Testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum.
OBJECTIVE
To investigate the effect of testosterone on PDE5 expression and PDE5 inhibitor tadalafil in vivo responsiveness in a rat model.


METHODS
PDE5 expression was localized by immunohistochemistry in the rat corpus cavernosum (CC) and quantified by both real-time RT-PCR and Western blot analysis in several tissues. In the in vivo study, control, castrated and testosterone (T) supplemented castrated rats were treated with acute or chronic oral tadalafil. Erectile function was evaluated by monitoring intracavernous pressure (ICP) following electro-stimulation (ES) of the cavernous nerve and intracavernous injection of NO donor, sodium nitroprusside (SNP).


RESULTS
Rat CC expressed the highest PDE5 mRNA level. PDE5 was specifically immunolocalized in endothelial and smooth muscle cells. Surgical castration induced a significant reduction of PDE5 gene and protein expression (p<0.05), and ES response at all stimulation frequencies (p<0.001). T supplementation completely restored PDE5 expression, erectile response to ES and responsiveness to PDE5 inhibitor. Both acute and chronic tadalafil treatment were ineffective in ameliorating the ES response in castrated rats. Injection of increasing concentrations of SNP in castrated rats resulted in a statistically significant increase in ICP/MAP ratio as that observed in intact rats. In addition, tadalafil did not amplify the SNP effect in castrated rats at all the doses tested (0.06-6 nmoles).


CONCLUSIONS
Our findings demonstrate that testosterone positively regulates PDE5 expression and in vivo responsiveness to PDE5 inhibitor, tadalafil, in the rat CC.
Zhang
Xin-Hua
XH
Andrology Unit, Department of Clinical Physiopathology, University of Florence, V.le G. Pieraccini, 6, 50139 Florence, Italy.
Morelli
Annamaria
A
Luconi
Michaela
M
Vignozzi
Linda
L
Filippi
Sandra
S
Marini
Mirca
M
Vannelli
Gabriella Barbara
GB
Mancina
Rosa
R
Forti
Gianni
G
Maggi
Mario
M
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002243:Carbolines / Q000494:pharmacology*; D002369:Castration; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D009599:Nitroprusside; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology; D010413:Penis / Q000187:drug effects* / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D000068581:Tadalafil; D013739:Testosterone / Q000378:metabolism*
D002243:Carbolines; D010726:Phosphodiesterase Inhibitors; D009599:Nitroprusside; D013739:Testosterone; D000068581:Tadalafil; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat