Protective Effect of Sildenafil against Estradiol-induced ROS production

Several reports suggest that xanthine dehydrogenase (XDH) and its oxidase form (XO) play an important role in various forms of ischemic and vascular injuries. Recently we have demonstrated that 17β-estradiol (E2) induces a significant decrease of the expression and activity of XDH and its conversion to XO in human mammary epithelial cells. E2 is known to induce upregulation of eNOS gene expression in aortic endothelial cells. In light of the ability of XO-derived O2•¯ to combine with •NO to yield ONOO¯, and considering that ONOO¯ converts XDH to XO, it is important to protect tissues against the XO increased activity and ROS increased production, that would in turn react with •NO to augment ONOO¯ production, thus creating a vicious cycle of oxidative stress. Our previous studies have indicated that sildenafil has a protective effect on human mammary epithelial cells as a consequence of the inhibition of XO and of the resulting decrease of free oxygen radical that may influence the expression of NADPH oxidase and PDE-5. We report that the contemporary inhibitory effect played by sildenafil on XO and PDE-5 is due to the structural modification induced by O2•¯, which involves the release of a piperazine group able to inhibit XO.