Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts

被引:48
作者
Tatsumi, T [1 ]
Akashi, K
Keira, N
Matoba, S
Mano, A
Shiraishi, J
Yamanaka, S
Kobara, M
Hibino, N
Hosokawa, S
Asayama, J
Fushiki, S
Fliss, H
Nakagawa, M
Matsubara, H
机构
[1] Kyoto Prefectural Univ Med, Dept Cardiovasc Med, Kamigyo Ku, Kyoto 6028566, Japan
[2] Eizai Co Ltd, Drug Safety Res Labs, Gifu 5016024, Japan
[3] Kyoto Prefectural Univ Med, Dept Dynam Pathol, Kamigyo Ku, Kyoto 6028566, Japan
[4] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5, Canada
关键词
nitric oxide; lipopolysaccharide; cytokine; endotoxin shock; mitochondrial dysfunction;
D O I
10.1016/j.yjmcc.2004.06.014
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:775 / 784
页数:10
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