Blood pressure, reactivity, metabolism and serotonin

该项目的主要目的是确定心血管疾病的几种生物学危险因素是否与中枢5-羟色胺能（5- HT）反应性降低有关，无论是单独的还是总体的。生物学风险因素包括血压、心血管反应性和其他自主神经失调指标，以及“胰岛素抵抗综合征”背后的代谢异常。第二个目的是确定中枢血清素能反应性不同的个体在血管疾病的临床前指标上是否也不同。最后的目的是探索高血压和胰岛素抵抗遗传易感性大鼠中枢血清素反应迟钝的潜在神经生物学机制。我们建议招募一个社区样本，包括600名男性和女性，年龄在30-50岁之间，没有心血管疾病史。受试者将接受神经精神药理学挑战，以评估中枢血清素能反应（血浆催乳素和ACTH对选择性5-羟色胺再摄取抑制剂西酞普兰的反应）。将对所有受试者进行生物风险因素的基本评估。从中枢5-羟色胺反应分布的上下三分之一（以受试者西酞普兰诱导的催乳素反应为指标）抽取300人的子样本，进行更详细的检查。这些包括动态血压监测；心理生理学实验室评估心血管对精神压力、心率变异性和压力感受器敏感性的反应；内脏脂肪组织的计算机断层扫描测量频率样静脉葡萄糖耐量试验测定胰岛素抵抗并测量内皮介导的肱动脉舒张、颈动脉内内侧厚度及动脉粥样硬化斑块。动物实验将开始阐明自发性高血压大鼠5- HT反应迟钝的神经机制。该项目将首次对以下假设进行系统测试：动脉粥样硬化疾病的几种风险来源聚集在一起，部分是在涉及中枢血清素能功能改变的共同神经生物学机制的影响下。支持这一假设将进一步加深我们对心血管疾病危险因素起源的理解，并为可能的病因共性提供线索。（应该注意的是，项目1的数据收集是基于相同的参与者队列）。

The principal objective of this Project is to establish whether several biological risk factors for cardiovascular disease are associated, individually and in aggregate, with diminished central serotonergic (5- HT) responsivity. Biological risk factors of interest include blood pressure, cardiovascular reactivity and other indices of autonomic dysregulation, and metabolic abnormalities underlying the "insulin resistance syndrome." A second aim is to determine whether individuals differing in central serotonergic responsivity also differs in preclinical indicators of vascular disease. A final objective is to explore the underlying neurobiologic mechanism, for blunted central serotonergic responsivity in rats genetically predisposed to hypertension and insulin resistance. We propose to recruit a community sample of 600 men and women, 30-50 years of age and without a history of cardiovascular disease. Subjects will be administered a neuropsychopharmacologic challenge to evaluate central serotonergic responsivity (plasma prolactin and ACTH responses to the selective 5-HT reuptake, inhibitor, citalopram. A basic evaluation of biological risk factors will be performed on all subjects. A subsample of 300 individuals, derived from the lower and upper tertiles of the distribution of central 5-HT responsivity (as indexed by subject's citalopram-induced prolactin responses), will undergo more detailed examinations. These include ambulatory blood pressure monitoring; psychophysiologic laboratory assessments of cardiovascular reactions to mental stress, heart rate variability, and baroreceptor sensitivity; measurement of visceral adipose tissue with computer tomography; determination of insulin resistance with the frequency sample intravenous glucose tolerance test; and measurement of endothelium-mediated dilation of the brachial artery, carotid artery intima-medial thickness and atherosclerotic plaque. Animal experiments will begin to elucidate the neural mechanism for blunted 5- HT responsivity in spontaneously hypertensive rats. THIS Project will provide the first systematic test of the hypotheses that several sources of risk for atherosclerotic disease aggregate, in part, under the influence of a common neurobiologic mechanism involving altered central serotonergic function. Support for this hypothesis will further our understanding of the origins of risk factors for cardiovascular disease and provide clues to possible commonalities of etiology. (It should be noted that Project 1 data collection is based upon the same participant cohort).