8-isoprostane F2α up-regulates the expression of type 5 phosphodiesterase in cavernosal vascular smooth muscle cells: inhibition with sildenafil, iloprost, nitric oxide and picotamide.

Objectives: To explore the possible role of of 8-isoprostane F(2α) (8-IPF(2α) ) in the aetiology of erectile dysfunction (ED), as the over-production of superoxide (O(2)(-)) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase results in the formation of 8-IPF(2α) in vascular tissue, which has similar properties to thromboxane A(2) (TXA(2) ). TXA(2) is vasoconstrictor and up-regulates the expression of NADPH oxidase and phosphodiesterase type 5 (PDE5).

Materials And Methods: Cavernosal vascular smooth muscle cells (CVSMCs) were incubated with 8-IPF(2α) or the TXA(2) analogue, U46619, ±sildenafil, iloprost (a stable prostacyclin [PGI(2) ] analogue) or the nitric oxide (NO) donor NONOate for 16 h. The formation of O(2)(-) was then measured, PDE5 expression assessed using Western blotting and PGI(2) and 8-IPF(2α) formation measured using enzyme-linked immunoassays.

Results: 8-IPF(2α) promoted the formation of O(2)(-) , an effect inhibited by apocynin (an NADPH oxidase inhibitor) and up-regulated the expression of PDE5. Under identical incubation conditions, 8-IPF(2α) induced an increase in the formation of 8-IPF(2α) but reduced the formation of PGI(2) . All, these effects were reversed by sildenafil, iloprost, NONOate and picotamide.

Conclusions: These data show that O(2) (-) derived from NADPH oxidase influences the relative balance of PGI(2) and 8-IPF(2α) in CVSMCs, which in turn alters the degree of PDE5 expression. This is a novel pathogenic mechanism underlying ED and a novel mechanism of action of sildenafil.