EFFECTS OF NAFTIDROFURYL ON HYPOXIA-INDUCED ACTIVATION AND MORTALITY OF HUMAN ENDOTHELIAL-CELLS

The present study was designed to elucidate the possible beneficial ef fects of naftidrofuryl on ischemia-induced endothelium damage. For thi s purpose, an in vitro model was developed wherein human endothelial c ells isolated from umbilical vein were submitted to hypoxia. Long-term hypoxia incubation (6 h) induced cell mortality, and naftidrofuryl st rongly protected endothelial cells against this mortality in a dose-de pendent manner and at concentrations as low as 10(-9) M. 66% protectio n was still observed after 16 h of hypoxia. Naftidrofuryl had to be pr esent during the hypoxia incubation to exert its action; preincubation up to 24 h in the presence of naftidrofuryl could not protect endothe lial cells incubated under hypoxia without naftidrofuryl. Short-term h ypoxia, which does not induce mortality, strongly activates the endoth elial cells with an increase in the cytosolic calcium concentration, i n 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 inhi bit this whole cascade of events in a dose-dependent manner. We also d emonstrated that naftidrofuryl could block the decrease in ATP concent ration that results from the hypoxic conditions. These results indicat e that by preserving the energetic level of the cells, naftidrofuryl p revents the activation of endothelial cells and the cell mortality ind uced by hypoxia. By maintaining an intact endothelium in vivo during i schemia, naftidrofuryl could prevent the further damage induced by leu kocyte recruitment and activation.