Alternans of action potential duration (APD) has been shown to be a precursor of ventricular fibrillation in ischaemic myocardium. We postulated that magnitude of alternans of APD during ischaemia depends not only on the severity of ischaemia but also on disturbed beat-to-beat restitution of APD. Monophasic action potentials were recorded simultaneously from right (RV) and left ventricular (LV) epicardial sites of isolated rabbit hearts. The inter-beat time courses of APD recovery were determined both during normal flow and ischaemia by interposing single cycle length changes ranging from 200 to 800 ms (= electrical restitution) simultaneously at the three recording sites. During normal perfusion, electrical restitution curves showed a steep initial recovery of APD, attaining steady-state values at extrastimulus cycle lengths of only 298 +/- 12 ms, with a high degree of uniformity between the three recording sites (inter-site variability < 2%). Ischaemia produced a marked slowing of electrical restitution which, on average, reached a plateau at extrastimulus cycle lengths of 415 +/- 45 ms, 650 +/- 72 ms and > 800 ms at 2 min, 5 min and 9 min of ischaemia, respectively (each P < 0.001 vs control). In addition, ischaemia resulted in a large inter-site variability, with RV and LV restitution curves deviating from each other by as much as 28.5% (P < 0.0001 vs baseline). We conclude that global ischaemia not only leads to a delayed but also non-uniform electrical restitution.(ABSTRACT TRUNCATED AT 250 WORDS)