MYOCARDIAL CALCIUM HANDLING DURING AND AFTER HYPOTHERMIA

轻度（27摄氏度）至中度（17摄氏度）低温用于 通过减缓代谢减少心肌能量消耗和功能 在瓣膜、冠状血管和升主动脉手术期间;重度（3 低温是用来保护捐赠者的心脏之前， 移植 但低温后再灌注时心功能的变化 仍然受损。 众所周知，轻度至中度体温过低 增加每搏心肌收缩力和严重体温过低 引起心脏舒张期挛缩， 热再灌注时的收缩和舒张。 改变Ca 2+处理 通过Ca 2+泵、电压调节的Ca 2+电导、Ca 2+连接的交换器 活性，改变的Ca 2+敏感性最终成为这些 收缩效应。 目前尚不清楚整体阳离子干扰 冷却过程中的体内平衡导致Ca 2+改变。 的机制 潜在的Ca 2+失调和不良的再灌注功能可能是 温度依赖性。 目的是研究特异性的相互作用机制， 负责心脏动作电位变化的阳离子， 在4小时的分级低温期间的收缩性，特别是 再灌注2小时。 有人认为低温会改变 通过与调节a）[Na+]i相关的机制实现Ca 2+稳态，通过 Na+ K+泵、Na+内流和Na+ H+和Na+ Ca 2+交换剂，B） [Ca2+]i，通过Ca 2+泵介导，c）肌丝Ca 2+敏感性， 和d）K+流出。 目标是发现阳离子平衡 和收缩功能被低温改变;为了发现是否轻微， 中度低温改变阳离子平衡和收缩功能 与严重低温不同;为了发现低流量冷灌注是否 比冷藏更好，并确定哪种治疗策略 最好是抵消有害的收缩作用， 再灌注 将使用三种豚鼠心脏模型测量： 细胞内Na+和H+线粒体Ca 2+浓度，以及 舒张期和收缩期肌浆Ca+荧光测定，左 心室压（LVP）和其他功能和代谢变量 在完整跳动的心脏中;全细胞电压钳位Na+、Ca+和K+ATP 通道电流在分离的心肌细胞，和; AP的亚 内皮细胞 低温和复温对Ca 2+的影响 将通过绘制LVP vs舒张压和收缩压曲线来评估灵敏度 [Ca2+]增加外部Ca。 这些研究将导致更好的 了解钙负荷和治疗，以保护低体温 心中

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.