EFFECT OF DRUGS UPON MYOCARDIAL HYPOXIA

本提案的长期目标是确定 钾(K)通道，特别是三磷酸腺苷调节的钾通道 钾(KATP)通道在心肌局部血液调节中的作用 不同心肌梗死模型的血流、心肌功能和细胞活力 缺血症。初步结果表明，几种新的K通道 开心剂(KCO)有不同的心脏作用，以改善功能和 心脏代谢的恢复和减少缺血后的梗塞面积 和非降压剂量的再灌流。相反，我们还展示了 依赖KATP的通道拮抗剂格列本脲阻断 KCO的有益行为，甚至可能加剧缺血性损伤。 因此，本提案的主要目标将是确定 可逆性损伤后KATP通道的开放或阻断功能 (“顿抑”)或不可逆性损伤(“梗死”)的心肌 麻醉犬接受短暂(15分钟)、延长(90分钟) 分钟)冠状动脉闭塞后再灌流和 所涉及的机制。在顿抑心肌中，节段性室壁运动 通过超声内径测量、局部心肌血流量进行评估 放射性微球和组织活检的代谢状态 分别于缺血和再灌流不同时间取材。在梗塞面积中 研究表明，组织死亡的程度将由 三苯基四氮唑组织化学技术。将允许再灌流 5或24小时，以确定KCO是否只是延迟或产生延长的 梗塞面积缩小。髓过氧化物酶将作为一项指标 中性粒细胞在正常、缺血型、非梗死型和梗死型中的浸润 心肌和体外实验将检测KATP通道的作用 用化学发光法评价中性粒细胞功能。初步 研究表明，几种KCO可减少中性粒细胞在 活体缺血心肌和抑制激活的超氧化物歧化酶的产生 体外培养的神经细胞。KCOS的促或抗心律失常性能或 拮抗剂也将通过Holter监测进行评估。因为少校 顿抑心肌和组织功能恢复的决定因素 梗死心肌的存活率是侧支血流量， 第二个主要目标将是确定KCO对 不同程度冠脉侧支循环的实验研究 附带发展。冠状动脉微动脉和侧支循环阻力 将被计算以确定KCO对这些物质的相对选择性 体内的血管。分离的大冠状动脉和成熟侧支血管 将在体外进行分离和研究，以进一步鉴定 KCOS扩张侧支血管的选择性。KATP通道 拮抗剂格列本脲、甲苯丁胺、5-羟基癸酸钠 用于确定对这些代理具有选择性的通道是否负责 KCO在侧枝血管中的有益行为。结果是 这些研究将为KATP的独特作用提供令人兴奋的新数据 心肌缺血再灌注损伤中的通道作用。

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.