Sildenafil inhibits the up‐regulation of phosphodiesterase type 5 elicited with nicotine and tumour necrosis factor‐α in cavernosal vascular smooth muscle cells: mediation by superoxide

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Abstract
OBJECTIVES: To determine whether there is an association between vascular phosphodiesterase type 5 (PDE‐5) and NADPH oxidase (NOX) in cavernosal vascular smooth muscle cells (CVSMCs), and to study the actions of the PDE‐5 inhibitor sildenafil; the pro‐erectile actions of nitric oxide (NO) are reduced by PDE‐5 which hydrolyses cGMP to inactive GMP, thus an up‐regulation of PDE‐5 and over‐production of O 2 ‐ derived from NOX might promote erectile dysfunction (ED). MATERIALS AND METHODS: To study the effects of nicotine and tumour necrosis factor‐α (TNF‐α) on superoxide (O 2 ‐ ) production and PDE‐5 expression, CVSMCs from rabbit penis were incubated with nicotine or TNF‐α, and superoxide dismutase (SOD), catalase, sildenafil citrate, or apocynin (NADPH inhibitor) for 16 h. The expression of PDE‐5 and of glyceraldehyde‐3‐phosphate dehydrogenase (internal standard) was assessed using Western blotting. O 2 ‐ was measured spectrophotometrically. RESULTS: After a 16‐h incubation, both nicotine (maximal at 10 µ m ) and TNF‐α (10 ng/mL) significantly increased O 2 ‐ formation in CVSMCs; this effect was blocked by co‐incubating with SOD, catalase, and sildenafil (1 µ m ). Apocynin also inhibited O 2 ‐ formation when added after 16‐h incubation with nicotine (10 µ m ) or TNF‐α. PDE‐5 expression was also significantly increased in CVSMCs incubated with nicotine and TNF‐α. This effect was negated by 16‐h co‐incubation with SOD, catalase, apocynin, and sildenafil. CONCLUSIONS: Nicotine and TNF‐α up‐regulate PDE‐5 expression in CVSMCs through an a priori up‐regulation of NOX and formation of O 2 ‐ . As PDE‐5 hydrolyses cGMP, this effect might ‘blunt’ the pro‐erectile actions of NO. Sildenafil inhibits O 2 ‐ formation, and ‘normalizes’ PDE‐5 expression. This represents a novel pathogenic mechanism underlying ED, and a novel mechanism of action of sildenafil.

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