Patients undergoing radical prostatectomy (RP) have a high incidence of postoperative erectile dysfunction (ED) refractory to treatment by oral phosphodiesterase-5 inhibitors (PDE5i). In the present studies, we investigated if a topically applied, nitric oxide microparticle delivery system (NO-MP) might act synergistically with an oral PDE5i (sildenafil) to improve erectile function outcomes in a rat model of RP. Thirty-five Sprague-Dawley rats underwent bilateral transection of the cavernous nerve (CN) for 1 week. After 1 week, animals were orally administered 0, 0.05, or 0.005 mg sildenafil/kg and the erectile response following topical application to the penile shaft of 250 or 100 mg NO-MP, or blank-MP, was monitored over a 2-h timeframe by recording the intracorporal pressure normalized to systemic blood pressure (ICP/BP, N = 5 animals/treatment group). Oral treatment with sildenafil by itself resulted in no observable erectile response. However, a combination of orally administered 0.05 sildenafil/kg with topical application of 250 mg NO-MP, compared to 250 mg NO-MP by itself, resulted in significantly more spontaneous erections (4.6 compared to 2 erections per hour, t-test; p value = 0.043), with a significantly faster onset for the first erectile response (11 compared to 22 min; t-test, p value = 0.041). Our results demonstrate a synergistic effect between orally administered PDE5i and topically applied NO-MP in eliciting an erectile response. Furthermore, they suggest a potential novel therapeutic approach to treat men with ED resulting from RP, through combination therapy of a topically applied NO-MP and an orally administered PDE5i.
Subscribe to Journal
Get full journal access for 1 year
only $32.38 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Rawla P. Epidemiology of prostate cancer. World J Oncol. 2019;10:63–89.
McCullough AR. Sexual dysfunction after radical prostatectomy. Rev Urol. 2005;7:S3–10.
Shabsigh R, Anastasiadis AG. Erectile dysfunction. Annu Rev Med. 2003;54:153–68.
Mallis D, Moisidis K, Kirana PS, Papaharitou S, Simos G, Hatzichristou D. Moderate and severe erectile dysfunction equally affects life satisfaction. J Sex Med. 2006;3:442–9.
Coughlin GD, Yaxley JW, Chambers SK, Occhipinti S, Samaratunga H, Zajdlewicz L, et al. Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: 24-month outcomes from a randomised controlled study. Lancet Oncol. 2018;19:1051–60.
Burnett AL, Musicki B. The nitric oxide signaling pathway in the penis. Curr Pharm Des. 2005;11:3987–94.
Sezen SF, Lagoda G, Burnett AL. Neuronal nitric oxide signaling regulates erection recovery after cavernous nerve injury. J Urol. 2012;187:757–63.
Ghalayini IF. Nitric oxide-cyclic GMP pathway with some emphasis on cavernosal contractility. Int J Impot Res. 2004;16:459–69.
Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, Rajfer J. Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun. 1990;170:843–50.
Huang SA, Lie JD. Phosphodiesterase-5 (PDE5) inhibitors in the management of erectile dysfunction. P T. 2013;38:407–19.
Andersson KE. PDE5 inhibitors—pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharm. 2018;175:2554–65.
Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for erectile dysfunction in the US. Am J Med. 2007;120:151–7.
Padma-Nathan H, McCullough AR, Levine LA, Lipshultz LI, Siegel R, Montorsi F, et al. Randomized, double-blind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy. Int J Impot Res. 2008;20:479–86.
Tar M, Cabrales P, Navati M, Adler B, Nacharaju P, Friedman AJ, et al. Topically applied NO-releasing nanoparticles can increase intracorporal pressure and elicit spontaneous erections in a rat model of radical prostatectomy. J Sex Med. 2014;11:2903–14.
Han G, Tar M, Kuppam DS, Friedman A, Melman A, Friedman J, et al. Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction. J Sex Med. 2010;7:224–33.
Abuzeid WM, Girish VM, Fastenberg JH, Draganski AR, Lee AY, Nosanchuk JD, et al. Nitric oxide-releasing microparticles as a potent antimicrobial therapeutic against chronic rhinosinusitis bacterial isolates. Int Forum Allergy Rhinol. 2018;8:1190–8.
Yang C, Mavelli GV, Nacharaju P, Li K, Cleare LG, Nosanchuk JD, et al. Novel nitric oxide-generating platform using manuka honey as an anti-biofilm strategy in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2020;10:223–32.
Draganski A, Tar MT, Villegas G, Friedman JM, Davies KP. Topically applied curcumin-loaded nanoparticles treat erectile dysfunction in a rat model of type-2 diabetes. J Sex Med. 2018;15:645–53.
Gur S, Sikka SC, Knight GE, Burnstock G, Hellstrom WJ. Purinergic contraction of the rat vas deferens in L-NAME-induced hypertension: effect of sildenafil. Asian J Androl. 2010;12:415–21.
Redfors B, Shao Y, Omerovic E. Influence of anesthetic agent, depth of anesthesia and body temperature on cardiovascular functional parameters in the rat. Lab Anim. 2014;48:6–14.
Azar T, Sharp J, Lawson D. Heart rates of male and female Sprague-Dawley and spontaneously hypertensive rats housed singly or in groups. J Am Assoc Lab Anim Sci. 2011;50:175–84.
Karakus S, Musicki B, Navati MS, Friedman JM, Davies KP, Burnett AL. NO-releasing nanoparticles ameliorate detrusor overactivity in transgenic sickle cell mice via restored NO/ROCK signaling. J Pharm Exp Ther. 2020;373:214–9.
Friedman AJ, Han G, Navati MS, Chacko M, Gunther L, Alfieri A, et al. Sustained release nitric oxide releasing nanoparticles: characterization of a novel delivery platform based on nitrite containing hydrogel/glass composites. Nitric Oxide. 2008;19:12–20.
Ushiyama M, Kuramochi T, Katayama S. Treatment with hypotensive agents affects the impaired relaxation of the penile corpus cavernosum in hypertensive rats. Hypertens Res. 2006;29:523–32.
Zucchi A, Costantini E, Scroppo FI, Silvani M, Kopa Z, Illiano E, et al. The first-generation phosphodiesterase 5 inhibitors and their pharmacokinetic issue. Andrology. 2019;7:804–17.
Mulhall JP, Brock G, Oelke M, Fode M, Probst KA, Henneges C, et al. Effects of tadalafil once-daily or on-demand vs placebo on return to baseline erectile function after bilateral nerve-sparing radical prostatectomy—results from a Randomized Controlled Trial (REACTT). J Sex Med. 2016;13:679–83.
The authors would like to thank Scott Pancoast and Lisa Lallos for suggestions to improve the manuscript.
This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [grants R41 DK121587 (awarded to K.P.D. and A.D.) and grants R01 DK109314 and P20 DK123969 (awarded to K.P.D)].
Conflict of interest
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Tar, M.T., Friedman, J.M., Draganski, A. et al. Topically delivered nitric oxide acts synergistically with an orally administered PDE5 inhibitor in eliciting an erectile response in a rat model of radical prostatectomy. Int J Impot Res (2021). https://doi.org/10.1038/s41443-021-00451-6