Coronary Vascular Response to Ischemia

这项建议中的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)或超氧化物歧化酶(02-)的变化是否影响缺血时的血管或心肌反应 地区。研究将在长期使用仪器的狗身上进行，在其中测量冠状动脉血流 超声微晶体评价局部收缩期室壁增厚。心肌 血流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 没有生产。计划进行三组不同的研究。第一组将检查侧支血管 每天5次2分钟冠状动脉闭塞后的发展情况；侧枝循环的发展情况将进行评估 根据在闭塞期间注射微球所获得的血流量测量。心肌间质液 将使用长期植入的导管收集，以测量血管内皮生长因子，NO 培养的内皮细胞和平滑肌细胞的代谢物和有丝分裂活性。因为NO是一个重要的调解人 对于侧支血管的生长，由于在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-是否可以增强络脉 成长。由于HMG辅酶A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促进侧枝血管的发育。一个 第二组研究将研究侧支血管内皮细胞功能障碍的机制 微血管通过侧支循环灌流。体内和体外研究将确定是否没有产生 侧支依赖区域的冠脉微血管中02-产生减少和/或增加。02的作用- 将通过确定超氧化物歧化酶模拟物是否可以改善微血管的内皮功能来进行检验 通过间接渠道。最后一组研究将检查心肌灌流后的生物能量变化。 通过间接渠道。这些研究将确定存活的侧支依赖心肌是否具有 持续性收缩功能障碍(冬眠心肌)表现出一种独特的高能磷酸盐模式。 (HEP)静息或应激状态下的含量不同于缺血或顿抑心肌。心肌讯问 脱氧肌球蛋白含量将显示静息或静息状态下侧支心肌的收缩异常 儿茶酚胺引起的应激反应是氧气不足的结果。最后一项研究将考察 关于侧支心肌的能量供需关系。

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.