After brief episode(s) of ischemia which cause no necrosis (non-lethal myocyte injury), the myocardium exhibits persistent metabolic and contractile changes and has increased tolerance to a later sustained episode of ischemia, a rapid adaptive change termed ischemic preconditioning. Preconditioned myocardium which again becomes ischemic has a much slower rate of energy utilization and a delayed onset of lethal cell injury manifest as a marked limitation of infarct size after 60 minutes of ischemia, followed by reperfusion. The cause(s) of infarct limitation and the reduced rate of energy metabolism are unknown but could be a direct effect of known changes in the intracellular milieu, e.g. excess sarcoplasmic Pi, Mg2+, glucose, and creatine phosphate (the CP overshoot), or less adenine nucleotide and glycogen. Alternatively, preconditioning could result from activation of one or more signaling pathways. One candidate pathway involves protein kinase C (PKC). Activated PKC phosphorylates many proteins, one or more of which may modulate key energy utilizing pathways in ischemic myocytes. The applicant hypothesizes that the major effector mechanism of the reduced energy demand and consequent infarct limitation involves enhanced opening of K+ATP channels. The applicant hypothesizes that PKC facilitates the opening of these channels, that increased K+ is released into the extracellular fluid (ECF), and that this increased K+ reduces energy demand by reducing ion traffic and contractile effort. The applicant will assess changes in the intracellular milieu in relation to the presence or absence of protection after different durations of reperfusion. The applicant also will study the role of the K+ATP channel in the cardioprotective and metabolic effects of preconditioning, using channel openers and inhibitors. The applicant will study the time-course of PKC activation in ischemia by biochemical and immunofluorescent assays and the role of PKC in ischemic preconditioning will be assessed using direct PKC activators and inhibitors. Cardioprotection will be assessed by measuring myocardial infarct size and the rate of ischemic metabolism (rate of change of adenine nucleotides and intermediates of anaerobic glycolysis during ischemia).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Renal Study Section (CVB)
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Duke University
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