Flögel U, Decking U K, Gödecke A, Schrader J
Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, Postfach 101007, Düsseldorf, 40001, Germany.
J Mol Cell Cardiol. 1999 Apr;31(4):827-36. doi: 10.1006/jmcc.1998.0921.
The contribution of endogenous NO to ischemia-reperfusion injury was studied 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 global no-flow ischemia and were subsequently reperfused for 1 h. Cardiac contractile function was evaluated and 31P-NMR spectroscopy was used to monitor myocardial energy status and the intracellular pH. During both baseline and ischemia, there were neither significant differences in mechanical function nor in energetic parameters between the two groups, for example at baseline left ventricular developed pressure (LVDP) was 56.5+/-5.4 mmHg in WT and 58.7+/-5.2 mmHg in eNOS-and phosphocreatine (PCr) level was 12.9+/-1.3 m m in WT and 12.7+/-1.7 m m in eNOS-. In reperfusion, however, a significant improvement of the post-ischemic functional and metabolic recovery became apparent in the eNOS-hearts. While in the WT group, LVDP recovered 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 recovery of PCr was significantly enhanced in the transgenic hearts as compared to WT (10.4+/-1.6 vs 8.1+/-1.3 m m, P<0.05). eNOS-hearts also showed a better restoration of dP/d t and a significant lower left ventricular enddiastolic pressure. In an additional series of wild-type hearts, the NO synthase inhibitor NG-monomethyl-L-arginine methyl ester (100 microm) also tended to improve the recovery of both LVDP (43.8+/-6.8 mmHg) and PCr (9.5+/-1.6 m m) in reperfusion (1 h), but the restoration of functional and metabolic parameters was less pronounced when compared with eNOS-. The results provide clear evidence that endogenously formed NO significantly contributes to ischemia-reperfusion injury in the saline-perfused mouse heart, most likely by peroxynitrite formation from NO.
在野生型（WT）和内皮型一氧化氮合酶基因敲除（eNOS-）小鼠的离体灌注心脏中，研究了内源性一氧化氮（NO）对缺血再灌注损伤的作用。心脏经历16分钟的全心无血流缺血，随后再灌注1小时。评估心脏收缩功能，并使用31P-NMR光谱监测心肌能量状态和细胞内pH值。在基线期和缺血期，两组之间的机械功能和能量参数均无显著差异，例如在基线期，WT组左心室舒张末压（LVDP）为56.5±5.4 mmHg，eNOS-组为58.7±5.2 mmHg；磷酸肌酸（PCr）水平在WT组为12.9±1.3 mM，eNOS-组为12.7±1.7 mM。然而，在再灌注期，eNOS-心脏的缺血后功能和代谢恢复有显著改善。WT组中，LVDP仅恢复到38.4±5.3 mmHg，而在eNOS-组中，再灌注60分钟末LVDP达到49.4±5.5 mmHg（P<0.05，n=8）。同样，与WT相比，转基因心脏中PCr的恢复显著增强（10.4±1.6对8.1±1.3 mM，P<0.05）。eNOS-心脏还显示出dP/dt的更好恢复以及显著更低的左心室舒张末压。在另一系列野生型心脏中，一氧化氮合酶抑制剂NG-单甲基-L-精氨酸甲酯（100 μM）在再灌注（1小时）时也倾向于改善LVDP（43.8±6.8 mmHg）和PCr（9.5±1.6 mM）的恢复，但与eNOS-相比，功能和代谢参数的恢复不太明显。结果提供了明确的证据，表明内源性生成的NO在生理盐水灌注的小鼠心脏中对缺血再灌注损伤有显著作用，很可能是通过NO形成过氧亚硝酸盐。
