Background. Cardioplegia has been shown to induce significant cell swelling. This study tested the hypothesis that (1) the [K+][Cl-] product of the cardioplegia solution is the main determinant of myocyte swelling, and (2) reperfusion myocyte shrinkage results from a rectifying Cl- conductance. Methods. Rabbit ventricular myocytes were superfused with 37°C Krebs-Henseleit solution for 10 minutes. Then cells underwent 20 minutes of superfusion with standard St. Thomas' solution ([K+][Cl-] product = 2566 mmol/L2) and two solutions with lower [K+][Cl-] product (1500 and 700 mmol/L2) at 9°C. Cells were then resuperfused with 37°C Krebs-Henseleit solution for 30 minutes. Cell volume was measured by videomicroscopy. Results. Cells superfused with St. Thomas' having [K+][Cl-] products of 2,566, 1,500, and 700 mmol/L2 swelled by 9.18% ± 3.57%, 5.51% ± 1.08%, and 1.49% ± 1.56%, respectively. Reexposure to Krebs-Henseleit solution caused these cells to shrink by 5.79% ± 1.41%, 8.72% ± 3.68%, and 13.46% ± 5.60%, respectively. This shrinkage was blocked by Cl- channel blockers given at the onset of superfusion. Conclusions. Lowering the [K+][Cl-] product of St. Thomas' solution attenuated myocyte edema. Myocyte shrinkage during reexposure to Krebs-Henseleit solution resulted from the volume-activated Cl- channel.(C) 2000 by The Society of Thoracic Surgeons.