ANESTHETICS EFFECTS ON ISCHEMIC MYOCARDIUM

麻醉药对缺血心肌的影响

• 批准号: 6389510
• 负责人: DAVID C. WARLTIER
• 金额: $ 42.57万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389510
• 关键词: adenosine triphosphate; anesthetics; biological signal transduction; conditioning; disease /disorder model; dogs; heart contraction; heart pharmacology; inhibitor /antagonist; isoflurane; isozymes; microdialysis; myocardial infarction; myocardial ischemia /hypoxia; potassium channel; protein kinase C; purinergic receptor; reperfusion; sarcolemma; stainings; tissue /cell culture; voltage /patch clamp; western blottings

DESCRIPTION (adapted from applicant's abstract) The long-term objective of this work is a comprehensive analysis of the cardioprotective effects of volatile anesthetics. These agents are capable of reducing the contractile deficit (myocardial stunning) following a brief period of ischemia and the extent of myocardial infarction following a prolonged period of coronary artery occlusion. Recently, it was found that a prior, brief exposure to the volatile anesthetic, isoflurane, could reduce myocardial infarct size after its discontinuation. This phenomenon has a strong similarity to ischemic preconditioning, in which a brief period of coronary artery occlusion and reperfusion renders myocardium resistant to infarction after a subsequent prolonged ischemia insult. Anesthetic-induced preconditioning (APC) demonstrates a powerful cardioprotective effect with short and long-term memories. The major hypothesis to be tested in the present investigation is that volatile anesthetics directly produce early and late preconditioning against both myocardial stunning and infarction via enhanced opening of ATP-dependent potassium (KATP) channels. Signal transduction pathways including adenosine receptors and protein kinase C serving as a mechanism(s) for APC will be characterized. APC-induced alterations in the interstitial concentration of adenosine and translocation of PKC isoforms will be measured in ischemic and control myocardium. Cardioprotective effects of the anesthetics will be studied in in vivo canine models of myocardial ventricular pressure-segment length diagrams, and myocardial infarct size will be measured by triphenyl tetrazolium histochemical staining. Alterations in potassium conductance through KATP channels will be studied directly by means of modification of the patch clamp technique in normal and previously ischemic ventricular myocytes. Because of the large number of patients with coronary artery disease undergoing infarction, the proposed research represents an investigation into a clinically relevant problem. Isoflurane has recently been shown to produce APC in patients undergoing coronary artery bypass graft surgery. Thus, this proposal will delineate mechanisms responsible for the novel and unique cardioprotective effects of volatile anesthetics against ischemia and reperfusion injury in vivo and provide direct evidence of the involvement of specific signal transduction pathways modulating the KATP channel in vitro.

描述（改编自申请人的摘要） 本项目的长期目标 工作是全面分析挥发性物质的心脏保护作用 麻醉剂。这些药物能够减少收缩缺陷 （心肌顿抑）经过短暂的缺血和程度 冠状动脉长时间阻塞后发生心肌梗塞 闭塞。最近，人们发现，之前短暂接触过挥发性物质 异氟烷麻醉剂可减少心肌梗死面积 停产。这种现象与缺血性脑损伤有很强的相似性。 预适应，其中短暂的冠状动脉闭塞和 再灌注使心肌在随后的梗死后具有抵抗力 长期缺血损伤。麻醉诱导预处理 (APC) 表现出强大的短期和长期心脏保护作用 回忆。本次调查要检验的主要假设是 挥发性麻醉剂直接产生早期和晚期预处理 通过增强开放性来对抗心肌顿抑和梗死 ATP 依赖性钾 (KATP) 通道。信号转导途径包括 腺苷受体和蛋白激酶 C 作为 APC 的机制将 被表征。 APC 引起的间质浓度变化 腺苷和 PKC 亚型的易位将在缺血和 控制心肌。将研究麻醉剂的心脏保护作用 犬体内心肌心室压力节段长度模型 图表，并用三苯基四唑测量心肌梗塞的大小 组织化学染色。通过 KATP 改变钾电导 通过修改膜片钳直接研究通道 正常和先前缺血的心室肌细胞的技术。由于 大量冠状动脉疾病患者正在接受治疗 梗死，拟议的研究代表了对临床的调查 相关问题。异氟烷最近被证明可以在患者体内产生 APC 正在接受冠状动脉搭桥手术。因此，该提案将 描述了新颖且独特的心脏保护作用的机制 挥发性麻醉药对体内缺血再灌注损伤的影响 并提供参与特定信号转导的直接证据 体外调节 KATP 通道的途径。