The objective is to gain a better understanding of thallium-201 (T1) transport kinetics under conditions of 1) coronary reperfusion following prior sustained occlusion; 2) repetitive brief periods of transient ischemia producing prolonged post-ischemic dysfunction; and 3) dipyridamole-induced vasodilation followed by antagonism with 8-phenyl-theophylline, a specific adenosine antagonist. A major secondary objective is the investigation of myocardial uptake and washout kinetics of a new technetium-99m labeled perfusion agent [Cu(1-methyl 2-methosypropyl 1-isonitrile)6)] under normal conditions, during transient ischemia and after myocardial infarction. In Protocol 1 we will test the hypothesis that delayed defect appearance after an initial normal T1 distribution (""""""""reverse redistribution"""""""") in a canine model of subendocardial infarction results from early increased T1 uptake in hyperemic epicardial zones and subsequent faster washout compared to normal zone washout. In Protocol 2, open chest dogs will undergo 10 repetitive 5 minute periods of transient LAD occlusion interspersed by 10 minutes of reflow to produce prolonged post-ischemic """"""""stunning"""""""". We will investigate whether membrane transport of T1 is altered in this model despite flow recovery and absence of necrosis. In Protocol 3, we will compare the kinetics of a new Tc-99m perfusion agent with T1 using dual isotope studies in various canine models of transient ischemia, reperfusion after 3 hrs of LAD occlusion and following dipyridamole. In Protocol 4, we propose to further investigate the mechanism of abnormal T1 washout and endocardial/epicardial """"""""steal"""""""" in a canine model of a partial coronary stenosis. In these experiments we will employ an 8-phenyl derivative of theophylline which has no sympathetic effects and solely blocks adenosine receptors. In all experiments, we will measure regional blood flow employing radioactive microspheres. In the sustained occlusion with reflow experiments, infarct size and risk area will be quantitated and correlated with flow and T1 kinetic measurements. Coronary artery disease is still the major cause of death in the United States and the development of noninvasive radionuclide approaches to assessing myocardial perfusion at rest or during exercise or pharmacologic stress is an important step in enhancing our ability to detect myocardial ischemia, to identify patients at high risk for a cardiac event and to determine myocardial viability.
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