Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts
Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts
复制标题
DOI：
10.1016/j.yjmcc.2004.06.014
复制
发表时间：
2004-09-01
影响因子：
5
通讯作者：
Matsubara, H
中科院分区：
文献类型：
--
作者：
Tatsumi, T;Akashi, K;Matsubara, H
感染性休克心脏抑制的机制尚不清楚。本研究探讨了诱导型一氧化氮合酶(INOS)过量产生的一氧化氮(NO)是否能抑制有氧能量代谢，损害内毒素处理的大鼠心脏功能。在48it治疗期间，脂多糖显著降低了对照组的收缩压(BP)至44%。对照组和内毒素处理组大鼠的心脏在朗宁多夫装置中灌流。注射内毒素后，左心室发展压(LVDP)明显降低，血浆NO_2~-/NO_3~-(NOx)浓度显著升高，心肌组织5‘-三磷酸腺苷(ATP)、磷酸肌酸(CRP)、ATP/5’-二磷酸腺苷(5‘-DDP)比值呈进行性下降。免疫学检测显示，内毒素处理的心肌细胞有明显的iNOS蛋白表达。诱导型一氧化氮合酶(INOS)的抑制剂氨基胍显著减轻了这些由内毒素引起的功能和代谢变化。注射内毒素后，心肌环鸟苷(CGMP)含量显著增加。可溶性鸟苷环化酶抑制剂亚甲蓝可拮抗这种cGMP的升高，并显著恢复内毒素所致的收缩功能障碍。此外，LVdP与心肌cGMP水平呈显著负相关，与血浆NO_2水平呈显著负相关。而注射内毒素后48h，亚甲蓝不再影响心功能，且LVdP与心肌ATP含量呈显著正相关。此外，内毒素处理48h后，线粒体NADH-CoQ还原酶、琥珀酸辅酶Q还原酶和ATPase的归一化活性(柠檬酸合成酶活性的比值)明显受到抑制，并出现线粒体脊的肿胀或断裂。氨基胍可显著改善内毒素引起的线粒体功能和形态障碍。提示在感染性休克早期，iNOS持续产生NO可通过cGMP导致心肌收缩功能障碍，但可直接损害心肌线粒体功能，降低心肌能量产生，在感染性休克晚期心肌功能障碍中起重要作用。(C)2004爱思唯尔有限公司。保留所有权利。
The mechanism responsible for cardiac depression in septic shock remains unknown. The present study examined whether nitric oxide (NO) overproduced by inducible NO synthase (iNOS) can inhibit aerobic energy metabolism and impair the myocardial function in endotoxin-treated rat hearts. Lipopolysaccharide (LPS) significantly decreased systolic blood pressure (BP) to 44% of control during the 48 It treatment. Hearts from control and LPS-treated rats were perfused in a Langendorff apparatus. After LPS injection, left ventricular (LV) developed pressure (LVDP) was significantly depressed, plasma NO2-/NO3- (NOx) concentration was markedly increased, and myocardial adenosine 5'-triphosphate (ATP), creatine phosphate (CrP), and the ratio of ATP/adenosine 5'-diphosphate were progressively decreased with time. Immunological examination showed a significant expression of iNOS protein in the LPS-treated myocytes. Aminoguanidine, an inhibitor of iNOS, significantly attenuated these LPS-induced functional and metabolic changes. Myocardial cyclic guanosine 3',5'-monophosphate (cGMP) content was significantly increased after LPS injection. Methylene blue, an inhibitor of soluble guanylate cyclase, blunted this increase in cGMP and significantly restored the LPS-induced contractile dysfunction 6 It after LPS injection. In addition, there was a significant negative correlation between LVDP and myocardial cGMP levels as well as a significant negative correlation between LVDP and plasma NO, levels. In contrast, 48 h after LPS injection, methylene blue no longer affected cardiac performance, and there was a significant positive correlation between LVDP and myocardial ATP content. Furthermore, the normalized activities (as a ratio of the citrate synthase activity) of mitochondrial NADH-CoQ reductase, succinate-CoQ reductase, and ATPase, were significantly inhibited, and the swelling or disruption of mitochondria cristae was seen in the 48 h LPS treatment. These LPS-induced functional and morphological disorders in the mitochondria were significantly improved by aminoguanidine. The findings suggest that sustained production of NO by iNOS leads to contractile dysfunction via cGMP in the early stage, but that it can directly impair the mitochondrial function, lower myocardial energy production, and contribute significantly to the myocardial dysfunction in the later stage of septic shock. (C) 2004 Elsevier Ltd. All rights reserved.