The isolated red blood cell-albumin perfused rabbit heart will be used to (1) investigate the use of the Patlak and Sokoloff methodologies to quantify myocardial glucose consumption with 18F-2-fluoro-2-deoxy-D-glucose (FDG), and (2) evaluate the kinetics of mitochondrial avid radiolabeled compounds. Three projects are designed to investigate potential problems in the use of the Patlak and Sokoloff tracer kinetic models to quantify myocardial glucose metabolism. In the first project, the applicants proposed to investigate potential inaccuracies of glucose metabolic rate (GMR) estimates by the Patlak multiple-time graphical analysis due to non-equilibration of FDG between plasma and reversible tissue compartments. In the second project, they would evaluate dephosphorylation of FDG-6-PO4 during an extended wash-out period with FDG-free perfusate. In the third project, they would investigate the possibility of reducing the complexity of the Sokoloff compartment model by measuring tracer delivery and distribution with the multiple indicator dilution technique. Rotenone and its analogues are neutral, lipophilic compounds that are potent inhibitors of Complex 1 of the mitochondrial electron transport chain. The applicants have synthesized 18F-dihydrorotenone (FDHR) and 125I-rotenone and have shown that they have a high extraction and long retention in the isolated rabbit heart. The central hypothesis to be tested is that myocardial extraction and retention of these radiolabeled rotenone compounds are primarily dependent on flow, subject to modification by changes in mitochondrial function. Rhodamine-123 and 99mTc-sestamibi accumulate in active mitochondria that have hemostatic membrane potentials. In all of proposed investigations, the applicants proposed to compare the extraction and retention of the rotenone compounds to Rhodamine-123 and 99mTc-sestamibi. They would evaluate myocardial extraction and retention of these mitochondrial-avid agents over a physiologically relevant flow range. Similarly, the effect(s) of altered rates of oxidative metabolism at constant flow on myocardial kinetics of these compounds will also be studied. Finally, the effect of oxygen deprivation of rotenone, Rhodamine-123, and 99mTc-sestamibi extraction and retention will be evaluated. In all studies of the mitochondrial-avid agents and in the investigation on the Sokoloff compartment model and FDG the multiple indicator dilution technique and the linear, time-invariant impulse responses mode will be used to analyze myocardial extraction and retention of these tracers. The major advantage of using the impulse response model is that it is possible to independently evaluate circulatory dispersion, interstitial diffusion, and cellular extraction and retention of the flow or metabolic tracer of interest.
| Marshall, Robert C; Powers-Risius, Patricia; Reutter, Bryan W et al. (2004) Kinetic analysis of 18F-fluorodihydrorotenone as a deposited myocardial flow tracer: comparison to 201Tl. J Nucl Med 45:1950-9 |
| Marshall, Robert C; Powers-Risius, Patricia; Reutter, Bryan W et al. (2003) Flow heterogeneity following global no-flow ischemia in isolated rabbit heart. Am J Physiol Heart Circ Physiol 284:H654-67 |
| Marshall, R C; Powers-Risius, P; Reutter, B W et al. (2001) Kinetic analysis of 125I-iodorotenone as a deposited myocardial flow tracer: comparison with 99mTc-sestamibi. J Nucl Med 42:272-81 |
