There are few investigations on azimilide effects during ischemia/reperfusion. We have therefore investigated low concentrations of azimilide (0.1 and 0.5 micromol/l) versus Controls on action potential parameters and occurrence of repetitive responses during simulated ischemia and reperfusion. An in vitro model of "border zone" in guinea-pig ventricular myocardium (n=30) was used. Azimilide 0.5 micromol/l lengthened action potential duration in normoxic but not in ischemic-like conditions. Therefore an increased dispersion of action potential duration at 90% of repolarization during simulated ischemia in presence of azimilide was seen. Upon reperfusion, both normal and reperfused myocardium showed azimilide-induced action potential duration increase. There was a neutral effect on the occurrence of arrhythmias during simulated ischemia; however azimilide showed significant (P=0.033) antiarrhythmic properties following reperfusion. To mimic I(Kr) and I(Ks) blocking properties of azimilide we further used dofetilide 10 nmol/l with HMR 1556 1 nmol/l (N=9), which was accompanied by less severe shortening (P<0.05) of action potential duration at 90% of repolarization at 30 min of ischemic-like conditions (-43+/-9%), as compared with azimilide 0.5 micromol/l (-64+/-5%) but similar to what seen with azimilide 0.1 micromol/l (-53+/-5%) and Controls (-52+/-6%). During reperfusion, 2/9 (22%) preparations had sustained activities, which was less than what observed in Controls (5/10, 50%) and with azimilide 0.5 micromol/l (0/10, 0%), although not statistically different (respectively, P=0.35 and P=0.21). Lack versus homogenous class III effects of azimilide in respectively simulated ischemia and reperfusion may explain its different efficacy on arrhythmias, although prevention of reperfusion arrhythmias calls for other than just its I(Kr) and I(Ks) blocking properties.