The Role of Epinephrine in Neurally Mediated Syncope

晕厥是一种常见的问题，多达30%的人会晕厥，占3%的人会晕厥。 急诊室访问复发性晕厥见于30-50%的患者， 当晕厥频率降低时，生活质量得到改善。这些患者中的大多数 神经介导性晕厥（NMS）NMS病理生理学的传统模型集中在先前的 交感神经激活增强，随后交感神经张力突然消退， 迷走神经紧张，导致血管舒张和心动过缓。最近的研究发现， 晕厥前肾上腺素升高。在具体目标#1中，我们将确定肾上腺素的贡献 释放和清除肾上腺素水平升高。一种β肾上腺素受体激动剂， 肾上腺素、异丙肾上腺素在临床上常用于诱导神经介导的晕厥。β阻滞 药物，特别是具有β-2拮抗作用的药物（内源性肾上腺素促进的受体 血管舒张），防止倾斜诱导的晕厥，并可能预防临床晕厥。在具体目标#2中，我们将 实验性地增加肾上腺素水平并测试这是否诱导神经介导的晕厥。的 对肾上腺素的反应很可能受到肾上腺素受体遗传异质性的显著影响。 这些受体的多态性可能很好地解释了个体间对药物敏感性的差异。 肾上腺素的血流动力学效应，可能因此也易发生晕厥。在 具体目标#3，我们将根据常见的基因多态性评估晕厥的易感性。 α-2B肾上腺素受体和β-2肾上腺素受体。利用这些具体目标，我们将测试 肾上腺素或其受体在神经介导的脑梗死发病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