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 i s 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL058691-01A2S1
Application #
6096538
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1999-01-15
Project End
2002-12-31
Budget Start
1999-08-01
Budget End
1999-12-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Riess, Matthias L; Rhodes, Samhita S; Stowe, David F et al. (2009) Comparison of cumulative planimetry versus manual dissection to assess experimental infarct size in isolated hearts. J Pharmacol Toxicol Methods 60:275-80
Riess, Matthias L; Camara, Amadou K S; Heinen, Andre et al. (2008) KATP channel openers have opposite effects on mitochondrial respiration under different energetic conditions. J Cardiovasc Pharmacol 51:483-91
Stowe, David F; Camara, Amadou K S; Heisner, James S et al. (2008) Low-flow perfusion of guinea pig isolated hearts with 26 degrees C air-saturated Lifor solution for 20 hours preserves function and metabolism. J Heart Lung Transplant 27:1008-15
Riess, Matthias L; Costa, Alexandre D; Carlson Jr, Richard et al. (2008) Differential increase of mitochondrial matrix volume by sevoflurane in isolated cardiac mitochondria. Anesth Analg 106:1049-55, table of contents
Heinen, Andre; Camara, Amadou K S; Aldakkak, Mohammed et al. (2007) Mitochondrial Ca2+-induced K+ influx increases respiration and enhances ROS production while maintaining membrane potential. Am J Physiol Cell Physiol 292:C148-56
Rhodes, Samhita S; Camara, Amadou K S; Ropella, Kristina M et al. (2006) Ischemia reperfusion dysfunction changes model-estimated kinetics of myofilament interaction due to inotropic drugs in isolated hearts. Biomed Eng Online 5:16
An, Jianzhong; Rhodes, Samhita S; Jiang, Ming Tao et al. (2006) Anesthetic preconditioning enhances Ca2+ handling and mechanical and metabolic function elicited by Na+-Ca2+ exchange inhibition in isolated hearts. Anesthesiology 105:541-9
Jiang, Ming Tao; Ljubkovic, Marko; Nakae, Yuri et al. (2006) Characterization of human cardiac mitochondrial ATP-sensitive potassium channel and its regulation by phorbol ester in vitro. Am J Physiol Heart Circ Physiol 290:H1770-6
Rhodes, Samhita S; Ropella, Kristina M; Camara, Amadou K S et al. (2006) Ischemia-reperfusion injury changes the dynamics of Ca2+-contraction coupling due to inotropic drugs in isolated hearts. J Appl Physiol 100:940-50
An, Jianzhong; Camara, Amadou K S; Riess, Matthias L et al. (2005) Improved mitochondrial bioenergetics by anesthetic preconditioning during and after 2 hours of 27 degrees C ischemia in isolated hearts. J Cardiovasc Pharmacol 46:280-7

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