Coronary Vascular Response to Ischemia

超出提供的空间。这项研究将检查冠状动脉对心肌缺血的反应，并确定一氧化氮(NO)或超氧化物(02-)的变化是否会影响缺血区的血管或心肌反应。研究将在长期使用仪器的狗身上进行，其中冠状动脉血流用多普勒血流计测量，而局部收缩期壁增厚则用超声微晶体评估。心肌灌注是用微球测量的；主动脉和冠状动脉静脉导管将允许测量冠状动脉一氧化氮的产生。计划进行三组不同的研究。第一组将检查每天5次2分钟冠状动脉闭塞后侧支血管的发育情况；侧支血管发育将通过闭塞期间注射微球获得的血流测量进行评估。心肌间质液将使用长期植入的导管收集，用于测定培养的内皮细胞和平滑肌细胞中血管内皮生长因子、一氧化氮代谢产物和促有丝分裂活性。由于NO是侧支血管生长的重要介质，而缺血和复氧过程中产生的超氧化物(O2-)消耗NO，一项研究将确定用超氧化物歧化酶(SOD)模拟物清除02-是否可以促进侧支血管生长。由于HMG CoA还原酶抑制剂增加了培养内皮细胞中NO的生物利用度，另一项研究将确定HMG CoA还原酶抑制剂阿托伐他汀是否可以促进侧枝血管的发育。第二组研究将研究侧支血管和通过侧支血管灌流的微血管内皮细胞功能障碍的机制。体内和体外研究将确定侧支依赖区域的冠状动脉微血管中NO的产生是否减少和/或02-产生的增加。02-的作用将通过确定SOD模拟物是否可以改善通过侧支循环灌流的微血管的内皮功能来检验。最后一组研究将检查通过侧支循环灌流的心肌中的生物能量变化。这些研究将确定存活的伴持续性收缩功能障碍的侧支依赖心肌(冬眠心肌)是否表现出与缺血或顿抑心肌不同的静息或应激状态下高能磷酸(HEP)含量的独特模式。对心肌脱氧肌球蛋白含量的询问将证明，在静息或儿茶酚胺诱导的应激过程中，侧支心肌的收缩异常是否是由于缺氧造成的。最后一项研究将探讨NO对侧支心肌能量供需关系的影响。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. The studies in this proposal will examine responses of the coronary vessels to myocardial ischemia, and determine whether alterations of nitric oxide (NO) or superoxide (02-) influence vascular or myocardial responses in ischemic regions. Studies will be performed in chronically instrumented dogs in which coronary artery blood flow is measured with a Doppler flowmeter while regional systolic wall thickening is assessed with ultrasonic microcrystals. Myocardial perfusion is measured with microspheres; aortic and coronary venous catheters will allow measurements of coronary NO production. Three different groups of studies are planned. The first group will examine collateral vessel development in response to five daily 2-minute coronary artery occlusions; collateral development will be assessed from blood flow measurements obtained by administering microspheres during occlusion. Myocardial interstitial fluid will be collected using a chronically implanted catheter for measurement of vascular endothelial growth factor, NO metabolites and mitogenic activity in cultured endothelial and smooth muscle cells. Since NO is an important mediator for collateral vessel growth, and since superoxide (O2-) produced during ischemia and reoxygenation consumes NO, a study will determine whether scavenging 02- with a superoxide dismutase (SOD) mimetic can augment collateral growth. Since HMG CoA reductase inhibitors increase NO bioavailability in cultured endothelial cells, another study will determine whether the HMG CoA reductase inhibitor atorvastastin can augment collateral vessel development. A second group of studies will examine mechanisms responsible for endothelial dysfunction in collateral vessels and microvessels perfused through collateral channels. In vivo and in vitro studies will determine whether NO production is decreased and/or 02- production increased in coronary microvessels in collateral-dependent regions. The role of 02- will be examined by determining whether the SOD mimetic can improve endothelial function in microvessels perfused through collateral channels. A final group of studies will examine bioenergetic alterations in myocardium perfused through collateral channels. These studies will determine whether viable collateral-dependent myocardium with persistent contractile dysfunction ("hibernating myocardium") demonstrates a unique pattern of high energy phosphate (HEP) content at rest or during stress different from ischemic or stunned myocardium. Interrogation of myocardial deoxymyoglobin content will demonstrate whether contractile abnormalities in collateralized myocardium at rest or during catecholamine-induced stress are the result of oxygen insufficiency. A final study will examine the influence of NO on the energy supply/demand relationship in collateralized myocardium. PERFORMANCE SITE ========================================Section End===========================================