CELLULAR BASIS FOR THE NEGATIVE INOTROPIC EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA IN THE ADULT MAMMALIAN HEART
CELLULAR BASIS FOR THE NEGATIVE INOTROPIC EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA IN THE ADULT MAMMALIAN HEART
复制标题
DOI：
10.1172/jci116834
复制
发表时间：
1993-11-01
影响因子：
15.9
通讯作者：
MANN, DL
中科院分区：
文献类型：
--
作者：
YOKOYAMA, T;VACA, L;MANN, DL
为了明确肿瘤坏死因子- α (TNFalpha)在成人心脏中负性肌力作用的机制，我们检测了TNFalpha在完整左心室和分离的成人心肌细胞中的功能作用。在心室和分离的成人心肌细胞中进行的研究表明，TNFalpha具有浓度和时间依赖性的负性肌力作用，在去除该细胞因子后完全可逆。此外，用中和性抗TNFalpha抗体治疗可在分离的肌细胞中阻止TNFalpha的负性肌力作用。上述发现的细胞基础是由研究提供的，这些研究表明，使用TNFalpha治疗导致收缩过程中细胞内钙峰值水平下降；此外，这些发现似乎并不继发于心肌细胞电生理特性的改变。进一步的研究表明，一氧化氮、新生蛋白合成和花生四烯酸途径代谢物水平的升高不太可能是tnfalpha诱导的收缩功能异常的原因。因此，这些研究初步证明了TNFalpha的负性肌力作用是成人心肌细胞内钙稳态改变的直接结果。
To define the mechanism(s) responsible for the negative inotropic effects of tumor necrosis factor-alpha (TNFalpha) in the adult heart, we examined the functional effects of TNFalpha in the intact left ventricle and the isolated adult cardiac myocyte. Studies in both the ventricle and the isolated adult cardiac myocyte showed that TNFalpha exerted a concentration- and time-dependent negative inotropic effect that was fully reversible upon removal of this cytokine. Further, treatment with a neutralizing anti-TNFalpha antibody prevented the negative inotropic effects of TNFalpha in isolated myocytes. A cellular basis for the above findings was provided by studies which showed that treatment with TNFalpha resulted in decreased levels of peak intracellular calcium during the systolic contraction sequence; moreover, these findings did not appear to be secondary to alterations in the electrophysiological properties of the cardiac myocyte. Further studies showed that increased levels of nitric oxide, de novo protein synthesis, and metabolites of the arachidonic acid pathway were unlikely to be responsible for the TNFalpha-induced abnormalities in contractile function. Thus, these studies constitute the initial demonstration that the negative inotropic effects of TNFalpha are the direct result of alterations in intracellular calcium homeostasis in the adult cardiac myocyte.