The two phases of the clinical validation of preclinical translational mechanistic research on PDE5 inhibitors since Viagra’s advent. A personal perspective

The FDA approval of Viagra (sildenafil) for the on demand treatment of erectile dysfunction (ED) through relaxation of the corporal and cavernosal vascular smooth muscle that results in an increase in blood flow to the corporal tissues stemmed from 2 decades of research, mainly at academic centers. This culminated in the finding of the nitric oxide/cGMP pathway as the mediator of penile erection, followed by some years of basic studies and clinical validation at Pfizer. Further on, new translational laboratory and animal research from our group initiated a second phase when we proposed an alternative therapeutic schedule and mechanism of action for PDE5 inhibitors (PDE5i) in both corporal veno-occlusive dysfunction (CVOD) and Peyronie’s disease (PD), specifically, continuous long-term administration (CLTA) to achieve sustained levels of cGMP within the penis. Due to the extended half-life of the long-acting PDE5i, tadalafil, this new alternative encompasses preferentially daily administration, although shorter half-life PDE5i, like sildenafil and vardenafil work too, depending on the duration, dose, and frequency of their administration This novel use was initially supported by showing the antifibrotic/antioxidant effects of nitric oxide and cGMP, produced by the induction of iNOS, as a mechanism of defense against collagen deposition in the localized fibrotic plaque of PD in an avascular tissue, the tunica albuginea. Our studies on iNOS and the progressive diffuse fibrosis occurring in the smooth muscle in CVOD, led to proposing the CLTA of PDE5i for maintaining sustained cGMP levels both in PD and in CVOD in order to halt or regress the penile fibrosis. In CVOD, we showed that PDE5i protect the corporal smooth muscle and reduce myofibroblast activation and number, counteracting the underlying corporal tissue pathology that causes CVOD, and potentially ameliorating long-term CVOD or even curing it. This review is focused on this novel PDE5i anti-fibrotic therapeutic concept.