Intracellular Sodium Accumulation During Ischemia as the Substrate for Reperfusion Injury

Abstract

Abstract —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 23 Na nuclear magnetic resonance spectroscopy. The extension of the ischemic period from 9 minutes to 15, 21, and 27 minutes (at 37°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–[Ca] o (0.15 mmol/L) solution, the time constants of the recovery (τ) 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 ([Ca] o =2.0 mmol/L, τ=3.58±0.28 minutes for 15-minute [ P <0.0001]; τ=3.02±0.20 for 21-minute [ P <0.0001]). A selective inhibitor of Na + /Ca 2+ exchanger also decelerated the [Na + ] i recovery, which suggests that the recovery reflects the Na + /Ca 2+ exchange activity. In contrast, high-[Ca] o reperfusion (5 mmol/L) accelerated the [Na + ] i recovery after 9-minute ischemia (τ=2.48±0.11 minute, n=5 [ P <0.0001]) and 15-minute ischemia (τ=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-[Ca] o 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 Ca 2+ influx, also determines the degree of injury.