MYOCARDIAL CALCIUM HANDLING DURING AND AFTER HYPOTHERMIA

低温期间和之后的心肌钙处理

• 批准号: 2752395
• 负责人: DAVID F STOWE
• 金额: $ 36.31万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-15 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2752395
• 关键词: action potentials; calcium flux; fluorimetry; guinea pigs; heart contraction; heart metabolism; induced hypothermia; ion transport; myocardium; potassium ion; reperfusion; sodium ion; voltage /patch clamp

Mild (27 degrees C) to moderate (17 degrees C) hypothermia is used to reduce myocardial energy consumption and function by slowing metabolism during valve, coronary vessel, and ascending aortic surgery; severe (3 degrees C) hypothermia is used to protect donor hearts prior to transplant. But cardiac function on reperfusion after hypothermia often remains impaired. It is known that mild to moderate hypothermia increases myocardial contractility per beat and severe hypothermia causes arrest with diastolic contracture and results in impaired contractility and relaxation on warm reperfusion. Altered Ca2+ handling by Ca2+ pumps, voltage-regulated Ca2+ conductance, Ca2+ linked exchanger activity, and altered Ca2+ sensitivity ultimately underlie these contractile effects. It is not known how disturbances in overall cation homeostasis during cooling lead to altered Ca2+. The mechanisms underlying Ca2+ deregulation and poor reperfusion function are likely temperature dependent. The aim is to investigate the mechanisms of interaction of specific cations responsible for changes in cardiac action potential and contractility during 4 hrs of graded hypothermia, and particularly during 2 hrs of reperfusion. It is proposed that hypothermia alters Ca2+ homeostasis via mechanisms linked to regulation of a) [Na+]i, via the Na+ K+ pump, Na+ influx, and Na+ H+ and Na+ Ca2+ exchangers, b) [Ca2+]i, mediated via the Ca2+ pump, c) myofilament Ca2+ sensitivity, and d) K+ efflux. The objectives are to discover how cation equilibrium and contractile function are altered by hypothermia; to find if mild and moderate hypothermia alter cation equilibrium and contractile function differently than severe hypo-thermia; to find if low-flow cold perfusion is better than cold storage, and to determine which treatment strategies are best to counteract deleterious contractile effects during reperfusion. Three guinea pig cardiac models will be used to measure: intracellular concentrations of Na+ and H+ mitochondrial Ca2+, and phasic diastolic and systolic myoplasmic Ca+ fluorometrically, with left ventricular pressure (LVP) and other functional and metabolic variables in intact beating hearts; whole cell voltage-clamped Na+, Ca+, and K+ATP channel currents in isolated cardio myocytes, and; AP's in sub endocardial cells. Hypothermia and rewarming effects on Ca2+ sensitivity will be assessed by plotting LVP vs diastolic and systolic [Ca2+] at increasing external Ca. These studies will lead to a better understanding of Ca2+ loading and therapies to protect hypothermic hearts.

轻度（27度c）至中度（17度C）体温过低（17度） 减少新陈代谢来减少心肌消耗和功能 在瓣膜，冠状血管和主动脉手术上升期间；严重（3 学位c）体温过低用于保护供体的心脏 移植。 但是体温过低后的再灌注中心脏功能 仍然受损。 众所周知，温和到中度的体温过低 每节拍增加心肌收缩力和严重的体温过低 因舒张期逮捕而导致逮捕并导致受损 收缩和放松温暖再灌注。 更改CA2+处理 通过Ca2+泵，电压调节的Ca2+电导，CA2+链接的交换器 活动，并改变Ca2+灵敏度最终是基础 收缩效果。 尚不知道整体阳离子中的干扰如何 冷却过程中的稳态导致CA2+改变。 机制 基本的CA2+放松管制和不良的再灌注功能可能是 温度取决于。 目的是研究特定相互作用的机制 负责心脏动作潜力变化的阳离子和 在4小时的低温下，特别是 在2小时的再灌注中。 有人提出体温过低会改变 Ca2+稳态通过与A）[Na+] I的机制，通过 Na+ K+泵，Na+涌入，Na+ H+和Na+ Ca2+交换器，b） [Ca2+] i，通过Ca2+泵介导，C）肌丝Ca2+灵敏度， 和d）K+外排。 目标是发现阳离子平衡 体温过低会改变收缩功能；寻找温和的 中等温度改变阳离子平衡和收缩功能 与严重的低疗法不同；找出低流冷灌注 比冷藏量更好，并确定哪些治疗策略 最好抵消有害的收缩效果 再灌注。 将使用三种豚鼠心脏模型来测量： Na+和H+线粒体Ca2+的细胞内浓度，以及 左侧的舒张舒张和收缩性肌瘤Ca+荧光图，左 心室压力（LVP）和其他功能和代谢变量 在完整的跳动中；全细胞电压链接Na+，Ca+和K+ATP 在孤立的有心肌细胞中通道电流，并且； AP在sub中 心内膜细胞。 体温过低和对CA2+的重新传播影响 敏感性将通过绘制LVP与舒张压和收缩期来评估 [Ca2+]在增加外部CA。 这些研究将导致更好 了解CA2+负载和疗法以保护低温 心。