Exercise Training and Myocardial K-ATP Channel Function

运动训练与心肌K-ATP通道功能

• 批准号: 6875637
• 负责人: Russell L Moore
• 金额: $ 25.86万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875637
• 关键词: adenosine triphosphate; artery occlusion; cardiac myocytes; cardiovascular function; cell population study; cellular pathology; electrophysiology; exercise; laboratory rat; myocardium; phosphates; potassium channel; reactive hyperemia; sarcolemma; voltage /patch clamp; western blottings

DESCRIPTION (provided by applicant): It is well known that endurance exercise training (Tr) renders the heart more resistant to ischemia and reperfusion injury. To date, the cellular basis for these adaptations has not been clearly identified. In the heart, ATP-sensitive K channels exist on the sarcolemma (sI-KATP) and in mitochondria (mito-KATP) and both have been implicated in protecting the heart against ischemic injury. We recently found that Tr elicits a marked reduction in the magnitude of an anoxia-inducible, glibenclamide-sensitive outward K current (IK,ATP) in single rat ventricular cardiocytes. In Specific Aim 1, we will use electrophysiological (whole cell and excised patch) and immunoblotting techniques to determine the cellular basis for this finding. We will examine the effect of training on (1) the sensitivity of sI-KATP to inhibition by ATP and ADP, (2) the protein expression of sI-KATP channel subunits (Kit6.2 and SUR2A), and (3) mitochondrial ATP production in the face of ischemic stress. We also found that following severe zonal ischemia elicited by coronary artery occlusion and then reperfusion, Tr produced infarct sparing and augmented mechanical function in isolated perfused hearts. We also observed a marked Tr-induced hyperemia that was apparent throughout the ischemia reperfusion protocol. In Specific Aim 2, we will use KATP antagonists that are selective for sl- and mito-KATP channels to identify the involvement of these specific channels in Tr-induced infarct sparing and preservation of mechanical function. Indomethacin and L-NAME will be used in studies to determine the cellular basis for the hyperemia that was exhibited during post-ischemic reperfusion, and the extent to which the Tr-induced hyperemia contributed to infarct sparing and the preservation of mechanical function in the heart. The experiments in Aim 2 include a comprehensive battery of LV function, metabolite, biochemical, and coronary flow measurements. Exercise training is known to be effective in the prevention and treatment of a wide variety of cardiopathologic conditions. Elucidation of the cellular changes that underlie these positive adaptations may be of particular importance in the design, development, and implementation of molecular and pharmacological heart disease treatment and prevention strategies. This is particularly significant in view of the fact that heart disease claims more North American lives than any other disease.

描述（由申请人提供）：众所周知，耐力运动训练（Tr）使心脏对缺血和再灌注损伤具有更强的抵抗力。迄今为止，这些适应的细胞基础尚未明确。在心脏中，ATP 敏感 K 通道存在于肌膜 (sI-KATP) 和线粒体 (mito-KATP) 中，两者都与保护心脏免受缺血性损伤有关。我们最近发现，Tr 会显着降低单个大鼠心室心肌细胞中缺氧诱导的、格列本脲敏感的外向 K 电流 (IK,ATP) 的强度。在具体目标 1 中，我们将使用电生理学（全细胞和切除的斑块）和免疫印迹技术来确定这一发现的细胞基础。我们将检查训练对 (1) sI-KATP 对 ATP 和 ADP 抑制的敏感性、(2) sI-KATP 通道亚基（Kit6.2 和 SUR2A）的蛋白质表达以及 (3) 面对缺血应激时线粒体 ATP 产生的影响。我们还发现，在冠状动脉闭塞引起严重的区域性缺血然后再灌注后，Tr 在离体灌注心脏中产生梗塞保留并增强机械功能。我们还观察到明显的 Tr 诱导的充血，这在整个缺血再灌注方案中都很明显。在具体目标 2 中，我们将使用对 sl- 和 mito-KATP 通道具有选择性的 KATP 拮抗剂来确定这些特定通道在 Tr 诱导的梗塞保留和机械功能保存中的参与。 Indomethacin 和 L-NAME 将用于研究以确定缺血后再灌注期间表现出的充血的细胞基础，以及 Tr 诱导的充血在多大程度上有助于梗塞保留和心脏机械功能的保存。目标 2 中的实验包括全面的左心室功能、代谢物、生化和冠状动脉流量测量。 众所周知，运动训练可有效预防和治疗多种心脏病。阐明这些积极适应背后的细胞变化对于分子和药理学心脏病治疗和预防策略的设计、开发和实施可能特别重要。鉴于心脏病比任何其他疾病夺去的北美生命更多，这一点尤其重要。