U. Flogel et al., Contribution of NO to ischemia-reperfusion injury in the saline-perfused heart: a study in endothelial NO synthase knockout mice, J MOL CEL C, 31(4), 1999, pp. 827-836
The contribution of endogenous NO to ischemia-reperfusion injury was studie
d in isolated perfused hearts of wild-type (WT) and endothelial NO synthase
knockout (eNOS(-)) mice. The hearts were subjected to a 16-min period of g
lobal no-flaw ischemia and were subsequently reperfused for 1 h. Cardiac co
ntractile function was evaluated and P-31-NMR spectroscopy was used to moni
tor myocardial energy status and the intracellular pH. During both baseline
and ischemia, there were neither significant differences in mechanical fun
ction nor in energetic parameters between the two groups, for example at ba
seline left ventricular developed pressure (LVDP) was 56.5 +/- 5.4 mmHg in
WT and 58.7+/-5.2mmHg in eNOS(-) and phosphocreatine (PCr) level was 12.9 /- 1.3 mM in WT and 12.7 +/- 1.7 mM in eNOS(-). In reperfusion, however, a
significant improvement of the post-ischemic functional and metabolic recov
ery became apparent in the eNOS(-) hearts. While in the WT group, LVDP reco
vered only to 38.4 +/- 5.3 mmHg, LVDP in the eNOS(-) group attained 49.4 +/
- 5.5 mmHg at the end of 60 min reperfusion (P<0.05, n=8), Similarly, the r
ecovery of PCr was significantly enhanced in the transgenic hearts as compa
red to WT (10.4+/-1.6 vs 8.1+/-1.3 mM, P<0.05), eNOS(-) hearts also showed
a better restoration of dP/dt and a significant lower left ventricular endd
iastolic pressure. In an additional series of wildtype hearts, the NO synth
ase inhibitor N-G-monomethyl-L-arginine methyl ester (100 mu M) also tended
to improve the recovery of both LVDP (43.8 +/- 6.8 mmHg) and PCr (9.5 +/-
1.6 mM) in reperfusion (1 h), but the restoration of functional and metabol
ic parameters was less pronounced when compared with eNOS(-). The results p
rovide clear evidence that endogenously formed NO significantly contributes
to ischemia-reperfusion injury in the saline-perfused mouse heart, most li
kely by peroxynitrite formation from NO. (C) 1999 Academic Press.