Coronary Vascular Response to Ischemia

描述（由申请方提供）：本提案中的研究将检查冠状血管对心肌缺血的反应，并确定一氧化氮（NO）或超氧化物（O2-）的改变是否影响缺血区域的血管或心肌反应。将在长期使用仪器的犬中进行研究，其中使用多普勒流量计测量冠状动脉血流，同时使用超声微晶评估局部收缩期壁增厚。用微球测量心肌灌注;主动脉和冠状静脉导管将允许测量冠状动脉NO的产生。计划进行三组不同的研究。第一组将检查对每日5次2分钟冠状动脉闭塞的侧支血管发育;将根据闭塞期间给予微球获得的血流测量值评估侧支血管发育。将使用长期植入的导管收集心肌间质液，用于测量培养的内皮细胞和平滑肌细胞中的血管内皮生长因子、NO代谢物和促有丝分裂活性。由于NO是侧支血管生长的重要介质，并且由于在缺血和再氧合期间产生的超氧化物（O2-）消耗NO，因此研究将确定用超氧化物歧化酶（SOD）模拟物清除O2-是否可以增强侧支血管生长。由于HMG CoA还原酶抑制剂增加了培养的内皮细胞中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增加侧支血管的发育。第二组研究将检查侧支血管和通过侧支通道灌注的微血管中内皮功能障碍的机制。体内和体外研究将确定在侧支依赖区域的冠状动脉微血管中NO产生是否减少和/或O2-产生是否增加。将通过确定SOD模拟物是否可以改善通过侧支通道灌注的微血管中的内皮功能来检查O2-的作用。最后一组研究将检查通过侧支通道灌注的心肌的生物能量变化。这些研究将确定具有持续收缩功能障碍的存活的侧支依赖性心肌（"冬眠心肌"）是否在静息或应激期间表现出不同于缺血或顿抑心肌的高能磷酸盐（HEP）含量的独特模式。询问心肌脱氧肌红蛋白含量将证实静息时或儿茶酚胺诱导的应激时侧支心肌的收缩异常是否是氧不足的结果。最后一项研究将检查NO对侧支心肌能量供应/需求关系的影响。

DESCRIPTION (provided by applicant): 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 (O2-) 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 O2- 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 O2- production increased in coronary microvessels in collateral-dependent regions. The role of O2- 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.