The Role of Epinephrine in Neurally Mediated Syncope

描述（由申请人提供）： 晕厥是一种常见的问题，高达30%的人会晕倒，占急诊室就诊的3%。复发性晕厥见于30-50%的患者，并与生活质量差有关，当晕厥频率降低时，生活质量会改善。这些患者中的大多数患有神经介导性晕厥（NMS）。NMS病理生理学的传统模型集中于先前增强的交感神经激活，随后是交感神经张力的突然撤回和迷走神经张力的增加，从而导致血管舒张和心动过缓。最近的研究发现，肾上腺素的水平上升之前，晕厥。在特定目标1中，我们将确定肾上腺素释放和清除对肾上腺素水平升高的贡献。异丙肾上腺素是一种与肾上腺素相似的β肾上腺素受体激动剂，临床上常用于诱导神经介导的晕厥。β-受体阻滞剂，特别是β-2拮抗剂（内源性肾上腺素促进血管舒张的受体），可预防倾斜诱导的晕厥，并可能预防临床晕厥。在具体目标#2中，我们将通过实验增加肾上腺素水平，并测试这是否会诱导神经介导的晕厥。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肾上腺素的血流动力学效应的敏感性个体间差异，并可能因此，也晕厥的易感性。在具体目标3中，我们将根据α-2B肾上腺素受体和β-2肾上腺素受体的常见多态性评估晕厥的易感性。利用这些特定目的，我们将检验肾上腺素或其受体在神经介导的晕厥发病机制中起重要作用的假设。

DESCRIPTION (provided by applicant): 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 clinically 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.