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© 1999 American Heart Association, Inc.
Original Contribution |
Intracellular Sodium Accumulation During Ischemia as the Substrate for Reperfusion Injury
From the Division of Tracer Kinetics, Biomedical Research Center, Osaka University Medical School, Suita, Osaka, Japan. The current affiliation for H.K. is the Institute for Clinical Research, Osaka National Hospital, Osaka, Japan.
Correspondence to Hideo Kusuoka, Institute for Clinical Research, Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka, 540-0006 Japan. E-mail nisimura{at}tracer.med.osaka-u.ac.jp
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 23Na 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 (
) 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, =3.58±0.28 minutes for
15-minute [P<0.0001]; =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 (=2.48±0.11 minute, n=5
[P<0.0001]) and 15-minute ischemia
(=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.
Key Words: [Na+]i • 23Na nuclear magnetic resonance spectroscopy • functional recovery • time constant • low-/high-[Ca]o reperfusion
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