Mori E, Haramaki N, Ikeda H, Imaizumi T
Department of Internal Medicine III, Kurume University School of Medicine, Japan.
Cardiovasc Res. 1998 Oct;40(1):113-23. doi: 10.1016/s0008-6363(98)00146-1.
The aim of this study was to investigate how the enhanced nitric oxide (NO) production by intra-coronary infusion of L-arginine acts in myocardial stunning in dogs by focusing on the involvement of peroxynitrite, a reaction product of NO and superoxide anion.
Dogs were divided into six groups; a control non-treated group (CON, n = 9), and NG-nitro L-arginine methyl ester (L-NAME, n = 6), 1 mM L-arginine (L-ARG, n = 8), D-arginine (D-ARG, n = 6), L-arginine plus superoxide dismutase (L-ARG + SOD, n = 6), and SOD alone (SOD, n = 6) treated groups. L-NAME, or L- or D-arginine was continuously infused into the left anterior descending coronary artery (LAD) starting just prior to reperfusion, whereas SOD was intravenously injected before occlusion. During 120 min of reperfusion after 15 min occlusion of LAD, myocardial contractile function in the ischemic region gradually recovered and reached approximately 70% of the preischemic level in CON, D-ARG and SOD, but it remained dyskinetic (-46%) in L-ARG. On the other hand, it was improved in L-NAME (90%). Tissue malondialdehyde was elevated (p < 0.005) after reperfusion, and myocardial NO metabolites measured by an intratissue-microdialyzer increased (approximately 150%, p < 0.05) in the ischemic region during reperfusion in L-ARG but not in the CON, L-NAME, D-ARG or SOD groups. In the L-ARG + SOD group, L-arginine-induced contractile dysfunction and elevation of malondialdehyde were prevented, but the increase in NO metabolites remained. These results suggest that L-arginine aggravated myocardial stunning through oxidative stress and the cytotoxicity was caused by NO derivatives but not by NO itself. The formation of nitrotyrosine, a footprint of peroxynitrite, was immunohistochemically confirmed in the ischemic region of L-ARG.
Our results demonstrate for the first time in vivo that NO has a detrimental role in myocardial stunning through the production of peroxynitrite.
本研究旨在通过关注过氧亚硝酸盐（一种一氧化氮和超氧阴离子的反应产物）的参与情况，探讨冠状动脉内注入L-精氨酸增强一氧化氮（NO）生成在犬心肌顿抑中的作用机制。
将犬分为六组：未处理的对照组（CON，n = 9）、NG-硝基-L-精氨酸甲酯（L-NAME，n = 6）、1 mM L-精氨酸（L-ARG，n = 8）、D-精氨酸（D-ARG，n = 6）、L-精氨酸加超氧化物歧化酶（L-ARG + SOD，n = 6）以及单独使用超氧化物歧化酶（SOD，n = 6）处理组。在再灌注前开始，将L-NAME或L-或D-精氨酸持续注入左前降支冠状动脉（LAD），而SOD在闭塞前静脉注射。在LAD闭塞15分钟后的120分钟再灌注期间，CON、D-ARG和SOD组缺血区域的心肌收缩功能逐渐恢复，达到缺血前水平的约70%，但L-ARG组仍表现为运动障碍（-46%）。另一方面，L-NAME组有所改善（90%）。再灌注后组织丙二醛升高（p < 0.005），在L-ARG组再灌注期间，通过组织内微透析仪测量的缺血区域心肌NO代谢产物增加（约150%，p < 0.05），而CON、L-NAME、D-ARG或SOD组未增加。在L-ARG + SOD组中，L-精氨酸诱导的收缩功能障碍和丙二醛升高得到预防，但NO代谢产物的增加仍然存在。这些结果表明，L-精氨酸通过氧化应激加重心肌顿抑，细胞毒性是由NO衍生物而非NO本身引起的。在L-ARG组的缺血区域通过免疫组织化学证实了过氧亚硝酸盐的足迹——硝基酪氨酸的形成。
我们的结果首次在体内证明，NO通过过氧亚硝酸盐的产生在心肌顿抑中起有害作用。
