THROMBIN, ENDOTHELIUM & VASOSPASM IN MYOCARDIAL ISCHEMIA

凝血酶，内皮

基本信息

批准号：
3356959
负责人：
DAVID D KU
金额：
$ 9.88万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-09-30 至 1991-09-29
项目状态：
已结题

项目摘要

The pathogenesis of coronary arterial spasm and its role in ischemic heart disease has long been a subject of great interest to both clinicians and basic scientists. Although extensive research efforts have been made to elucidate the mechanism of coronary vasospasm, it has, to a large extent, remained not well understood. In our studies with isolated canine as well as human coronary arteries, we reported that an important bioregulatory enzyme, thrombin, which is readily activated during vascular injury produced two contrasting coronary vascular effects. In coronary arteries with intact endothelium, thrombin produces a potent vasorelaxation, while in endothelium-disrupted canine and human coronaries or in ischemically injured canine coronary arteries, thrombin produces a potent vasoconstrictory effect. Results of these studies suggest that intimal endothelial cells might play a far more important role in the regulation of coronary circulation and vascular reactivity than has been thought previously, and that an altered vascular response in coronary arteries with pathologically or mechanically injured endothelium may contribute to the development of severe coronary vasoconstriction and vasospasm. Therefore, the primary overall objective as well as the long term goal of our research proposal is to study the pathophysiological role of intimal endothelial cells in the modulation of human coronary vascular reactivity and its alterations in ischemic heart disease. Specifically, attempts will be made 1) to determine the mechanism(s) as well as the pathophysiological role of thrombin- induced endothelium-dependent vasodilation and, perhaps more importantly, its direct endothelium-independent vasoconstriction in human coronary arteries, 2) to determine the effects of myocardial ischemia and atherosclerosis on human coronary vascular responsiveness to thrombin and other vasoactive agents, and 3) to determine possible changes in the vascular responsiveness of human saphenous veins to thrombin and other vasoactive agents following their transplantation to the coronary circulation. It is hoped that results of these proposed studies will provide a better control of the patency of the grafts and human coronary arteries to minimize the incidences of recurring occlusion.

冠状动脉痉挛的发病机制及其在冠状动脉痉挛中的作用缺血性心脏病长期以来一直是人们非常感兴趣的课题临床医生和基础科学家。尽管进行了广泛的研究人们努力阐明冠心病的机制血管痉挛，在很大程度上，仍然不好明白了。在我们对孤立的犬类和人类的研究中冠状动脉，我们报道了一个重要的生物调节凝血酶，在血管生成过程中很容易被激活损伤产生两种截然不同的冠状血管效应。在冠状动脉内皮完整，凝血酶产生有效的血管舒张作用，而在内皮细胞破坏的犬科动物中人类冠状动脉或缺血性损伤的犬冠状动脉凝血酶在动脉中产生有效的血管收缩作用。这些研究结果表明内膜内皮细胞可能在冠状动脉的调节中发挥更重要的作用循环和血管反应性比想象的要高以前，冠状动脉血管反应改变内皮受到病理或机械损伤的动脉可能会导致严重冠心病的发展血管收缩和血管痉挛。因此，首要的总体目标和长期目标我们研究计划的目标是研究病理生理学内膜内皮细胞在人体调节中的作用缺血性心脏冠状血管反应性及其变化疾病。具体来说，将尝试 1) 确定机制以及凝血酶的病理生理学作用诱导内皮依赖性血管舒张，也许更多重要的是，它具有直接的内皮依赖性血管收缩作用在人类冠状动脉中，2) 确定人体冠状动脉心肌缺血和动脉粥样硬化血管对凝血酶和其他血管活性剂的反应， 3) 确定血管可能发生的变化人类隐静脉对凝血酶和其他物质的反应移植到冠状动脉后的血管活性药物循环。希望这些拟议研究的结果能够更好地控制移植物和人体的通畅冠状动脉，以尽量减少复发的发生率闭塞。