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8‐isoprostane F 2α up‐regulates the expression of type 5 phosphodiesterase in cavernosal vascular smooth muscle cells: inhibition with sildenafil, iloprost, nitric oxide and picotamide
Author(s) -
Hotston Matthew,
Jeremy Jamie Y.,
Persad Raj,
Bloor Jonathon,
Shukla Nilima
Publication year - 2010
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/j.1464-410x.2010.09270.x
Subject(s) - iloprost , nadph oxidase , sildenafil , apocynin , prostacyclin , cgmp specific phosphodiesterase type 5 , nitric oxide , vascular smooth muscle , chemistry , endocrinology , medicine , nicotinamide adenine dinucleotide phosphate , pharmacology , superoxide , xanthine oxidase , vasodilation , oxidase test , reactive oxygen species , biochemistry , enzyme , smooth muscle
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.