Objectives: A donor heart preservation solution was designed to use hyperpolarized arrest with the adenosine triphosphate-sensitive potassium-channel opener pinacidil. This solution contained concentrations of potassium, sodium, calcium, magnesium, lactobionate, and the buffer histidine specifically chosen to minimize intracellular calcium accumulation associated with prolonged ischemia. Methods: Twenty-four rabbit hearts were randomly assigned to receive 1 of 3 preservation solutions in a crystalloid-perfused Langendorff model: (1) prototype solution containing a 0.5 mmol/L concentration of pinacidil, (2) prototype solution without pinacidil as control, and (3) University of Wisconsin solution. Thirty minutes of initial perfusion preceded baseline data acquisition. Data comprised left ventricle pressure-volume curves generated by inflating an intraventricular latex balloon. After cardioplegic administration, hearts underwent 4 hours of hypothermic storage, followed by 60 minutes of reperfusion and postischemic data acquisition. Results: Postischemic developed pressure was better preserved by pinacidil solution (92.4% ± 4.5%) than by the control (74.9% ± 3.4%, P = .01) and University of Wisconsin solutions (66.7% ± 5.1%, P = .001). Diastolic negative dP/dT was better preserved by pinacidil solution (104.4% ± 10.2%) than by the control (80.2% ± 4.2%, P = .034) and University of Wisconsin solutions (71.7% ± 7.0%, P = .015), Diastolic compliance, expressed as baseline/postischemic diastolic slope ratios, was more poorly preserved by University of Wisconsin solution (0.67 ± 0.07) than by the pinacidil (0.88 ± 0.05, P = .041) and control solutions (0.87 ± 0.05, P = .021). Postischemic coronary flow was higher in hearts exposed to pinacidil solution. (77.8% ± 3.0%) than in those exposed to the control (66.8% ± 2.4%) and University of Wisconsin solutions (70.9% ± 4.0%, P = .07). Conclusions: The superiority of the pinacidil solution in this experiment demonstrated that hyperpolarized arrest with potassium-channel openers improves donor heart preservation when administered in a novel histidine-buffered lactobionate-enriched vehicle.