Cardiac Electrophysiology in Anesthetic-Induced Preconditioning

麻醉诱导预处理中的心脏电生理学

• 批准号: 7553291
• 负责人: Wai-Meng Kwok
• 金额: $ 21.76万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7553291
• 关键词: action potentials; anesthetics; antiarrhythmic agent; calcium channel; cardiac myocytes; cytoprotection; genetic strain; genetic susceptibility; heart electrical activity; heart pharmacology; heart rhythm; laboratory rat; mitogen activated protein kinase; myocardial ischemia /hypoxia; organ culture; potassium channel; protein kinase C; protein tyrosine kinase; sodium channel; tissue /cell culture; voltage gated channel

The overall goal of Project III is to investigate the ionic mechanisms underlying the effects of volatile anesthetics and anesthetic-induced preconditioning (APC) on cardiac electrophysiology. APC mimics ischemic preconditioning (IPC) as quantified by reduction in infarct size, but whether it also provides protection from cardiac arrhythmias during myocardial ischemia and reperfusion is not well established. The experiments proposed in Project In will characterize cardiac rhythm in APC rats using the Langendorff isolated heart methodology, and investigate the underlying ionic mechanisms using the patch clamp technique. Though activation of the sarcolemmal KATPchannel, hypothesized to occur during APC, can profoundly affect cardiac electrophysiology, the intracellular signaling pathways thought to mediate APC, for example, PKC (protein kinase C), PTK (protein tyrosine kinase), and MAPK (mitogen-activated protein kinase) pathways, also modulate the voltage-gated channels. The key question is whether these changes in signal transduction have a "delayed" effect on the ion channels to coincide with the time course of APC. The general hypothesis to be tested in this proposal is that volatile anesthetics produce cardioprotective antiarrhythmic effects by facilitating the actions of the kinase-dependent pathways potentiated or triggered by APC on the voltage-gated ion channels, specifically the fast Na, L-type Ca and transient outward K channels. This will be tested by utilizing rats post-APC and various genetic strains of rats with differential sensitivity to APC. The following aims and hypotheses will be pursued: Aim I: To characterize the effects of APC on cardiac rhythm using the Langendorff isolated heart. Aim II: To characterize the effects of volatile anesthetics on the cardiac action potential in ventricular myocytes isolated from normal and APC rat hearts. Aim III: To characterize the modulation of I(Na), I(Ca),L and I(to) in ventricular myocytes isolated from normal and APC rat hearts. Functional protection, particularly with regard to suppression of arrhythmias associated with myocardial ischemia and reperfusion, has yet to be clearly established. The experiments designed in this proposal will characterize the role of ion channels other than the sarcolemmal K(ATP) channel in contributing to the antiarrhythmic effects of APC.

项目III的总体目标是研究挥发性麻醉剂和麻醉诱导预处理（APC）对心脏电生理学影响的离子机制。APC模拟缺血预处理（IPC），通过减少梗死面积来量化，但它是否也提供心肌缺血和再灌注期间心律失常的保护还没有得到很好的确定。项目中提出的实验将使用Langendorff离体心脏方法表征APC大鼠的心律，并使用膜片钳技术研究潜在的离子机制。尽管假设在APC期间发生的肌膜KATP通道的激活可以深刻地影响心脏 在电生理学中，被认为介导APC的细胞内信号传导途径，例如PKC（蛋白激酶C）、PTK（蛋白酪氨酸激酶）和MAPK（促分裂原活化蛋白激酶）途径，也调节电压门控通道。关键问题是这些信号转导的变化是否对离子通道具有“延迟”效应，以与APC的时间过程相一致。在这个建议中要检验的一般假设是，挥发性麻醉剂通过促进APC对电压门控离子增强或触发的激酶依赖性途径的作用而产生心脏保护性抗心律失常作用。 通道，特别是快速Na，L型Ca和瞬时外向K通道。这将通过使用APC后的大鼠和对APC具有不同敏感性的各种遗传品系的大鼠进行测试。将追求以下目标和假设： 目的一：利用Langendorff离体心脏研究APC对心脏节律的影响。 目标二：研究吸入麻醉药对正常和APC大鼠心室肌细胞动作电位的影响。 目的III：研究正常和APC大鼠心室肌细胞I（Na）、I（Ca）、L和I（to）的调节。 功能保护，特别是抑制与心肌缺血和再灌注相关的心律失常，尚未明确建立。在这个建议中设计的实验将表征离子通道的作用，而不是肌膜K（ATP）通道，有助于APC的抗肿瘤作用。