ENERGETICS & CATION MOVEMENTS IN POSTISCHEMIC HEART

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Proposed mechanisms for decreased myocardial systolic function following ischemic injury include two interrelated processes: impaired energy production, utilization or transfer, and abnormalities of electromechanical coupling related to cation metabolism. Identifying the energetic requirements for maintaining normal transmembrane ion gradients during reperfusion following ischemic insult is an important and unsolved problem. By employing newly developed techniques using 31p, 23Na and 39K NMR spectroscopy, we are now in an unique position to define changes in energetics and transmembrane cation gradients, and their relation, during and following ischemic injury. By using cation NMR techniques developed in this laboratory, we can now define the transsarcolemmal proton, sodium and potassium gradients during and following ischemic injury. In this application, we propose four specific aims using NMR spectroscopy and imaging to define high-energy phosphate content and turnover and the transmembrane gradients of the cations, H+, NA+ K+ and Ca2+, while simultaneously monitoring cardiac performance in postischemic myocardium. 1) to define movements of Na+, K+,H+, and Ca2+ across the sarcolemma in the postischemic myocardium following mild (stunned), moderate and severe ischemia; 2) to construct a kinetic model describing these movements; 3) to relate these changes in cation transport to changes in high-energy phosphate content and turnover rates; and 40 to use 23Na chemical shift imaging in combination with a cationic shift reagent to track the movements of intra-and extracellular Na+ during and following regional ischemia in the isolated heart and the heart in situ.