Mechanisms of Vasovagal Syncope

血管迷走性晕厥的机制

基本信息

批准号：
8793208
负责人：
JULIAN M STEWART
金额：
$ 52.43万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8793208
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 Health 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 research study response vasoconstriction young woman

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 Health 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 research study response vasoconstriction young woman

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项目摘要

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）：血管腔晕厥（VV，简单的淡淡）是意识瞬时丧失的最常见原因，是体位不耐受的急性情节形式（OI）。姿势心动过速综合征（POTS）是OI的常见慢性形式。两者都是通过使症状和体征使人衰弱的，而靠着依赖的症状和体征则可以。病理生理机制仍然难以捉摸，尽管我们过去的工作表明，由于缺陷的腹膜动脉和静脉收缩，过度直立的中枢性低血容量是由于斑点血液汇集而导致的。初步数据支持以下假设：这些患者的一氧化氮（NO）的产生可增强，导致降低了交感神经能神经传递在术前和官能后部位。我们的方法是两个方面：1）我们将使用皮内微透析和激光多普勒流量指甲（LDF）来描述无需调节去甲肾上腺素能神经传递的微血管机制，没有任何混杂的全身反射变化。 2）我们将系统地将这种机制应用于原位应力，下身体负压（LBNP）的模型，同时使用散布物学技术通过散布斑点变化和肌肉交感神经活动来测量气体恢复，区域血容量和区域血流。将招募30个VV，锅和控制受试者14-29岁。我们将使用化学发光来测量微疗法中的NO，以测试OI中是否增加了它。使用微料去甲肾上腺素（NE）的HPLC分析，将通过步骤明智的酪胺剂量来评估官能神经传递。在用甲灵基封锁后，LDF对NE的逐步增加，将评估神经传递后的神经传递。刺激的基础和局部热量将被评估。我们将通过硝基-L-精氨酸（NLA）进行NOS抑制后重复研究以及在用NLA+NLA+硝化钠（SNP）灌注过程中抑制NOS抑制作用，而NO在NOS抑制后是否重复研究，我们将确定对神经传递的抑制是不明显的。我们将获得用于NOS同工蛋白和表达的NOS活检。我们将确定全身性NO是否抑制了OI突触肾上腺素能活性，从而改变了对LBNP的反应。突触前神经传递将通过逐步增加LBNP和测量等离子NE响应来评估。突触后神经传递将通过对逐步增加苯肾上腺素剂量的全身反应来评估。为了确认NO特异性，用L-NG惯性甲基精氨酸（L-NMMA），在用L-NMMA +SNP灌注期间的NO抑制后，将重复研究研究，以及低剂量的苯肾上腺素作为MSNA和血管构成基线转移的控制。 L-NMMA在许多小时内缓慢进入中枢神经系统。为了确定其中心效应，我们将在实验结束时测量MSNA。研究将建立皮肤人类替代模型中常见和使OI的共同形式的分子机制，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且有效的医疗疗法对于重要的OI患者组。