Intracellular Sodium Accumulation During Ischemia as the Substrate for Reperfusion Injury

To elucidate the role of intracellular Na+ kinetics during ischemia and reperfusion in postischemic contractile dysfunction, intracellular Na+ concentration (Na+i) was measured in isolated perfused rat hearts using 23Na nuclear magnetic resonance spectroscopy. The extension of the ischemic period from 9 minutes to 15, 21, and 27 minutes (at 37 degrees C) increased Na+i at the end of ischemia from 270.0+/-10.4% of preischemic level (mean+/-SE, n=5) to 348.4+/-12.0% (n=5), 491.0+/-34.0% (n=7), and 505.3+/-12.1% (n=5), respectively, whereas the recovery of developed pressure worsened with the prolongation of the ischemic period (95.1+/-4.2%, 84.3+/-1. 2%, 52.8+/-13.7%, and 16.9+/-6.4% of preischemic level). The kinetics of Na+i recovery during reperfusion was analyzed by the fitting of a monoexponential function. When the hearts were reperfused with low-Cao (0.15 mmol/L) solution, the time constants of the recovery (tau) after 15-minute (8.07+/-0.85 minutes, n=5) and 21-minute ischemia (6.44+/-0.90, n=5) were significantly extended, with better functional recovery (98.5+/-1.4% for 15-minute P<0.05; 98.0+/-1.0% for 21-minute P<0.05) compared with standard reperfusion (Cao=2.0 mmol/L, tau=3.58+/-0.28 minutes for 15-minute P<0.0001; tau=3.02+/-0.20 for 21-minute P<0.0001). A selective inhibitor of Na+/Ca2+ exchanger also decelerated the Na+i recovery, which suggests that the recovery reflects the Na+/Ca2+ exchange activity. In contrast, high-Cao reperfusion (5 mmol/L) accelerated the Na+i recovery after 9-minute ischemia (tau=2.48+/-0.11 minute, n=5 P<0.0001) and 15-minute ischemia (tau=2.10+/-0.07, n=6 P<0. 05), but functional recovery deteriorated only in the hearts with 15-minute ischemia (29.8+/-9.4% P<0.05). Na+i recovery after 27-minute ischemia was incomplete and decelerated by low-Cao reperfusion, with limited improvement of functional recovery (42. 5+/-7.9%, n=5 P<0.05). These results indicate that intracellular Na+ accumulation during ischemia is the substrate for reperfusion injury and that the Na+i kinetics during reperfusion, which is coupled with Ca2+ influx, also determines the degree of injury.