Proinflammatory cytokines depress cardiac efficiency by a nitric oxide-dependent mechanism
Proinflammatory cytokines depress cardiac efficiency by a nitric oxide-dependent mechanism
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DOI：
10.1152/ajpheart.1998.275.3.h1016
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发表时间：
1998-09-01
影响因子：
4.8
通讯作者：
Schulz, R
中科院分区：
文献类型：
--
作者：
Panas, D;Khadour, FH;Schulz, R
促炎细胞因子（白细胞介素-1 β、肿瘤坏死因子-α和干扰素-γ; Cytomix）通过刺激诱导型一氧化氮（NO）合酶（iNOS）的表达部分抑制心肌收缩工作。由于NO和过氧亚硝酸盐抑制心肌O-2消耗（M（V）对点O-2），我们研究了这种机制是否有助于减少心脏工作。在对照离体工作大鼠心脏中，心脏作功稳定60分钟，随后从60分钟下降到120分钟，M（V）在O-2点上没有变化。Cytomix缩短了起效时间（20-40 min内），增强了对心脏作功和效率的抑制，并在80 min后抑制了M（V）超过点O-2。巯基乙基胍（MEG）是一种iNOS抑制剂和过氧亚硝酸根清除剂，或糖皮质激素地塞米松（Dex）可消除Cytomix的作用。Cytomix可使iNOS表达增加10倍，Dex可消除iNOS表达，但MEG不能。尼古丁诱导的心脏做功抑制先于O-2点上的M（V）降低，这表明，至少在早期反应中，NO和/或过氧亚硝酸盐可能不会通过抑制线粒体呼吸而损害心脏功能，但会降低心脏利用ATP进行收缩功的能力。
Proinflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma; Cytomix) depress myocardial contractile work partially by stimulating expression of inducible nitric oxide (NO) synthase (iNOS). Because NO and peroxynitrite inhibit myocardial O-2 consumption (M(V) over dot O-2), we examined whether this mechanism contributes to reduced cardiac work. In control isolated working rat hearts, cardiac work was stable for 60 min, followed by a decline from 60 to 120 min, without change in M(V) over dot O-2. Cardiac efficiency (work/M(V) over dot O-2) was therefore reduced from 60 to 120 min. Cytomix shortened the onset (within 20-40 min) and enhanced the depression in cardiac work and efficiency and inhibited M(V) over dot O-2 after 80 min. Mercaptoethylguanidine (MEG), an iNOS inhibitor and peroxynitrite scavenger, or the glucocorticoid dexamethasone (Dex) abolished the effects of Cytomix. iNOS expression was increased 10-fold by Cytomix and abolished by Dex but not MEG. That cytokine-induced depression in cardiac work precedes the reduction in M(V) over dot O-2 suggests, at least in the early response, that NO and/or peroxynitrite may not impair heart function by inhibiting mitochondrial respiration but reduce the heart's ability to utilize ATP for contractile work.