The Role of Epinephrine in Neurally Mediated Syncope

晕厥是一种常见的问题，高达30%的人晕倒，占3% 急诊室就诊。30%-50%的患者出现反复晕厥，并与较差的 当晕厥频率减少时，生活质量会得到改善。这些患者中的大多数都遭受着 来自神经介导性晕厥(NMS)。传统的NMS病理生理学模型主要集中在先证者 交感神经高度激活，随后交感神经张力突然消失， 迷走神经紧张症，伴随血管扩张和心动过缓。最近的研究发现， 肾上腺素在晕厥之前升高。在特定的目标#1中，我们将确定肾上腺素的贡献 释放和清除升高的肾上腺素水平。一种β肾上腺素受体激动剂，类似于 肾上腺素、异丙肾上腺素是临床上常用的诱发神经源性晕厥的药物。Beta-阻止 药物，特别是那些具有β-2拮抗作用的药物(内源性肾上腺素促进的受体 血管扩张)，防止倾斜诱导的晕厥，并可能防止临床晕厥。在具体目标2中，我们将 通过实验增加肾上腺素水平，并测试这是否会导致神经介导性晕厥。这个 肾上腺素受体的遗传异质性可能在很大程度上影响对肾上腺素的反应。 这些受体的多态可能很好地解释了个体之间对 肾上腺素对血流动力学的影响，并可能导致晕厥的易感性。在……里面 具体目标#3，我们将根据常见的基因多态性来评估晕厥的易感性 α-2B肾上腺素受体和β-2肾上腺素受体。使用这些特定的目标，我们将测试 肾上腺素或其受体在神经介导性糖尿病发病机制中起重要作用的假说 晕厥

Syncope is a common problem experienced by up to 30% of people fainting and accounting for 3% of emergency room visits. Recurrent syncope is seen in 30-50% of patients and is associated with a poor quality of life that improves when the frequency of syncope is reduced. The majority of these patients suffer from neurally mediated syncope (NMS). The traditional model of NMS pathophysiology has focused on prior heightened sympathetic activation, followed by a sudden withdrawal of sympathetic tone and increase in vagal tone, with resultant vasodilation and bradycardia. Recent studies have found that the level of epinephrine rises PRIOR to syncope. In Specific Aim #1, we will determine the contributions of epinephrine release and clearance to the elevated epinephrine levels. A beta adreneroreceptor agonist similar to epinephrine, isoproterenol is commonly used clincially to induce neurally mediated syncope. Beta- blocking drugs, in particular those with beta-2 antagonism (the receptor at which endogenous epinephrine promotes vasodilation), prevent tilt-induced syncope, and might prevent clinical syncope. In Specific Aim #2, we will experimentally increase the epinephrine level and test whether this induces neurally mediated syncope. The response to epinephrine is likely to be substantially influenced by genetic heterogeneity in adrenoreceptors. Polymorphisms of these receptors might well account for inter-individual differences in sensitivity to the hemodynamic effects of epinephrine, and possibly in consequence, also susceptibility to syncope. In Specific Aim #3, we will assess the susceptibility to syncope based upon common polymorphisms of the alpha-2B adrenoreceptor and the beta-2 adrenoreceptor. Using these Specific Aims, we will test the hypothesis that epinephrine or its receptors play an important role in the pathogenesis of neurally mediated syncope