(540) Synergy in Improving the Erectile Responses in a Rat Model of Radical Prostatectomy Between PDE5 Inhibitors and a Topically Applied Nitric Oxide Delivery System

Introduction Our previous work using a rat model of radical prostatectomy (RP) involving bilateral transection of the cavernous nerve (CN) demonstrated that combining orally administered sildenafil with a topically applied nitric oxide–releasing microparticle formulation (NO-MP) significantly improved erectile responses compared to NO-MP alone. Several other phosphodiesterase type 5 inhibitors (PDE5i) are approved for clinical use in erectile dysfunction (ED); although they share the same primary mechanism, PDE5 inhibition, they differ in pharmacokinetics and other properties that could influence their performance in combination therapies. Objective The present study aimed to evaluate whether other FDA-approved PDE5i also act synergistically with topical NO-MP to enhance erectile responses in this RP model. Methods Male Sprague–Dawley rats underwent bilateral CN transection to establish a post-RP model. One week after surgery, animals received oral administration of sildenafil (0.05 mg/kg), tadalafil (0.005 mg/kg), vardenafil (0.01 mg/kg), or avanafil (0.1 mg/kg). Under anesthesia, intracavernosal pressure (ICP) and systemic blood pressure (BP) were continuously recorded via cannulation. Once stable baselines were achieved, 100 mg of NO-MP or control empty microparticles were applied topically to the penile shaft, and erectile responses were monitored. Results Combining oral sildenafil with topical NO-MP led to a significantly faster onset of the first erectile response (11 min vs. 22 min; p = 0.041) and a higher frequency of spontaneous erections (4.6 vs. 2 erections/hour; p = 0.043) compared to NO-MP alone. Maximal ICP/BP ratios did not differ significantly between combination and NO-MP-only treatments. Similar synergistic effects were observed when tadalafil, vardenafil, or avanafil were used in place of sildenafil, with all PDE5i accelerating erectile onset and increasing spontaneous erection frequency to a comparable extent, without altering maximal ICP/BP values relative to NO-MP alone. Conclusions These findings support a novel therapeutic strategy for post-prostatectomy ED, combining topical nitric oxide delivery with oral PDE5 inhibition. The comparable efficacy between different PDE5i highlights the potential flexibility of this approach in clinical applications. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Zylotherapeutics, Inc