Michiels C, Arnould T, Janssens D, Alexandre I, Houbion A, Remacle J
Laboratoire de Biochimie Cellulaire, Facultés Universitaires Notre Dame de la Paix, Belgium.
J Pharmacol Exp Ther. 1993 Nov;267(2):904-11.
The present study was designed to elucidate the possible beneficial effects of naftidrofuryl on ischemia-induced endothelium damage. For this purpose, an in vitro model was developed wherein human endothelial cells isolated from umbilical vein were submitted to hypoxia. Long-term hypoxia incubation (6 h) induced cell mortality, and naftidrofuryl strongly protected endothelial cells against this mortality in a dose-dependent manner and at concentrations as low as 10(-9) M. 66% protection was still observed after 16 h of hypoxia. Naftidrofuryl had to be present during the hypoxia incubation to exert its action; preincubation up to 24 h in the presence of naftidrofuryl could not protect endothelial cells incubated under hypoxia without naftidrofuryl. Short-term hypoxia, which does not induce mortality, strongly activates the endothelial cells with an increase in the cytosolic calcium concentration, in the phospholipase A2 activity, and in the synthesis of prostaglandin and of platelet-activating factor. It also enhances the adherence of polymorphonuclear neutrophils. Naftidrofuryl was able to markedly inhibit this whole cascade of events in a dose-dependent manner. We also demonstrated that naftidrofuryl could block the decrease in ATP concentration that results from the hypoxic conditions. These results indicate that by preserving the energetic level of the cells, naftidrofuryl prevents the activation of endothelial cells and the cell mortality induced by hypoxia. By maintaining an intact endothelium in vivo during ischemia, naftidrofuryl could prevent the further damage induced by leukocyte recruitment and activation.
本研究旨在阐明萘呋胺酯对缺血诱导的内皮损伤可能的有益作用。为此，建立了一种体外模型，其中将从脐静脉分离的人内皮细胞置于缺氧环境中。长期缺氧孵育（6小时）可诱导细胞死亡，而萘呋胺酯能以剂量依赖方式并在低至10^(-9) M的浓度下强力保护内皮细胞免受这种死亡。在缺氧16小时后仍观察到66%的保护作用。萘呋胺酯必须在缺氧孵育期间存在才能发挥其作用；在萘呋胺酯存在下预孵育长达24小时并不能保护在无萘呋胺酯的缺氧条件下孵育的内皮细胞。不诱导细胞死亡的短期缺氧会通过增加胞质钙浓度、磷脂酶A2活性以及前列腺素和血小板活化因子的合成来强力激活内皮细胞。它还会增强多形核中性粒细胞的黏附。萘呋胺酯能够以剂量依赖方式显著抑制这一整个事件级联反应。我们还证明，萘呋胺酯可以阻止由缺氧条件导致的ATP浓度降低。这些结果表明，通过维持细胞的能量水平，萘呋胺酯可防止内皮细胞的激活以及缺氧诱导的细胞死亡。通过在体内缺血期间维持完整的内皮，萘呋胺酯可以防止由白细胞募集和激活引起的进一步损伤。
