Changes in action potential duration (APD) were studied during ischemic/reperfusion injury preceded or not by preconditioning in isolated rat hearts. Hearts were perfused on a Langendorff apparatus with Krebs-Henseleit carbonate buffer and submitted to 25-min global low-flow ischemia (coronary flow, 0.3 mol x min-1) followed by 30-min reperfusion. In hearts that had been preconditioned, two intermittent periods of total ischemia for 5 min each, separated by 5-min reflow, were performed before low-flow ischemia. At the end of the ischemic period, APs were significantly prolonged in nonpreconditioned hearts; this prolongation was abolished by preconditioning. Moreover, preconditioning increased the recovery of the contractile function. Therefore, ischemia can widen APD. The results also showed that in rats, preconditioning can be produced in a manner qualitatively similar to preconditioning in other species. Verapamil (3 x 10(-9) mol x min(-1)) or 4-aminopyridine (4-AP, 3 x 10(-6) mol x min(-1)) applied exclusively during low-flow ischemia significantly improved postischemic contractile function in nonpreconditioned hearts (25.9 +/- 4.4. and 37.9 +/- 2.4 vs. 12.9 +/- 5.3%, respectively) as well as in preconditioned hearts (61.8 +/- 4.2 and 55.5 +/- 4.7 vs. 36.0 +/- 1.4%, respectively). With verapamil, this protection was associated with a decrease in APD at 90% of repolarization in the nonpreconditioned hearts (APD90 32.2 +/- 0.1 vs. 71.1 +/- 6.7 ms at the end of ischemia). With 4-AP, this same protection was associated with an increase in APD in the preconditioned hearts (APD90 67.7 +/- 0.7 vs. 48.5 +/- 2.6 ms at the end of ischemia). Both agents given during a 25-min ischemic challenge improved myocardial recovery in nonpreconditioned and preconditioned hearts, despite discordant effects on the AP. Furthermore, the action of these agents was cumulative with the effect of preconditioning.