MYOCARDIAL CALCIUM HANDLING DURING AND AFTER HYPOTHERMIA

轻度(27摄氏度)至中度(17摄氏度)低温用于 通过减缓新陈代谢降低心肌的能量消耗和功能 在瓣膜、冠状动脉和升主动脉手术中；严重(3 摄氏度)低温用于保护供者心脏 移植。但低温后再灌流时的心功能往往 仍然是受损的。众所周知，轻到中度的低温 增加每搏动时的心肌收缩能力和严重低温 导致心跳骤停并伴有舒张期痉挛 热再灌流时的收缩和松弛。改变的钙离子处理 由钙离子泵、电压调节的钙离子电导、钙离子联动的交换器 活性，以及改变的钙敏感性，最终是这些 收缩效应。目前尚不清楚整体阳离子的扰动是如何 降温过程中的动态平衡导致钙离子的变化。其作用机制 潜在的钙离子失调和再灌流功能不良可能是 取决于温度。 其目的是为了研究特定基因相互作用的机制。 阳离子引起心脏动作电位和 分级低温4小时内的收缩能力，特别是 再灌流2小时内。有人提出，体温过低会改变 通过与a)[Na+]i调节相关的机制实现钙离子内稳态 Na~+-K~+泵、Na~+内流、Na~+-H~+和Na~+-Ca~(2+)交换器， [Ca~(2+)]i，通过钙泵介导，c)肌丝对钙的敏感性， D)K+外流。其目标是发现阳离子平衡是如何 和收缩功能因低温而改变；为了找出是否轻度和 亚低温改变阳离子平衡和收缩功能 与严重低温不同；要找出低流量冷灌流 比冷藏更好，并确定哪种处理策略 最好的办法是抵消有害的收缩效应 再灌流。将使用三种豚鼠心脏模型来测量： 线粒体Ca~(2+)、Na~+和H~+浓度 舒张期和收缩期肌浆钙离子荧光计量学，左侧 室压(LVP)和其他功能和代谢变量 在完整跳动的心脏中；全细胞电压钳制的Na+，Ca+和K+ATP 分离的心肌细胞的通道电流，以及亚单位的AP 心内膜细胞。低温和复温对钙离子的影响 敏感性将通过绘制LVP与舒张压和收缩压的关系图进行评估 [Ca~(2+)]。这些研究将导致更好的 对钙离子负荷的认识及预防低温症的治疗 红心。

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.