The applicant's overall goal is to evaluate the role of increased intracellular Ca2+ concentration, (Ca2+)i, in the pathogenesis of stunning and lethal myocardial ischemic injury. All of the protocols proposed in this application are designed to test the hypotheses: 1) that increased (Ca2+)i plays a major role in stunning and lethal ischemic injury; and 2) that interventions which decrease stunning and/or reduce or delay lethal injury, such as preconditioning, are associated with attenuation of the rise in (Ca2+)i. The experimental protocols would use the following NMR methods to measure ion and metabolite changes throughout the myocardium: 19F NMR to measure (Ca2+)i using 5FBAPTA, 23Na NMR to measure intracellular sodium using the extracellular shift reagent thulium DOTP, and 31P NMR to measure pHi, ATP, and creatine phosphate. The applicant would use a new fluorine-labeled calcium indicator in parallel with 5FBAPTA in the proposed protocols to characterize fully the changes in (Ca2+)i during ischemia and reperfusion. The experimental protocols are designed to manipulate the rise in (Ca2+)i during ischemia and during reperfusion and to correlate the changes in (Ca2+)i with the effects on stunning and lethal injury.
The specific aims of the proposal are toanswer the following questions: 1) Does the rise in (Ca2+)i during ischemia play an important role instunning and lethal ischemic injury? 2) Can calcium influx during reperfusion play an important role in stunning and lethal ischemic injury? 3) Can the effects of preconditioning on (Ca2+)i, stunning, and lethal ischemic injury be dissociated? 4) Can the effects of adenosine treatment during ischemia on (Ca2+)i, stunning, and lethal injury be dissociated? and 5) Is adenosine involved in the preconditioning-induced attenuation of the rise in (Ca2+)i during subsequent ischemia?
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