We have shown that positron emission scintigraphy detects changes in the uptake of 18-F 2-deoxyglucose and 13-N ammonia by the acutely rejecting myocardium in a nonworking model of heterotopic heart transplantation in the rat. We developed a new working model of heterotopic heart transplantation to determine the possible relevance of these changes to clinical transplantation. Moderate aortic valvular regurgitation was produced allowing the heterotopic left ventricle to fill and eject. Rejecting allografts and nonrejecting isografts (controls) were studied 4 days after transplantation. Histologically, isografts were normal and all allografts showed mild acute rejection. Decay-corrected uptakes of 18-F 2-deoxyglucose and 13-N ammonia reflect glucose metabolism and blood flow, respectively. Values are presented as percent of injected dose per gram of tissue. Uptake of 18-F 2-deoxyglucose was higher in rejecting allografts compared with nonrejecting isografts (3.0 +/- 1.8 versus 1.1 +/- 0.4; p = 0.024). Ammonia uptake was elevated in allografts compared with isografts (2.2 +/- 0.5 versus 1.3 +/- 0.5; p = 0.023). Uptakes of 18-F 2-deoxyglucose and 13-N ammonia are higher in mildly rejecting allografts, implying increased glucose utilization and blood flow during acute rejection. These data support our earlier findings of changes in myocardial metabolism in the absence of diminishing blood flow in acutely rejecting hearts. This model may lead to a better understanding of the physiology and metabolism of acute rejection.