title: Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa.
abstract: By real-time RT-PCR and Western blot analysis, we found that phosphodiesterase type 5 (PDE5) mRNA and protein abundance was several fold higher in human male than in female reproductive tracts. The highest mRNA level (>1 x 10(7) molecules/microg total RNA) was detected in human corpora cavernosa (CC), where PDE5 protein was immunolocalized in both muscular and endothelial compartment. The possible role of androgens in regulating PDE5 expression was studied using a previously established rabbit model of hypogonadotropic hypogonadism. In this model, hypogonadism reduced, and testosterone (T) supplementation restored, CC PDE5 gene and protein expression. In addition, T supplementation completely rescued and even enhanced cyclic GMP conversion to metabolites, without changing IC(50) for sildenafil (IC(50) = 2.16 +/- 0.62 nm). In control CC strips, sildenafil dose-dependently increased relaxation induced by electrical field stimulation, with EC(50) = 3.42 +/- 1.7 nm. Hypogonadism reduced, and T increased, sildenafil effect on electrical field stimulation, again without changing their relative EC(50) values. CC sensitivity to the NO-donor NCX4040 was greater in hypogonadal rabbit strips than in control or T-treated counterparts. Moreover, sildenafil enhanced NCX4040 effect in eugonadal rabbit strips but not in hypogonadal ones. This suggests that androgens up-regulate PDE5 in rabbit penis. We also measured PDE5 gene expression and metabolic activity in human CC from male-to-female transsexual individuals, chronically treated with estrogens and cyproterone acetate. Comparing the observed values vs. eugonadal controls, PDE5 mRNA, protein, and functional activity were significantly reduced. In conclusion, we demonstrated, for the first time, that androgens positively regulate PDE5, thus providing a possible explanation about the highest abundance of this enzyme in male genital tract.
authors.affiliation: Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence 50139, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Morelli
authors.forename: Sandra
authors.initials: S
authors.lastname: Filippi
authors.forename: Rosa
authors.initials: R
authors.lastname: Mancina
authors.forename: Michaela
authors.initials: M
authors.lastname: Luconi
authors.forename: Linda
authors.initials: L
authors.lastname: Vignozzi
authors.forename: Mirca
authors.initials: M
authors.lastname: Marini
authors.forename: Claudio
authors.initials: C
authors.lastname: Orlando
authors.forename: Gabriella Barbara
authors.initials: GB
authors.lastname: Vannelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Aversa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Natali
authors.forename: Gianni
authors.initials: G
authors.lastname: Forti
authors.forename: Mauro
authors.initials: M
authors.lastname: Giorgi
authors.forename: Emmanuele A
authors.initials: EA
authors.lastname: Jannini
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Ledda
authors.forename: Mario
authors.initials: M
authors.lastname: Maggi
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D000918:Antibody Specificity; D015153:Blotting, Western; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004822:Epididymis / Q000201:enzymology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007006:Hypogonadism / Q000201:enzymology; D007150:Immunohistochemistry; D008297:Male; D010413:Penis / Q000201:enzymology*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011467:Prostate / Q000201:enzymology; D011687:Purines; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068677:Sildenafil Citrate; D013450:Sulfones; D013737:Testis / Q000201:enzymology; D013739:Testosterone / Q000008:administration & dosage; D014649:Vas Deferens / Q000201:enzymology
chemical_list: D000728:Androgens; D010879:Piperazines; D011687:Purines; D012333:RNA, Messenger; D013450:Sulfones; D013739:Testosterone; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human