Sildenafil inhibits the formation of superoxide and the expression of gp47^phox NAD[P]H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells

Abstract

assessed using Western blot analysis. The role of NAD[P]H oxidase and cGMP was further studied by using specific inhibitors of each. RESULTSSuperoxide formation was significantly greater in cells incubated with U46619 after 1 and 16 h incubation than in controls, an effect blocked by NADP(H) oxidase inhibitors. These effects of U46619 were inhibited by sildenafil (1 and 10 nmol/L), which in turn were negated by the guanylyl cyclase inhibitor, ODQ; 10 nmol/L sildenafil inhibited p47phox expression induced by U46619. CONCLUSIONSSildenafil is a potent inhibitor of superoxide formation in CVSMCs. This effect is mediated through the inhibition of PDE-5 which in turn augments the inhibitory action of the NOcGMP axis on NAD[P]H oxidase expression and activity. This mechanism constitutes a new pharmacological action of sildenafil, consolidates the potential role of superoxide in ED, and indicates that thromboxane A 2 may be an important mediator of intrapenile oxidative stress.

Beneficial Effect of the Nitric Oxide Donor Compound 3-(1,3-Dioxoisoindolin-2-yl)Benzyl Nitrate on Dysregulated Phosphodiesterase 5, NADPH Oxidase, and Nitrosative Stress in the Sickle Cell Mouse Penis: Implication for Priapism Treatment

“…In mouse erectile tissue, the soluble guanylyl cyclase stimulator BAY 41-2272 reduces superoxide anion formation through inhibition of NADPH oxidase activity and reduction of NADPH oxidase subunit gp91 phox expression, an effect mediated by a cGMP-dependent mechanism (Teixeira et al, 2007;Nunes et al, 2015). Likewise, the PDE5 inhibitor sildenafil inhibits p47 phox NADPH oxidase subunit expression and superoxide anion formation in cavernosal smooth muscle cells (Koupparis et al, 2005). In contrast, the NO donor DETANONOate inhibits NADPH oxidase-dependent superoxide anion production by a cGMP-independent mechanism in human endothelial cells, without changing the protein expression of gp91 phox (Selemidis et al, 2007).…”

Sildenafil Increases Endothelial Progenitor Cell Function and Improves Ischemia-Induced Neovascularization in Hypercholesterolemic Apolipoprotein E–Deficient Mice

“…21,29 Here we found that sildenafil therapy significantly reduces oxidative stress in ischemic tissues of ApoE Ϫ/Ϫ mice. Therefore, it is conceivable that the antioxidant properties of sildenafil 30,31 could contribute to restore angiogenesis in hypercholesterolemic conditions. Recent studies suggest that postnatal neovascularization relies not exclusively on the sprouting of mature endothelial cells in preexisting vessels (angiogenesis) but also involves A and B, The number of bone marrow-derived EPCs was assessed using 1,1Ј-dioetadeeyl-3,3,3Ј,3Ј-tetramethylindocarboeyanine perchlorate acetylated low-density lipoprotein (DiIacLDL), fluorescein isothiocyanate (FITC)-lectin, and 4Ј,6-diamidino-2-phenylindole (DAPI) stains (A).…”

Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species

“…These observations suggest a role for intracellular ROS in controlling protein expression and represent a potential mechanism for regulating TP expression. This currently untested hypothesis is especially interesting given that NADPH oxidase, a major source of vascular ROS (15), is an effector for TP (16,17), while antagonism of the TP offset NADPH oxidase expression and renal oxidant stress in diabetic hyperlipidemic mice (18). Indeed, similar to other vasoactive mediators (15), NADPH oxidase-derived cellular ROS may be integral to TxA 2 ʼs cardiovascular actions (16,17).…”