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The Role of Vascular Innervation on Tissue-type Plasminogen Activator Release

血管神经支配对组织型纤溶酶原激活剂释放的作用

基本信息

批准号：
8476246
负责人：
James Anthony Sheerin Muldowney
金额：
$ 12.63万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8476246
关键词：
Acetylcholine Adrenergic Antagonists Allografting Alteplase Argipressin Biopsy Blood Vessels Blood flow Bradykinin Cardiac Cardiac Catheterization Procedures Catecholamines Clinical Research Coagulation Process Coronary Cyclosporine Dexmedetomidine Endothelium Equilibrium Fibrin Forearm Generations Health Heart Transplantation Hemostatic function Human Hyperlipidemia Hypertension Immunosuppression Impairment In Vitro Infusion procedures Instruction Lead Location Measures Mediating Modification Neurohormones Neurons Obesity Pain Participant Pathway interactions Peptide Hydrolases Physiological Plasma Plasminogen Activator Play Population Prevalence Public Health Risk Factors Role Schedule Sirolimus Smoking Smooth Muscle Substance P System Testing Thrombin Thrombosis Time Tissues Translating Transplant Recipients Transplantation Vascular Diseases Vasomotor graft failure in vivo insight nerve supply novel response standard of care vascular bed

项目摘要

The fibrinolytic system is the physiologic counterbalance to the thrombosis cascade. The generation, extent, and location of the fibrin clot are critical when hemostasis is compromised. Tissue-type plasminogen activator or t-PA is the initial protease of this pathway and is released from the vasculature in response to numerous neurohormones including acetylcholine, catecholamines, substance P, arginine vasopressin and bradykinin. Physiologic release of t-PA is deleteriously altered by modifiable cardiac risk factors such as smoking, hypertension, hyperlipidemia and obesity. Modification of these risk factors favorably alters vascular t-PA release. Our group has found that thrombin, but not bradykinin stimulates endothelial t-PA release in vitro. Furthermore, here has been recent evidence that sympathetic neurons, in addition to the endothelium, release t-PA in response to bradykinin in vivo. Taken together, these findings suggest that adventitial sympathetic neurons may play a critical role in vascular health. The central hypothesis of this proposal is that vascular innervation is a critical participant in human vascular t-PA release and overall vascular function. In order to test this hypothesis, we propose the following clinical studies. We intend measure bradykinin mediated t-PA release in the human forearm before and after blockade of systemic sympathetic outflow with the short acting central alpha-2 adrenergic antagonist dexmedetomidine. We also propose to perform intracoronary bradykinin infusions in order to measure the change in t-PA release and flow in response to bradykinin in transplant recipients and controls who are undergoing elective cardiac catheterization. Subjects will be asked return to the General Clinical Research Center to have t-PA release and flow measured in the forearm in response. In addition, elevated plasma t-PA levels and the absence of arteriolar smooth muscle t-PA predict accelerated transplant vasculopathy and graft failure in allograft recipients. As this may effect the response of bradykinin mediated t-PA release, we will compare the effects of intrabrachial and intracoronary bradykinin infusions on t-PA release in transplant recipients with and without transplant vasculopathy. RELEVANCE (See instructions): A better understanding of the impact of sympathetic innervation on vascular function, especially with regard to fibrinolytic balance, will provide novel insights that would lead to new strategies and paradigms in the management of vascular diseases. With the overwhelming prevalence of vascular disease nationally, and worldwide, new insights and strategies have the potential translate to a tremendous public health impact.

纤溶系统是血栓级联反应的生理平衡。一代人，当止血受到影响时，纤维蛋白凝块的范围和位置至关重要。组织纤溶酶原激活剂或t-PA是该途径的初始蛋白酶，并响应于许多神经激素，包括乙酰胆碱、儿茶酚胺、P物质、精氨酸加压素和缓激肽t-PA的生理性释放被可改变的心脏风险因素如吸烟、高血压、高脂血症和肥胖。这些风险因素的改变有利于改变血管t-PA释放。我们的研究小组已经发现，凝血酶，而不是缓激肽刺激内皮t-PA 体外释放。此外，最近有证据表明，除了交感神经元外，内皮细胞对缓激肽的反应释放t-PA。综上所述，这些发现表明，外膜交感神经元可能在血管健康中起关键作用。这个提议的中心假设是血管神经支配是一个重要的参与者，人血管t-PA释放和整体血管功能。为了验证这一假设，我们提出了以下临床研究。我们打算阻滞全身交感神经前后缓激肽介导的人前臂t-PA释放短效中枢α-2肾上腺素能拮抗剂右美托咪定。我们亦建议进行冠状动脉内缓激肽输注，以测量t-PA释放和流量的变化，心脏移植受者和对照者对缓激肽的反应漂浮导管将要求受试者返回综合临床研究中心进行t-PA放行并测量前臂中的流量作为响应。此外，血浆t-PA水平升高和缺乏小动脉平滑肌t-PA预测同种异体移植物加速性血管病变和移植物衰竭受惠人士由于这可能影响缓激肽介导的t-PA释放的反应，我们将比较肱动脉内和冠状动脉内输注缓激肽对移植受者t-PA释放的影响没有移植血管病变。相关性（参见说明）：更好地理解交感神经支配对血管功能的影响，特别是关于纤溶平衡，将提供新的见解，将导致新的战略和范式，血管疾病的管理。随着血管疾病在全国范围内的压倒性流行，在世界范围内，新的见解和战略有可能转化为巨大的公共卫生影响。