Different Effects of Angiotensin Converting Enzyme Inhibitors on Endothelin-1 and Nitric Oxide Balance in Human Vascular Endothelial Cells: Evidence of an Oxidant-Sensitive Pathway

摘要

Angiotensin converting enzyme inhibitors (ACE-I) are known to affect the endothelial function decreasing the formation of the potent vasoconstrictor angiotensin II and increasing the bioavailability of the vasodilators bradykinin and nitric oxide. In order to test the potential differences among the class of ACE-I, we have evaluated their effects on endothelin-1 and nitric oxide availability, and on reactive oxygen species generation in human vascular endothelial cells (HUVECs) obtained from umbilical cord veins. HUVECs were cultured in the presence of either sulfhydryl-containing ACE-I (zofenoprilat or captopril) or nonsulfhydryl-containing ACE-I (enalaprilat or lisinopril). After 24 hours, all ACE-I reduced endothelin-1 secretion and increased nitric oxide production. However, zofenoprilat (−42% after 8 hours of incubation) was more effective (P<.05) than enalaprilat (−25%), lisinopril (−21%), and captopril (−30%) in reducing endothelin-1 secretion. Similarly, zofenoprilat (+110% after 8 hours of incubation) was more effective (P<.05) than enalaprilat (+64%), lisinopril (+63%), and captopril (+65%) in increasing nitrite plus nitrate production. The effect of ACE-I on the nitric oxide availability and on endothelin-1 secretion is mediated by the activation of bradykininB2receptor being reverted, at least in part, by a specific antagonist. Zofenoprilat and, to a lesser extent, captopril also blunted tumour necrosis factor (TNF)α-stimulated production of reactive oxygen species and decreased TNFα-stimulated glutathione consumption in endothelial cells. In conclusion, structural differences among the class of ACE-I play a role in their interaction with mediators that influence the homeostasis of the endothelium. The marked antioxidant effects exerted by zofenoprilat due to its sulphydryl group and lipophilia seem to be responsible for its greater endothelium protective activity.