The Role of Epinephrine in Neurally Mediated Syncope

肾上腺素在神经介导性晕厥中的作用

• 批准号: 6979853
• 负责人: SATISH R RAJ
• 金额: $ 12.4万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6979853
• 关键词: adrenergic receptor; beta antiadrenergic agent; clinical research; disease /disorder etiology; epinephrine; genetic polymorphism; genetic susceptibility; human subject; neuroregulation; patient oriented research; postural hypotension; syncope

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.

描述（由申请人提供）： 晕厥是多达30％的晕倒和占急诊室就诊的3％的常见问题。在30-50％的患者中可以看到复发性的晕厥，并且与降低晕厥频率时的生活质量差有关。这些患者中的大多数患有神经介导的晕厥（NMS）。 NMS病理生理学的传统模型集中在事先提高交感神经激活上，然后突然戒断交感神经音调和迷走神经张力的增加，导致血管舒张和心动过缓。最近的研究发现，肾上腺素的水平在晕厥之前上升。在特定的目标＃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。与肾上腺素类似的β肾上腺激动剂激动剂，异丙肾上腺素通常在临床上用于诱导神经介导的晕厥。 β-阻断药物，尤其是患有β-2拮抗作用的药物（内源性肾上腺素促进血管舒张的受体），可以防止倾斜诱导的晕厥，并可能阻止临床晕厥。在特定的目标＃2中，我们将通过实验提高肾上腺素水平，并测试这是否诱导神经介导的晕厥。肾上腺素对肾上腺素的反应可能受到肾上腺受体的遗传异质性的显着影响。 这些受体的多态性很可能解释了对肾上腺素血液动力学作用的敏感性的个体间差异，也可能导致对晕厥的敏感性。在特定的目标＃3中，我们将根据α-2B肾上腺受体和β-2肾上腺受体的常见多态性评估晕厥的敏感性。使用这些特定目的，我们将检验以下假设：肾上腺素或其受体在神经介导的晕厥的发病机理中起重要作用。