EFFECT OF DRUGS UPON MYOCARDIAL HYPOXIA

本提案的长期目标是确定 钾（K）通道，特别是腺苷三磷酸调节的 钾通道（KATP）在局部心肌血流量调节中的作用 在不同的模型中， 缺血 初步结果表明，几个新的K通道， 开放器（KCO）具有不同的心脏效应，以改善功能和 心脏的代谢恢复和减少缺血后的梗死面积 和再灌注。 相反，我们还表明， KATP依赖性通道拮抗剂格列本脲， KCO的有益作用，甚至可能加剧缺血性损伤。 因此，本提案的主要目标是确定 开放或阻断KATP通道在可逆性损伤中的作用 （“休克”）或不可逆损伤（“梗死”）的心肌 麻醉犬接受短暂（15分钟）的长时间（90 分钟）的冠状动脉闭塞时间，然后再灌注， 所涉及的机制。 在顿抑心肌中，局部室壁运动将 通过超声尺寸测量仪、局部心肌血流量 通过放射性微球和组织活检的代谢状态 在缺血和再灌注期间的不同时间获得。 梗死面积 研究中，组织死亡的程度将由 三苯基四氮唑组织化学技术。 允许再灌注 5或24小时，以确定KCO是否仅延迟或产生延长的 减少梗塞面积。 将使用骨髓过氧化物酶作为 中性粒细胞浸润至正常、缺血性非梗死和梗死 心肌和体外实验将检查KATP通道的作用 对中性粒细胞功能的影响。 初步 研究表明，几种KCO减少了中性粒细胞浸润， 在体缺血心肌和抑制激活的超氧化物产生 体外嗜神经细胞。 KCO的亲或抗肿瘤性质或 拮抗剂也将通过霍尔特监测进行评估。 自从少校 顿抑心肌和组织功能恢复决定因素 梗死心肌的存活率是侧支血流量， 第二个主要目标是确定KCO对 不同程度冠状动脉侧支循环 并行发展 冠状小动脉和侧支血管阻力 将计算以确定KCO对这些的相对选择性。 体内血管 孤立性大冠状动脉和成熟侧支血管 将在体外分离和研究，以进一步表征 KCO扩张侧支血管的选择性。 KATP通道 拮抗剂，格列本脲，甲苯磺丁脲，5-羟基癸酸钠，将是 用于确定对这些代理有选择性的通道是否负责 KCO对侧支血管的有益作用。 的结果 这些研究将为KATP的独特作用提供令人兴奋的新数据 通道在心肌缺血再灌注损伤中的作用。

The long term goal of the present proposal is to determine the role of potassium (K) channels, particularly adenosine triphosphate-regulated potassium (KATP) channels in the regulation of regional myocardial blood flow, cardiac muscle function and cell viability in different models of ischemia. Preliminary results indicate that several novel K channel openers (KCOs) have a different cardiac effect to improve functional and metabolic recovery of the heart and reduce infarct size following ischemia and reperfusion at nonhypotensive doses. Conversely, we have also shown that the KATP-dependent channel antagonist, glyburide, blocks the beneficial actions of the KCOs and may even exacerbate ischemic injury. Thus, the major objective of the present proposal will be to determine the function of opening or blocking KATP channels in the reversibly injured ("stunned") or irreversibly injured ("infarcted") myocardium of anesthetized dogs subjected to brief (15 minutes ) of prolonged (90 minutes) periods of coronary artery occlusion followed by reperfusion and the mechanisms involved. In stunned myocardium, regional wall motion will be assessed by ultrasonic dimension gauges, regional myocardial blood flow by radioactive microspheres and metabolic status by tissue biopsies obtained at various times during ischemia and reperfusion. In infarct size studies, the extent of tissue death will be determined by the triphenyltetrazolium histochemical technique. Reperfusion will be allowed for 5 or 24 hours to determine if KCOs only delay or produce a prolonged reduction in infarct size. Myeloperoxidose will be used as an index of neutrophil infiltration into normal, ischemic non-infarcted and infarcted myocardium and in vitro experiments will examine the role of KATP channels on neutrophil function as assessed by chemiluminescence. Preliminary studies have shown that several KCOs reduce neutrophil infiltration into ischemic myocardium in vivo and inhibit superoxide production in activated neurophils in vitro. The pro- or antiarrhythmic properties of the KCOs or antagonists will also be assessed by Holter monitoring. Since the major determinant of functional recovery in stunned myocardium and tissue survival in infarcted myocardium is the amount of collateral blood flow, a second major objective will be to determine the effects of KCOs on the coronary collateral circulation in dogs with different degrees of collateral development. Coronary arteriolar and collateral resistances will be calculated to determine relative selectivity of KCOs for these vessels in vivo. Isolated large coronary and mature collateral vessels will be isolated and studied in vitro to further characterize the selectivity of KCOs to dilate collateral vessels. KATP channel antagonists, glyburide, tolbutamide, sodium 5-hydroxydeconoate, will be used to determine if channels selective to these agents are responsible for the beneficial actions of the KCOs in collateral vessels. The results of these studies will provide exciting new data on the unique role of KATP channels in myocardial ischemia-reperfusion injury.