MYOCARDIAL CALCIUM HANDLING DURING AND AFTER HYPOTHERMIA

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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.