Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

Abstract

It was recently reported in the rat that vardenafil given in a continuous long-term manner was successful in preventing smooth muscle fibrosis in the penile corpora cavernosa and corporal venoocclusive dysfunction (CVOD) that occur following bilateral cavernosal nerve resection (BCNR), a model for human erectile dysfunction after radical prostatectomy. To expand on this finding and to determine whether this effect was common to other PDE5 inhibitors, and occurred in part by stimulation of the spontaneous induction of inducible nitric oxide synthase (iNOS, also known as NOS2), male Fischer 344 rats (N ¼ 10/group) were subjected to either BCNR or unilateral cavernosal nerve resection (UCNR) and treated with sildenafil (20 mg kg À1 day À1 ) in the drinking water daily for 45 days. Additional BCNR groups received L-NIL (6.7 mg kg À1 day À1 ) as inhibitor of iNOS activity, with or without concurrent sildenafil administration. It was determined that sildenafil, like vardenafil, (1) prevented the 30% decrease in the smooth muscle cell/collagen ratio, and the 3-4-fold increase in apoptosis and reduction in cell proliferation, and partially counteracted the increase in collagen, seen with both UCNR and BCNR; and (2) normalized the CVOD, measured by dynamic infusion cavernosometry, induced by both BCNR and UCNR. The long-term inhibition of iNOS activity exacerbated corporal fibrosis and CVOD in the BCNR rats, but sildenafil functional effects were not affected by L-NIL. These data suggest that the salutary effects of continuous long-term PDE5 inhibitors on erectile function post-cavernosal nerve resection involve their ability to prevent the alterations in corporal histology induced by cavernosal nerve damage, in a process apparently independent from endogenous iNOS induction.

Rationale for phosphodiesterase 5 inhibitor use post-radical prostatectomy: experimental and clinical review

“…It is possible that the ablation by neuropraxia of certain key growth factors produced by the cavernosal nerves may be responsible for eliciting the smooth muscle fibrosis and atrophy observed in corporal tissue. However, the production of cytokines and noxious agents by the damaged nerve axons may also be the causal factor of the increased early smooth muscle apoptosis, 15,16 which in turn may trigger collagen deposition to replace the lost cells. Similarly to the situation with skeletal muscle atrophy after denervation, 17,18 the molecular and cellular etiology of the tissue atrophy subsequent to cavernosal nerve damage remains to be elucidated.…”

“…18 The nitric oxide from the nerve endings of the cavernosal nerve is produced by the neuronal isoform of the nitric oxide synthase (nNOS) enzyme 20 whereas the nitric oxide that emanates from the cavernosal smooth muscle cells once the neural injury occurs is derived, at least in part, from the induction of the inducible isoform of nitric oxide synthase (iNOS). 15,16 There is a marked distinction between these two isoforms. While nitric oxide in the corpora during sexual stimulation is believed to be produced immediately upon sexual stimulation, albeit in small amounts, primarily by the activation of nNOS, the production of nitric oxide from iNOS in the corpora is very different from that of nNOS in that it is unrelated to sexual stimulation and occurs by transcriptional induction that results in the production of sustained amounts of nitric oxide, although somewhat delayed in its onset.…”

“…30 Finally, specifically in cavernosal nerve damage, a similar treatment with L-NIL exacerbates CVOD and the underlying fibrosis of the corpora. 16 It is assumed that prolonged endogenous induction of iNOS to moderate levels produces sufficient nitric oxide as to reduce collagen synthesis, quench reactive oxygen species (ROS), inhibit TGFb1 expression and myofibroblast differentiation, and activate metalloproteinases that break down collagen. 17 If nitric oxide reaches excessive levels it may turn to be deleterious by causing cell death and oxidative stress, and this will depend on the tissue environment.…”

“…Although cGMP seems to stabilize iNOS mRNA or activate its transcription, 32 and thus may upregulate nitric oxide production, recent evidence suggest that this is not the case for the long-term effects of tadalafil on corporal fibrosis after cavernosal nerve damage in the rat. 16 Although there have been reports in the literature regarding the clinical effects of administration of these PDE5 inhibitors postprostatectomy, [33][34][35][36] the rationale behind the use of these drugs on a prolonged and continuous basis in the post-prostatectomy patient has never been fully and scientifically delineated. The recent publication by Ferrini et al 15 examined the effects of the administration of the PDE5 inhibitor, vardenafil, and demonstrated that the prolonged and continuous administration of the compound was effective in preventing both the fibrosis and loss of smooth muscle seen following bilateral cavernosal nerve resection (Figure 3).…”

Should penile rehabilitation become the norm following radical prostatectomy?

“…The protective nature of these agents appears to be a class effect, with evidence showing robust measurable improvements in smooth muscle and erectile function with both short-and long-acting drugs. In another study, Kovanecz and colleagues 18 showed that long-term continuous sildenafil resulted in improvement of venous leak following cavernous nerve resection. Using a diabetic rat model in our laboratory, De Young and colleagues 19 demonstrated improved endothelial and smooth muscle protein expression and penile histological morphology with chronic vardenafil use, compared with controls.…”