Abstract
During ischemia and reperfusion, with an increase in intracellular
Na$^+$ and a depolarized membrane potential, Ca$^2+$ may
enter the myocyte in exchange for intracellular Na$^+$ via reverse-mode
Na$^+$-Ca$^2+$ exchange (NCX). To test the role of Ca$^2+$
entry via NCX during ischemia and reperfusion, we studied mice with
cardiac-specific ablation of NCX (NCX-KO) and demonstrated that reverse-mode
Ca$^2+$ influx is absent in the NCX-KO myocytes. Langendorff
perfused hearts were subjected to 20 minutes of global ischemia followed
by 2 hours of reperfusion, during which time we monitored high-energy
phosphates using 31P-NMR and left-ventricular developed pressure.
In another group of hearts, we monitored intracellular Na$^+$
using 23Na-NMR. Consistent with Ca$^2+$ entry via NCX during
ischemia, we found that hearts lacking NCX exhibited less of a decline
in ATP during ischemia, delayed ischemic contracture, and reduced
maximum contracture. Furthermore, on reperfusion following ischemia,
NCX-KO hearts had much less necrosis, better recovery of left-ventricular
developed pressure, improved phosphocreatine recovery, and reduced
Na$^+$ overload. The improved recovery of function following
ischemia in NCX-KO hearts was not attributable to the reduced preischemic
contractility in NCX-KO hearts, because when the preischemic workload
was matched by treatment with isoproterenol, NCX-KO hearts still
exhibited improved postischemic function compared with wild-type
hearts. Thus, NCX-KO hearts were significantly protected against
ischemia-reperfusion injury, suggesting that Ca$^2+$ entry via
reverse-mode NCX is a major cause of ischemia/reperfusion injury.
- 16179590
- action
- animals,
- ca,
- calcium,
- cardiac,
- contraction,
- energy
- exchanger,
- extramural,
- gov't,
- injury,
- isoproterenol,
- knockout,
- lcium,
- metabolism,
- mice,
- myocardial
- myocardium,
- myocytes,
- n.i.h.,
- non-u.s.
- p.h.s.,
- phenotype,
- potentials,
- reperfusion
- research
- sarcolemma,
- sodium,
- sodium-calcium
- support,
- u.s.
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