Coronary Vascular Response to Ischemia

描述（由申请人提供）：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。研究将在长期使用仪器的狗身上进行，用多普勒流量计测量冠状动脉血流，同时用超声微晶体评估局部收缩壁增厚。用微球测定心肌灌注；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。第一组将检查每天5次2分钟冠状动脉闭塞后侧支血管的发育情况；侧枝发育将通过在闭塞期间使用微球获得的血流测量来评估。采用长期植入导管收集心肌间质液，测定培养的内皮细胞和平滑肌细胞的血管内皮生长因子、NO代谢物和有丝分裂活性。由于NO是侧支血管生长的重要介质，并且由于缺血和再氧化过程中产生的超氧化物（O2-）消耗NO，因此一项研究将确定用超氧化物歧化酶（SOD）模拟物清除O2-是否可以促进侧支血管生长。由于HMG辅酶a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辅酶a还原酶抑制剂阿托伐他汀是否可以促进侧支血管的发育。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内皮功能障碍的机制。体内和体外研究将确定在侧枝依赖区域的冠状动脉微血管中是否会减少NO的产生和/或增加O2的产生。O2-的作用将通过确定SOD模拟物是否可以改善通过侧支通道灌注的微血管的内皮功能来检验。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改变。这些研究将确定具有持续性收缩功能障碍的活的侧脉依赖性心肌（“冬眠心肌”）在休息或应激时是否表现出与缺血或休克心肌不同的独特的高能磷酸盐（HEP）含量模式。对心肌脱氧肌红蛋白含量的询问将证明静息或儿茶酚胺诱导应激时侧索心肌的收缩异常是否是氧不足的结果。最后的研究将探讨一氧化氮对侧支心肌能量供需关系的影响。

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.