Objective: The potassium channel opener, pinacidil, has been shown to be an effective cardioplegic agent over short periods of ischemia. However, clinical settings typically involve longer ischemic periods. This study tested the hypothesis that myocardial protection with a potassium channel opener is feasible during prolonged periods of arrest and is comparable with the traditional St. Thomas' Hospital solution. Methods: With a blood- perfused, isolated rabbit heart model, hearts underwent 1 hour of global normothermic ischemia followed by 30 minutes of reperfusion. During ischemia, three different cardioplegic solutions were administered either intermittently by infusion every 20 minutes or as continuous low-flow cardioplegia (150 ml total volume in all groups): (1) Krebs-Henseleit solution alone (control), (2) Krebs-Henseleit solution + pinacidil (50 μmol/L), or (3) St. Thomas' Hospital solution. Initial potassium channel opener infusions contained 5 mmol/L procaine. Postreperfusion systolic function (percent of developed pressure) was measured. Compliance changes were integrated from the end-diastolic pressure/volume relationships. Results: For intermittent cardioplegia, only St. Thomas' Hospital solution improved function (62.5% ± 4.0%) versus control (43.6% ± 3.3%, p < 0.001). However, with continuous cardioplegia, only pinacidil (75.6% ± 4.8%) exceeded control (62.7% ± 2.2%, p < 0.001) and was significantly better than St. Thomas' Hospital solution. Compared with the intermittent control group, all other groups showed significant preservation of preischemic diastolic properties. Conclusions: Myocardial protection during a longer, more clinically relevant ischemic period is feasible with a potassium channel opener only when it is given continuously. Continuous low-flow pinacidil cardioplegia was superior to St. Thomas' Hospital solution given either as an intermittent or continuous infusion.