The long-term objective of this proposal is to determine how metabolic abnormalities common to ischemia and congestive heart failure produce defects in cellular excitation-contraction (E-C) coupling. These defects are responsible for the contractile abnormalities that typify cardiogenic shock in patients sustaining a large myocardial infarction or suffering from end-stage dilated and ischemic cardiomyopathies. We have three specific aims: 1) We will investigate the metabolic regulation of cardiac E-C coupling gain and subcellular Ca2+ release events in adult ventricular myocytes. A major goal is to determine whether E-C coupling is preferentially dependent upon ATP derived from glycolysis versus oxidative metabolism; 2) We will determine how single Ca2+ channel properties are regulated by glycolytic versus oxidative metabolism. We will also determine the relative roles of the Ca2+ current, and the ryanodine receptor, on changes in Ca2+ spark probability during metabolic inhibition; 3) We will study alterations in total transmembranous Ca2+ flux produced by metabolic inhibition, and determine the extent to which Ca2+ current activates sodium-calcium exchange under these conditions. Our general approach is to study the response of subcellular Ca2+ movements and transmembranous Ca2+ fluxes to metabolic inhibitors, in patch clamped isolated ventricular cardiac myocytes from rats and rabbits loaded with fluorescent Ca2+ indicators. Metabolic inhibitors will be chosen to block, alternatively, glycolytic metabolism, oxidative metabolism, or both glycolytic and oxidative metabolism simultaneously. We will use novel confocal imaging strategies to record subcellular Ca2+ movements during metabolic stress with unusually high spatial and temporal resolution. We will, for the first time, assess the effects of metabolic inhibition on the single channel properties of L-type Ca2+ channels in cell-attached patches on rat and rabbit ventricular myocytes. We will use a novel epifluorescence approach to sort out the effects of metabolic inhibition on the complex interaction between L-type Ca2+ channels and the sodium-calcium exchanger. A better understanding of these issues will assist in the development of new therapies to restore contractile function in patients with cardiac failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070828-04
Application #
6910876
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Przywara, Dennis
Project Start
2002-07-15
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$490,848
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Pott, Christian; Muszynski, Adam; Ruhe, Matthias et al. (2012) Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca 2+ exchanger overexpression: whole heart and cellular mechanisms. Basic Res Cardiol 107:247

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