Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase
Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase
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DOI：
10.1006/jmcc.1996.0153
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发表时间：
1996-08-01
影响因子：
5
通讯作者：
Thoenes, M
中科院分区：
文献类型：
--
作者：
Stein, B;Frank, P;Thoenes, M
感染性休克或心肌炎等炎症性心脏病患者心肌收缩力下降。这些患者循环中细菌内毒素（脂多糖，LPS）和促炎细胞因子如白细胞介素-1 β (il -1 β)或肿瘤坏死因子- α (tnf - α)水平升高。目前尚不清楚LPS和/或细胞因子是否对心肌细胞有直接的肌力作用，以及这些作用是否像在血管平滑肌细胞中所显示的那样是通过l -精氨酸-一氧化氮合酶（NOS）途径介导的。因此，我们检测了LPS、IL-1 β和tnf - α对离体豚鼠心室心肌细胞收缩性和cGMP含量的直接影响。此外，还研究了NOS抑制剂n - g -硝基- l -精氨酸（L-NNA）和地塞米松对这些作用的影响以及诱导的NOS （iNOS）蛋白表达的影响。LPS （1000 ng/ml）、IL-1 β (25 ng/ml)和tnf - α (100 ng/ml)使心肌细胞在长期治疗（18 h）后收缩力分别下降48%、55%和65%，cGMP含量分别增加135%、88%和70%，短期治疗（30 min）后收缩力和cGMP含量未发生变化。这些作用被L-NNA （100 μ M）和地塞米松（3 μ M）阻断。此外，iNOS蛋白在LPS和细胞因子处理的心肌细胞中表达。这些结果表明，LPS、IL-1 β和tnf - α对心肌细胞有直接的负性肌力作用，并伴有cGMP含量的增加。这些作用是通过心肌iNOS的从头合成介导的。内毒素和细胞因子对心肌细胞的直接负性肌力作用可能部分促成感染性休克或炎症性心脏病患者观察到的收缩功能障碍。(C) 1996学术出版社有限公司
In patients with septic shock or inflammatory cardiac diseases like myocarditis myocardial contractility is depressed. These patients have elevated circulating levels of bacterial endotoxins (lipopolysaccharides, LPS) and pro-inflammatory cytokines like interleukin-1 beta (IL-alpha 1 beta) or tumor necrosis factor-alpha (TNF-alpha). It is not clear, whether LPS and/or cytokines have direct inotropic effects on cardiomyocytes and whether these effects are mediated via the L-arginine-nitric oxide synthase (NOS) pathway as demonstrated in vascular smooth muscle cells. Therefore, we examined the direct effects of LPS, IL-1 beta and TNF-alpha on contractility and cGMP content in isolated guinea-pig ventricular cardiomyocytes. Furthermore, the influence of the NOS inhibitor N-G-nitro-L-arginine (L-NNA) and dexamethasone on these effects was studied as well as inducible NOS (iNOS) protein expression. LPS (1000 ng/ml), IL-1 beta (25 ng/ml) and TNF-alpha (100 ng/ml) decreased contractility by 48%, 55% and 65% and augmented cGMP content by 135%, 88% or 70% after longterm treatment (18 h) in cardiomyocytes, without altering contractility or cGMP content after short-term treatment (30 min). These effects were blocked by L-NNA (100 mu M) and dexamethasone (3 mu M). Furthermore iNOS protein was expressed in LPS- and cytokine-treated cardiomyocytes. These findings demonstrate that LPS, IL-1 beta and TNF-alpha have direct negative inotropic effects on cardiomyocytes, which are accompanied by an increase in cGMP content. These effects are mediated via de novo synthesis of a myocardial iNOS. The direct negative inotropic effects of endotoxins and cytokines on cardiomyocytes may in part contribute to the contractile dysfunction observed in patients with septic shock or inflammatory cardiac diseases. (C) 1996 Academic Press Limited