The present study was undertaken to determine whether class Ic antiarrhythmic agents, flecainide and pilsicainide, improve ischemia/reperfusion-induced cardiac contractile dysfunction. Isolated rat hearts were subjected to a 35-min global ischemia, followed by a 60-min reperfusion, and the functional and metabolic consequences were examined. Ischemia/reperfusion resulted in no recovery of contractile function and a sustained rise in left ventricular and diastolic pressure of the perfused heart during reperfusion. The ischemia/reperfusion also induced increases in tissue sodium and calcium levels, decreases in potassium and magnesium ion contents and the release of creatine kinase and purine nucleosides and bases (ATP metabolites) from the heart, suggesting a pronounced change in cardiac transmembrane flux of ions, substrates and macromolecules. Treatment of the perfused heart with either 5 to 50 microM flecainide or 10 to 100 microM pilsicainide during preischemia resulted in diminishing the postischemic contractile dysfunction; suppressing the changes in tissue sodium, potassium, calcium and magnesium contents; and attenuating the release of creatine kinase and ATP metabolites in a concentration-dependent manner. Tissue sodium accumulation and potassium loss were also observed at the end of ischemia, which was attenuated by pretreatment with these agents. These results provided evidence that class Ic antiarrhythmic agents are capable of diminishing ischemia/reperfusion-induced contractile dysfunction and tissue ionic disturbance.