Yokoyama T, Vaca L, Rossen R D, Durante W, Hazarika P, Mann D L
Department of Medicine, Veterans Affairs Medical Center, Houston, Texas 77030.
J Clin Invest. 1993 Nov;92(5):2303-12. doi: 10.1172/JCI116834.
To define the mechanism(s) responsible for the negative inotropic effects of tumor necrosis factor-alpha (TNF alpha) in the adult heart, we examined the functional effects of TNF alpha in the intact left ventricle and the isolated adult cardiac myocyte. Studies in both the ventricle and the isolated adult cardiac myocyte showed that TNF alpha exerted a concentration- and time-dependent negative inotropic effect that was fully reversible upon removal of this cytokine. Further, treatment with a neutralizing anti-TNF alpha antibody prevented the negative inotropic effects of TNF alpha in isolated myocytes. A cellular basis for the above findings was provided by studies which showed that treatment with TNF alpha 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 TNF alpha-induced abnormalities in contractile function. Thus, these studies constitute the initial demonstration that the negative inotropic effects of TNF alpha are the direct result of alterations in intracellular calcium homeostasis in the adult cardiac myocyte.
为了确定肿瘤坏死因子-α（TNFα）对成年心脏产生负性肌力作用的机制，我们研究了TNFα对完整左心室和分离的成年心肌细胞的功能影响。在心室和分离的成年心肌细胞中进行的研究均表明，TNFα具有浓度和时间依赖性的负性肌力作用，去除该细胞因子后这种作用可完全逆转。此外，用中和抗TNFα抗体处理可防止TNFα对分离的心肌细胞产生负性肌力作用。研究为上述发现提供了细胞基础，这些研究表明，用TNFα处理会导致收缩期收缩序列中细胞内钙峰值水平降低；此外，这些发现似乎并非继发于心肌细胞电生理特性的改变。进一步的研究表明，一氧化氮水平升高、从头合成蛋白质以及花生四烯酸途径的代谢产物不太可能是TNFα诱导的收缩功能异常的原因。因此，这些研究首次证明，TNFα的负性肌力作用是成年心肌细胞内钙稳态改变的直接结果。
