The goal of this project is to define how changes in the extracellular environment, particularly ion accumulation, influence the electrophysiological properties of heart during myocardial ischemia and hypoxia. An experimental model, the arterially perfused rabbit ventricle, has been developed in which it is feasible to study these relationships in a quantitative and comprehensive manner. K+ and pH sensitive extracellular electrodes will be used in conjunction within tracellular electrodes and multiple extracellular electrodes to monitor [K]o and [H]o accumulation, intracellular potential, threshold of excitability, refractory periods, conduction intervals and tension during ischemia and hypoxia in the isolated arterially perfused rabbit ventricle. Changes in [K]o, pHo and electrophysiological parameters during the first 10-15 minutes of global ischemia are reversible, reproducible, and reasonably homogeneous, making it possible to study the contributions of various components of ischemia to electrophysiological alterations by altering the perfusate to simulate the ischemic environment. In addition to ion accumulation, other components of ischemia can be simulated, including catecholamine release, hypoxia, lactate accumulation, hypoglycemia, free fatty acids, and lysophosphoglycerides. The principle hypotheses which will be tested are: 1) During early global ischemia most electrophysiological changes can be attributed to extracellular K+ accumulation, acidosis, and catecholamine release. The other factors listed above may modify these electrophysiological alterations. 2) The electrophysiological actions of drugs known to influence arrhythmogenesis during ischemia may modify or be modified by [K]o accumulation, acidosis, or other components of ischemia. 3) During early hypoxia, electrophysiological alterations cannot be attributed to changes in [K]o or pH, and most probably result directly from the depression of metabolism. 4) The electrophysiological alterations during early global ischemia predispose this preparation to reentrant arrhythmias in the setting of regional ischemia. Regional perfusion of the preparation with perfusate modified to simulate the ischemic environment produces similar arrhythmias.
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