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-[Ca]o (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 ([Ca]o=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-[Ca]o 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-[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 Ca2+ influx, also determines the degree of injury.
Imahashi
K
K
Division of Tracer Kinetics, Biomedical Research Center, Osaka University Medical School, Suita, Osaka, Japan.
Kusuoka
H
H
Hashimoto
K
K
Yoshioka
J
J
Yamaguchi
H
H
Nishimura
T
T
D000818:Animals; D002118:Calcium / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D009924:Organ Culture Techniques; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D012975:Sodium Isotopes; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D012975:Sodium Isotopes; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D013890:Thiourea; D002118:Calcium