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

• 批准号: 8073032
• 负责人: James Anthony Sheerin Muldowney
• 金额: $ 12.73万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073032
• 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; 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

DESCRIPTION (provided by applicant): 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 in nervation 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. 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.

描述（由申请人提供）：纤溶系统是血栓级联反应的生理平衡。当止血受到影响时，纤维蛋白凝块的产生、范围和位置至关重要。组织型纤溶酶原激活剂或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）而从脉管系统释放。t-PA的生理释放被可改变的心脏危险因素如吸烟、高血压、高脂血症和肥胖所有害地改变。这些危险因素的改变有利地改变了血管t-PA的释放。我们的小组已经发现，凝血酶，而不是缓激肽刺激内皮t-PA释放在体外。此外，最近有证据表明，交感神经元，除了内皮细胞，释放t-PA在体内缓激肽的反应。总之，这些发现表明，外膜交感神经元可能在血管健康中发挥关键作用。该建议的中心假设是，血管神经支配是人体血管t-PA释放和整体血管功能的关键参与者。为了验证这一假设，我们提出了以下临床研究。我们打算测量缓激肽介导的t-PA释放的人前臂之前和之后的阻断全身交感神经流出的短效中枢α-2肾上腺素能拮抗剂右美托咪定。我们还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，在移植受者和对照谁正在接受择期心导管插入术缓激肽。将要求受试者返回综合临床研究中心，测量前臂的t-PA释放和流量。此外，血浆t-PA水平升高和小动脉平滑肌t-PA缺失可预测同种异体移植受者的加速移植血管病变和移植失败。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缓激肽输注对有和无移植血管病变的移植受者t-PA释放的影响。 更好地了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，这将导致新的战略和范式在血管疾病的管理。随着血管疾病在全国和世界范围内的压倒性流行，新的见解和策略有可能转化为巨大的公共卫生影响。