Interstitial Norepinephrine and Heart Failure

间质性去甲肾上腺素和心力衰竭

基本信息

批准号：
7247983
负责人：
JIANHUA LI
金额：
$ 24.84万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7247983
关键词：
Adenosine Triphosphate Autonomic nervous system Blood Pressure Cardiovascular Diseases Classification Congestive Heart Failure Control Animal Coronary artery Data Dimensions Efferent Neurons Evaluation Exercise Goals Heart Rate Heart failure Impairment Isometric Exercise Knowledge Laboratories Left Left Ventricular Ejection Fraction Ligation Measures Mediating Methods Microdialysis Modeling Monoamine Oxidase Muscle Muscle Contraction Myocardial Infarction Nerve Neurons Norepinephrine Nuclear Magnetic Resonance P2X-receptor Patients Peripheral Plasma Play Publishing Range Rattus Reflex action Regulation Rest Role Skeletal Muscle Stretching Stroke Volume Sympathetic Nervous System Techniques Testing Time Uracil Ventricular Ventricular End-Systolic Volumes base indexing interstitial pressure research study response reuptake tripolyphosphate uptake vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): The long-range goal of the PI is to better understand the mechanisms that regulate the autonomic responses during exercise in normal subjects and in patients with heart failure (HF). It is known that sympathetic nervous system activity is increased with exercise in normal subjects and is increased in HF subjects at rest and in response to exercise. Heightened peripheral sympathetic nerve activity and the resultant increased neurovascular levels of norepinephrine (NE) evoke vasoconstriction. In this proposal, we will measure interstitial concentrations of NE with the microdialysis method. Interstitial concentrations of NE provide an outstanding index of NE concentrations at the neurovascular junction. The proposed experiments are based on recently published studies from our laboratory as well as pilot data that have been gathered over the past year. The first and second specific aims are to examine the mechanisms for the rise in interstitial NE (NEi) and adenosine triphosphate (ATPi) in exercising muscle. We will examine if enhanced NEi is due to: 1) activation of the sympathetic nerves; 2) an ATP mediated increase in NE release; and/or 3) an ATP mediated inhibition of neuronal re-uptake of NE (uptake 1). Our data suggests that ATPi concentrations in skeletal muscle rise with muscle contraction. We hypothesize that elevated ATP increases NEi by activation of P2X receptors on the sympathetic efferent nerves, and/or by inhibition of uptake 1. The third and fourth specific aims are to examine why NEi and ATPi are higher in skeletal muscle of rats with congestive heart failure (myocardial infarctions model). We will examine if higher levels of NEi in HF rats are due to: 1) an increase in NE release by sympathetic nerve; 2) an impairment of uptake 1; 3) an inhibition of uptake 1 by elevated ATP; or 4) to activation of sympathetic nerve terminal P2X receptors by ATP. The fifth specific aim is to determine if interstitial NE and ATP change as a function of time after the myocardial infarct that induces HF. These experiments will examine ATP and NE at rest, during muscle contraction, and during muscle stretch. A key feature of this proposal is that microdialysis techniques will be used to: 1) determine NEi and ATPi; and 2) deliver specific substances to the interstitial space. Our laboratory has substantial expertise with these methods. To the best of our knowledge, experiments such as these have never been performed in a HF model. Completion of these studies in this proposal will provide a systematic evaluation of circulatory regulation during exercise in an important cardiovascular disease.

描述（由申请人提供）：PI的远距离目标是更好地了解正常受试者和心力衰竭患者（HF）运动过程中调节自主反应的机制。众所周知，正常受试者的运动随着运动而增加，在休息时HF受试者中增加并响应运动。外周交感神经活性的提高，导致的去甲肾上腺素（NE）唤起血管收缩的神经血管水平增加。在此提案中，我们将使用微透析法测量NE的间隙浓度。 NE的间质浓度在神经血管连接处提供了NE浓度的出色指数。拟议的实验是基于我们实验室最近发表的研究以及过去一年收集的试验数据。第一个和第二个特定的目的是检查运动肌肉中间质NE（NEI）和三磷酸腺苷（ATPI）升高的机制。我们将检查增强的NEI是否是由于：1）交感神经的激活； 2）ATP介导的NE释放增加；和/或3）ATP介导的NE神经元重摄取的抑制（摄取1）。我们的数据表明，随着肌肉收缩，骨骼肌的ATPI浓度升高。我们假设升高的ATP通过在交感神经传出神经上激活P2X受体和/或通过抑制摄取1来增加NEI。第三和第四个具体的目的是检查为什么NEI和ATPI在具有充血性心脏失败的大鼠骨骼肌中较高的NEI和ATPI较高（心脏衰减模型）。我们将检查HF大鼠中较高水平的NEI是否是由于：1）交感神经的NE释放增加； 2）摄取1; 3）升高ATP对摄取1的抑制作用；或4）通过ATP激活交感神经末端P2X受体。第五个具体目的是确定诱导HF的心肌梗死后的时间内部和ATP是否随时间变化。这些实验将在静止，肌肉收缩期间和肌肉伸展过程中检查ATP和NE。该提案的关键特征是微透析技术将用于：1）确定NEI和ATPI； 2）将特定物质运送到间质空间。我们的实验室在这些方法方面具有丰富的专业知识。据我们所知，诸如此类的实验从未在HF模型中进行。在重要的心血管疾病中，该提案中这些研究的完成将对运动过程中的循环调节进行系统的评估。