Profound alterations in cardiac excitability and contractile function occur within minutes of inhibiting energy metabolism in the heart, whether the inhibition is by ischemia, hypoxia, or chemical poisoning. The arrhythmias accompanying such a decline in the metabolic rate, as well as during the restoration of energy flux, are often fatal. Intervention into the pathological consequences of abrupt changes in energy metabolism will require a detailed understanding of the relationship between substrate supply, the control of metabolism, and the sensitivity of ion channels to perturbations of energy metabolites. The project explores this relationship by studying a cellular experimental model which displays dynamic coupling between energy metabolism and ion channel activity. Specifically, a metabolic control loop in isolated ventricular cardiomyocytes that is prone to oscillation when substrate input is altered (as during the withdrawal or reintroduction of extracellular glucose) has been identified. This mild metabolic stress leads to cyclical increases in the activity of ATP-sensitive K+ channels (K,ATP channels) and a coordinated suppression of excitation-contraction coupling. Both of these functional events are synchronized with the transient oxidation of nicotinamide adenine dinucleotides that serve as markers of a primary metabolic oscillator. Preliminary data indicating that the oscillator is sensitive to the extracellular glucose concentration and to rapid perturbations of intracellular adenine nucleotides induced by flash photolysis suggest that the source of oscillation is in glycolysis, most likely as a result of the control properties of a single enzyme, phosphofructokinase.
The aims of the proposal are to elucidate the mechanism of the metabolic oscillations at the cellular level through biological experimentation and computer modeling; to study the molecular basis for energy-sensing by ion channels (L-type Ca2+ and K,ATP); and to determine the effects of the oscillations on the electrical excitability of cardiomyocytes. The ultimate goal of the work is to identify strategies for preventing or controlling cardiac electrical mechanical dysfunction during ischemia and reperfusion.
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