Kobara Miyuki, Tatsumi Tetsuya, Takeda Mitsuo, Mano Akiko, Yamanaka Satoshi, Shiraishi Jun, Keira Natsuya, Matoba Satoaki, Asayama Jun, Nakagawa Masao
Second Dept. of Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Basic Res Cardiol. 2003 Sep;98(5):319-28. doi: 10.1007/s00395-003-0423-x. Epub 2003 Jun 20.
Nitric oxide (NO) is known to act as a mediator of tissue injury as well as being a potent endogenous vasodilator. The functional and metabolic effects of NO on ischemia-reperfusion injury are still controversial. The aim of this study was to clarify the relationship between the degree of NO synthase (NOS) inhibition and the effects on ischemia-reperfusion injury.
Langendorff-perfused rat hearts were subjected to 30 minutes of global ischemia followed by 30 minutes of reperfusion. The recovery of left ventricular developed pressure (LVDP), creatine kinase (CK) release, and myocardial high energy phosphates were measured in hearts perfused with or without NOS inhibitors, L-N(G)-monomethyl arginine (L-NMMA) or N(G)nitro-L-arginine methylester (L-NAME). NOS inhibitors exerted different effects on the recovery of LVDP and CK release depending on the concentration. The low dose of L-NMMA improved the recovery of LVDP, decreased the CK release during reperfusion, and preserved the myocardial adenosine triphosphate content after reperfusion. In contrast, the high dose of L-NMMA had adverse effects. L-NMMA reduced NO release in coronary effluent in a dose-dependent fashion. Both effects of L-NMMA were abolished by excessive co-administration of L-arginine and the same doses of D-N(G)-monomethyl arginine (D-NMMA) showed no effect on ischemia-reperfusion injury. Therefore, both effects were due to NOS inhibition. In addition, L-NMMA suppressed the myocardial malondialdehyde accumulation, an indicator of oxidative stress, which might be attributed to the beneficial effects by partial NOS inhibition. On the other hand, the high dose L-NMMA significantly decreased coronary fl ow during aerobic perfusion and reperfusion. Therefore, it is conceivable that the vasoactive NOS inhibition contributes to the harmful effects, which might exceed the beneficial effects due to a decrease in oxidative stress.
The present results showed that NO inhibitors had dual effects on mechanical function and energy metabolism depending on the concentration. Non-vasoactive inhibition of NOS had beneficial effects due to the suppression of oxidative injury. However, strong vasoactive inhibition of NOS exacerbated the ischemia-reperfusion injury.
一氧化氮（NO）既是一种内源性强效血管舒张剂，也被认为是组织损伤的介质。NO对缺血再灌注损伤的功能和代谢影响仍存在争议。本研究旨在阐明一氧化氮合酶（NOS）抑制程度与缺血再灌注损伤效应之间的关系。
采用Langendorff灌注法对大鼠心脏进行30分钟全心缺血，随后再灌注30分钟。在灌注有或没有NOS抑制剂L-N(G)-单甲基精氨酸（L-NMMA）或N(G)-硝基-L-精氨酸甲酯（L-NAME）的心脏中，测量左心室舒张末压（LVDP）的恢复、肌酸激酶（CK）释放以及心肌高能磷酸化合物。NOS抑制剂对LVDP恢复和CK释放的影响因浓度而异。低剂量的L-NMMA可改善LVDP的恢复，减少再灌注期间的CK释放，并在再灌注后保留心肌三磷酸腺苷含量。相反，高剂量的L-NMMA则产生不良影响。L-NMMA以剂量依赖性方式降低冠状动脉流出液中的NO释放。L-NMMA的这两种效应均可通过过量共同给予L-精氨酸而消除，相同剂量的D-N(G)-单甲基精氨酸（D-NMMA）对缺血再灌注损伤无影响。因此，这两种效应均归因于NOS抑制。此外，L-NMMA抑制了心肌丙二醛的积累，丙二醛是氧化应激的指标，这可能归因于部分NOS抑制带来的有益效应。另一方面，高剂量L-NMMA显著降低有氧灌注和再灌注期间的冠状动脉血流量。因此，可以想象，具有血管活性的NOS抑制会导致有害影响，这可能超过因氧化应激降低而产生的有益影响。
目前的结果表明，NO抑制剂对机械功能和能量代谢具有双重影响，这取决于浓度。对NOS的非血管活性抑制因抑制氧化损伤而具有有益作用。然而，对NOS的强烈血管活性抑制会加重缺血再灌注损伤。
