This research will obtain fundamental knowledge of effects of electrical defibrillation shocks in the heart that is needed to understand defibrillation. Defibrillation is thought to occur in three steps: 1) The shock changes transmembrane voltages during the shock pulse. 2) The changes in transmembrane voltages alter transmembrane voltage-dependent ion channels which excite the cells or prolong action potential repolarization after the pulse. 3) The excitation or prolonged repolarization produces defibrillation. Mechanisms for the steps are not known. This project will use transmembrane voltage-sensitive dye fluorescence and a laser scanner system to study up to 127 locations on isolated arterially perfused rabbit hearts. The distributions of transmembrane voltages during the shock pulse, the excitation or prolonged repolarization after the pulse and the changes in activation patterns and block required to produce defibrillation will be determined. The maximum dV/dt of action potentials measured with microelectrodes and the sodium channel modulators, tetrodotoxin and high potassium, will be used to study transmembrane voltage-dependent fast inward sodium channel recovery during monophasic and biphasic shocks. The importance of the fast inward sodium channel recovery for the prolonged repolarization produced by the shocks will be determined. The impacts of pharmacological sodium, calcium or potassium channel blockade, present in some patients who receive shocks. on prolonged repolarization will be determined. Calcium-sensitive dye fluorescence will be measured with the laser scanner system to study the roles of ischemia, fibrillation and the transmembrane voltages during shocks in producing elevated intracellular calcium. The importance of the elevated intracellular calcium for spontaneous fibrillation induction, fibrillation maintenance and defibrillation will be determined. The project will yield insights that are necessary in order to advance understanding of cellular bases of defibrillation.
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