MYOCARDIAL ISCHEMIA AND CORONARY ARTERY REPERFUSION

心肌缺血和冠状动脉再灌注

基本信息

批准号：
2217166
负责人：
STEPHEN F VATNER
金额：
$ 31.34万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-01-01 至 1996-05-31
项目状态：
已结题

项目摘要

The majority of experiments examining the effects of myocardial ischemia have been conducted in laboratory animals, most commonly dogs, cats and rats. There are relatively little data available on the effects of myocardial ischemia in primates. The objective of this research proposal is to examine the effects of coronary artery occlusion and reperfusion on measurements of regional myocardial function, i.e. endocardial and epicardial wall thickening and segment shortening, regional blood flow (radioactive microspheres), and regional biochemistry and molecular biology in chronically instrumented, conscious baboons, pigs, and dogs. There are seven specific aims. 1) To determine the relationship among the timing of coronary artery reperfusion on infarct size and recovery of regional myocardial function in conscious dogs, pigs, and baboons. 2) To determine whether the salvaged myocardium or stunned myocardium responds appropriately to inotropic stress in terms of either mechanical function or beta-adrenergic receptor signalling. 3) To determine whether collateral dependent myocardium responds appropriately to inotropic stress in terms of either mechanical function or beta-adrenergic receptor signalling. 4) To determine if the decrease in adenylyl cyclase activity in reperfused or collateralized hearts is due to a decrease in the number of units of catalyst per mg sarcolemma or due to a decrease in specific activity of the catalyst. To do this, we will: a) Use highly purified sarcolemma and perform immunoblotting to detect the amount of catalyst per mg sarcolemma. In addition, messenger RNA levels will be quantitated for the predominant cardiac isoforms of adenylyl cyclase, i.e., Types IV, V and VI. b) The catalyst of adenylyl cyclase will be purified from sarcolemma by affinity chromatography and the specific activity determined. 5) To determine whether myocardial stunning is augmented by pretreatment with Nw-nitro-L-arginine or diminished by pretreatment with L-arginine. 6) To determine whether pre-treatment can reduce "myocardial stunning" with brief periods of coronary artery occlusion in the conscious baboon using agents that affect: a. O2 free radicals or b. Calcium. 7) To determine ryanodine and dihydropyridine receptor density in membrane preparations from canine, baboon, and porcine hearts during myocardial stunning. These studies are designed to provide insight into basic mechanisms of myocardial ischemia and its relief by coronary artery reperfusion by comparing responses in chronically instrumented, conscious dogs, pigs and baboons. there are three novel features of this application. 1) To study mechanisms of myocardial ischemia in conscious primates. 2) The direct and continuous measurement of regional subendocardial vs. subepicardial function in response to ischemia in chronically-instrumented, conscious animals. 3) The ability to correlate the physiological studies above with studies at the cellular and molecular level.

大多数实验检查心肌缺血的作用已经在实验室动物，最常见的狗，猫和老鼠。关于效果的数据相对较少灵长类动物中的心肌缺血。该研究建议的目的是检查冠状动脉阻塞和再灌注的影响关于区域心肌功能的测量，即心内膜和心外膜壁增厚和段缩短，区域血流（放射性微球）以及区域生物化学和分子长期仪器，有意识的狒狒，猪和狗的生物学。有七个具体目标。 1）确定之间的关系关于梗塞大小和恢复的冠状动脉再灌注时间有意识的狗，猪和狒狒的区域心肌功能。 2）确定挽救的心肌还是惊呆的心肌根据任何一种机械响应肌力压力功能或β-肾上腺素受体信号传导。 3）确定是否附带依赖的心肌对肌力做出适当反应机械功能或β-肾上腺素能受体的压力信号。 4）确定腺苷环酶活性的减少是否减少在重复或抵押的心脏中，由于数量减少每毫克肌膜的催化剂单位或由于特定的降低催化剂的活性。为此，我们将：a）使用高度纯化肌膜并进行免疫印迹以检测催化剂的量每毫克的肌膜。此外，会员RNA水平将被定量对于腺苷环酶的主要心脏同工型，即IV型， V和VI。 b）将从亲和色谱法和特定活性决定。 5）确定心肌令人惊叹是否被增强用NW-硝基-L-精氨酸预处理或通过预处理减少 L-精氨酸。 6）确定预处理是否可以减少“心肌令人惊叹的“冠状动脉阻塞短期有意识的狒狒使用影响： O2自由基或b。钙。 7）确定ryanodine和二氢吡啶受体密度在犬，狒狒和猪心的膜制剂中心肌惊人。这些研究旨在提供有关心肌缺血的基本机制及其冠状动脉的缓解通过比较长期有意识的响应来再灌注狗，猪和狒狒。有三个新颖的功能应用。 1）研究意识中心肌缺血的机制灵长类动物。 2）区域的直接和连续测量心内膜下与心发功能响应于缺血的功能长期有意识的动物。 3）关联的能力上面的生理研究与细胞的研究和分子水平。