Synapses; Syncope; Syndrome; Tachycardia; Techniques; Temperature; Testing; Tyramine; Unconscious State; Vasodilation; Vasovagal Syncope; Venous; Western Blotting; Work; adrenergic; constriction; electric impedance; hemodynamics; neurotransmission; noradrenergic; omega-N-Methylarginine; peripheral blood; presynaptic; prevent; protein expression; public health relevance; research study; response; vasoconstriction; young woman

DESCRIPTION (provided by applicant): Vasovagal syncope (VVS, simple faint) is the most common cause of transient loss of consciousness and is the acute episodic form of orthostatic intolerance (OI). Postural tachycardia syndrome (POTS) is the common chronic form of OI. Both are defined by debilitating symptoms and signs while upright relieved by recumbency. Pathophysiological mechanisms have remained elusive although our past work shows that excessive upright central hypovolemia results from splanchnic blood pooling due to defective splanchnic arterial and venous constriction. Preliminary data support the hypothesis that production of nitric oxide (NO) is enhanced in these patients resulting in reduced sympathetic noradrenergic neurotransmission at pre-junctional and post-junctional sites. Our approach is two-fold: 1) We will use intradermal microdialysis and laser Doppler flowmetry (LDF) to delineate the microvascular mechanisms of NO modulation of noradrenergic neurotransmission free of confounding systemic reflex changes. 2) We will systemically apply this mechanism to a model of orthostatic stress, lower body negative pressure (LBNP), while measuring cardiac output by inert gas rebreathing, regional blood volume, and regional blood flow using plethysmographic techniques focusing on splanchnic changes, and muscle sympathetic nerve activity by peroneal microneurography. 30 each of VVS, POTS and control subjects ages 14-29 years will be recruited. We will use chemiluminescence to measure NO in microdialysate to test whether it is increased in OI. Pre-junctional neurotransmission will be assessed by step wise tyramine doses using HPLC analysis of microdialysate norepinephrine (NE). Post-junctional neurotransmission will be assessed by LDF responses to step-wise increases of NE after endogenous blockade with bretylium. Basal and local heat stimulated NO will be assessed. We will determine whether inhibition of neurotransmission is NO-specific by repeating studies after NOS inhibition with nitro-L-arginine (NLA) and after repletion of NO during perfusion with NLA+sodium nitroprusside (SNP). We will obtain skin biopsies for NOS isoform protein and expression. We will determine if systemic NO inhibits pre and post synaptic adrenergic activity in OI, altering the response to LBNP. Presynaptic neurotransmission will be assessed by step-wise increasing LBNP and measuring plasma NE response. Post-synaptic neurotransmission will be assessed by the systemic response to stepwise increasing phenylephrine doses. To confirm NO-specificity, studies will be repeated after NOS inhibition with L-NG-monomethyl Arginine(L-NMMA), after repletion of NO during perfusion with L-NMMA +SNP, and after low dose phenylephrine as a control for baseline shifts of MSNA and vasoconstriction. L-NMMA enters the CNS slowly over many hours. To ascertain its central effects we will measure MSNA at the end of experiments. Studies will establish the molecular mechanism for common and debilitating forms of OI in the cutaneous human surrogate model, and apply this knowledge to the integrative physiology of OI. This research will lead to targeted and effective medical therapy for important groups of OI patients.

描述（由申请人提供）：血管迷走性晕厥（VVS，单纯性昏厥）是短暂性意识丧失的最常见原因，是直立不耐受（OI）的急性发作形式。体位性心动过速综合征（POTS）是OI的常见慢性形式。两者都定义为衰弱的症状和体征，而直立通过躺卧缓解。病理生理机制仍然难以捉摸，虽然我们过去的工作表明，过多的直立中枢血容量不足的结果内脏血液池由于缺陷内脏动脉和静脉收缩。初步数据支持的假设，即一氧化氮（NO）的生产是在这些患者中，导致减少交感神经去甲肾上腺素能神经传递在连接前和连接后的网站增强。我们的方法是双重的：1）我们将使用皮内微透析和激光多普勒血流仪（LDF）来阐明NO调节去甲肾上腺素能神经传递的微血管机制，而不受混杂的全身反射变化的影响。2)我们将系统地将这种机制应用于直立性应激模型，下体负压（LBNP），同时通过惰性气体再呼吸测量心输出量，使用体积描记技术测量局部血容量和局部血流量，重点关注内脏变化，并通过腓神经显微神经造影术测量肌肉交感神经活动。将招募14-29岁的VVS、POTS和对照受试者各30例。我们将使用化学发光法测定微透析液中的NO，以检测OI是否增加。将使用微透析液去甲肾上腺素（NE）的HPLC分析，通过逐步酪胺剂量评估连接前神经传递。将通过用溴苄铵内源性阻断后LDF对NE逐步增加的反应来评估连接后神经传递。将评估基础和局部热刺激NO。我们将通过重复研究用硝基-L-精氨酸（NLA）抑制NOS后和用NLA+硝普钠（SNP）灌注期间NO补充后，确定神经传递的抑制是否是NO特异性的。我们将获得皮肤活检的NOS亚型蛋白和表达。我们将确定是否全身NO抑制前和突触后肾上腺素能活动在OI，改变对LBNP的反应。通过逐步增加LBNP和测量血浆NE反应来评估突触前神经传递。突触后神经传递将通过对逐步增加的苯肾上腺素剂量的全身反应来评估。为了确认NO特异性，在用L-NG-单甲基精氨酸（L-NMMA）抑制NOS后、在用L-NMMA +SNP灌注期间NO补充后以及在低剂量苯肾上腺素作为MSNA和血管收缩的基线变化的对照后重复研究。L-NMMA在数小时内缓慢进入CNS。为了确定其中心效应，我们将在实验结束时测量MSNA。研究将在皮肤人类替代模型中建立常见和衰弱形式的OI的分子机制，并将这些知识应用于OI的综合生理学。这项研究将导致有针对性的和有效的药物治疗 对于重要的OI患者群体。