Background. Previous work from our laboratory has demonstrated the advantage of adenosine triphosphate-sensitive potassium-channel openers as cardioplegic agents when compared with hyperkalemic (20 mmol/L KCl) Krebs-Henseleit solution. However, Krebs-Henseleit with 20 mmol/L KCl is not an ideal hyperkalemic cardioplegia. Therefore, we investigated the hypothesis that hyperpolarized arrest with pinacidil and aprikalim could provide equal or superior myocardial protection to hyperkalemic arrest with the widely accepted St. Thomas' solution. Methods. Myocardial protection was compared in the blood-perfused isolated parabiotic rabbit heart Langendorff model. Twenty-four hearts were protected with a 50-mL infusion of cardioplegia for a 30-minute global normothermic ischemic period followed by 30 minutes of reperfusion. Systolic function (percent recovery of developed pressure) and the diastolic properties of the left ventricle were measured. Coronary blood flow was measured throughout each experiment. Results. The percent recovery of developed pressure (mean ± standard error of the mean) for St. Thomas' solution, pinacidil, and aprikalim was 53.1% ± 5.4%, 64.0% ± 3.0%, and 62.4% ± 3.2%, respectively. The time (minutes) until mechanical and electrical arrest was significantly longer in the pinacidil (4.82 ± 0.10 and 12.06 ± 1.07) and aprikalim (3.33 ± 0.28 and 11.12 ± 0.94) groups when compared with the St. Thomas group (1.84 ± 0.74, and 3.17 ± 1.44). Coronary blood flow upon reperfusion was significantly greater in the pinacidil (16.4 ± 2.1 mL/min) and aprikalim (19.4 ± 2.8 mL/min) groups compared with the St. Thomas' solution group (8.0 ± 1.0 mL/min), and this returned to baseline after 15 minutes of reperfusion. Conclusions. Myocardial protection-with pinacidil and aprikalim is comparable with that of St. Thomas' solution in the blood-perfused isolated rabbit heart despite prolonged mechanical and electrical activity during ischemia.