The specific impact of ischaemia on the myocardial kinetics of thallium-201 and technetium-99m 2-methoxy-2-isobutylisonitrile (MIBI) remains a matter of debate. Using an isolated heart model perfused with red blood cell-enhanced perfusate, we compared the overall first-pass kinetics of 201Tl and MIBI under haemodynamically stable conditions of low-flow ischaemia (> 50% reduction in normal coronary flow and a > or = 20 mmHg fall in systolic contraction pressure, n = 10) and normoxia (n = 11). For both 201Tl and MIBI, we found that under ischaemic conditions (as compared with normoxia) there was a higher initial net extraction fraction (201Tl: 0.78 +/- 0.03 vs 0.72 +/- 0.06, P = 0.006; MIBI: 0.49 +/- 0.10 vs 0.39 +/- 0.11, P = 0.03), a lower clearance rate in the 30 min following extraction (% decrease in cardiac uptake: 201Tl: 30 +/- 12 vs 47 +/- 14, P = 0.02; MIBI: 5 +/- 5 vs 13 +/- 11, P = 0.02) and a higher retention fraction at 30 min (20lTl: 0.54 +/- 0.10 vs 0.39 +/- 0.12, P = 0.004; MIBI: 0.46 +/- 0.08 vs 0.33 +/- 0.12, P = 0.01). Multivariate analyses, however, revealed that all myocardial kinetic parameters of both tracers were dependent only on coronary flow rates, without any additional significant impact of the presence of ischaemia or states of contractility or oxidative metabolism. We conclude that the myocardial fractional retention of both 201Tl and MIBI is strongly correlated with the decrease in coronary flow during ischaemia. This inverse relationship with coronary flow derives from both the flow-dependent increase in the initial myocardial extraction and the decrease in the subsequent myocardial washout of the tracers.