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  • Title: Sildenafil inhibits the formation of superoxide and the expression of gp47 NAD[P]H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells.
    Author: Koupparis AJ, Jeremy JY, Muzaffar S, Persad R, Shukla N.
    Journal: BJU Int; 2005 Aug; 96(3):423-7. PubMed ID: 16042742.
    Abstract:
    OBJECTIVE: To assess the effect of sildenafil on superoxide formation and p47(phox) (the active subunit of NADPH oxidase) expression in cultured corpus cavernosal smooth muscle cells (CVSMCs). MATERIALS AND METHODS: CVSMCs derived from rabbit penis were incubated with U46619 (thromboxane A2 analogue) with or without sildenafil for 1 or 16 h at 37 degrees C. Superoxide dismutase-inhibitable superoxide formation was assessed using the reduction of ferricytochrome c measured spectrophotometrically, and gp47(phox) assessed using Western blot analysis. The role of NAD[P]H oxidase and cGMP was further studied by using specific inhibitors of each. RESULTS: Superoxide 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. CONCLUSIONS: Sildenafil 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 NO-cGMP 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.
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