Pharmacological Prevention and Reversion of Erectile Dysfunction After Radical Prostatectomy, by Modulation of Nitric Oxide/cGMP Pathways

摘要

This project aims to find a novel therapy to prevent or correct erectile dysfunction (ED) after radical prostatectomy (RP) for prostate cancer. This was done by determining in a rat model of bilateral cavernosal nerve resection (BCNR): a) the time course of the histological/biochemical alterations in the penile corpora cavernosa associated with corporal veno- occlusive dysfunction (CVOD), the type of ED that develops after RP; and b) whether continuous long-term treatment (CLTT) with PDE5 inhibitors (PDE5i) and/or nitric oxide (NO) generators oppose these changes by counteracting fibrosis, oxidative stress and the loss of smooth muscle cells (SMC) subsequent to nerve damage. We have shown that: a) apoptosis, SMC loss, fibrosis, and iNOS induction preceded CVOD; b) CLTT oral PDE5i (tadalafil and sildenafil; as previously vardenafil) at high doses, prevented these processes; c) oral sildenafil at a lower dose, + or - the NO generator molsidomine, also prevented CVOD, although the underlying histopathology was less ameliorated than with the higher dose, and the combination treatment did not improve efficacy; d) corporal implantation of muscle derived stem cells (MDSC) prevented CVOD, but the efficacy was not enhanced by sildenafil. We conclude that CVOD results indirectly from neuropraxia post-RP, and that an early CLTT with PDE5i, as opposed to on demand regimens, prevent CVOD through preservation of the corporal SM. This supports and drives the emerging clinical interest in preventing or 'curing' post-RP ED ('penile rehabilitation') with CLTT PDE5i.