Cardiac Electrophysiology in Anesthetic-Induced Preconditioning

项目III的总体目标是研究挥发性麻醉剂和麻醉剂诱导的预适应(APC)对心脏电生理影响的离子机制。APC模拟缺血预适应(IPC)，通过减少梗死面积来量化，但它是否还能提供对心肌缺血和再灌流期间心律失常的保护尚未得到很好的证实。在Project in中提出的实验将使用Langendorff离体心方法来表征APC大鼠的心率，并使用膜片钳技术来研究潜在的离子机制。尽管肌膜KATP通道的激活被认为发生在APC期间，但可以深刻地影响心脏 电生理学，即被认为介导APC的细胞内信号通路，例如PKC(蛋白激酶C)、PTK(蛋白酪氨酸激酶)和MAPK(丝裂原活化蛋白激酶)通路，也调节电压门控通道。关键的问题是，这些信号转导的变化是否会对离子通道产生延迟效应，从而与APC的时间进程相一致。这项建议中要检验的一般假设是，挥发性麻醉剂通过促进APC增强或触发的激酶依赖通路在电压门控离子上的作用而产生心脏保护抗心律失常的作用。 通道，特别是快钠、L型钙通道和瞬时外向钾通道。这将通过利用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I：用朗宁多夫离体心研究APC对心率的影响。 目的II：研究挥发性麻醉药对正常和APC大鼠心肌细胞动作电位的影响。 目的：研究I(Na)、I(Ca)、L和I(To)在正常和急性心肌梗死大鼠心肌细胞中的调节作用。 功能保护，特别是在抑制与心肌缺血和再灌流相关的心律失常方面，尚未明确确立。在这项建议中设计的实验将表征除肌膜K(ATP)通道外的离子通道在APC抗心律失常作用中的作用。

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.