Objectives: Radical prostatectomy is an effective therapy for clinically localized prostate cancer. A significant number of men develops post-prostatectomy erectile dysfunction (PPED), due to surgery-related nervous damage. PPED is relatively refractory to PDE5i therapy. In a rat model of bilateral cavernous neurotomy we evaluated whether chronic tadalafil treatment (CTT) could ameliorate anatomical and functional damage to corpora cavernosa (CC).
Methods: Tadalafil (2 mg/Kg/daily) was added in drinking water in a subgroup of neurectomized rats (CTT). After 3 months, penile tissues were removed and hypoxia and muscular/fibrous ratio revealed using semi-quantitative immunohystochemistry with hypoxyprobeTM and Masson staining, respectively. Endothelin receptor B (ETB), PDE5, nNOS and eNOS expression and functional activity were also studied.
Results: Penile denervation induced massive hypoxia and a decreased muscular/fibrous ratio, which were completely restored by CTT. Functional studies indicated that hypoxic tissues were hypersensitive to the relaxant effect of the ETB agonist IRL-1620, due to the previously described hypoxia-induced over-expression of ETB (Granchi et al. Mol Hum Reprod 8:1053, 2002; Filippi et al. Mol Hum Reprod 9:765, 2003). CTT restored normal sensitivity to IRL-1620, and normalized ETB gene (real-time RT-PCR) and protein (Western) expression. Hypoxic CC were more sensitive to the relaxant effect of the NO-donor sodium nitroprusside (SNP), while they were unresponsive to acute tadalafil (100 nM) amplification of SNP effect. According to these findings, PDE5 mRNA and protein expression were reduced in neurectomized penile tissue. By restoring PDE5, CTT decreased SNP-induced relaxation and rescued sensitivity to acute tadalafil (100 nM). However, in hypoxic CC, CTT was unable to normalize other observed events, as acetylcholine hypo-responsiveness or decreased nNOS and eNOS, at both mRNA or protein levels.
Conclusion: CTT restores several (but not all) of the neurotomy-induced penile alterations, including PDE5 expression and in vitro responsiveness to PDE5 inhibitors, such as tadalafil