Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Topically delivered nitric oxide acts synergistically with an orally administered PDE5 inhibitor in eliciting an erectile response in a rat model of radical prostatectomy


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: A typical experimental result and trace of the ICP/BP response following topical application of the control (blank-MP) or NO-MP.
Fig. 2: A typical experimental ICP/BP trace following orally administered 0.05 mg sildenafil/kg, with or without subsequent topical application of 250 mg NO-MP after 50 min.
Fig. 3: The major synergistic effects of orally administered sildenafil followed by topical application of NO-MP.
Fig. 4: The rationale for the studies presented here investigating synergy between treatments that elevate local NO penile tissue levels and inhibit PDE5 in eliciting an erectile response.

Similar content being viewed by others


  1. Rawla P. Epidemiology of prostate cancer. World J Oncol. 2019;10:63–89.

    Article  CAS  Google Scholar 

  2. McCullough AR. Sexual dysfunction after radical prostatectomy. Rev Urol. 2005;7:S3–10.

    PubMed  PubMed Central  Google Scholar 

  3. Shabsigh R, Anastasiadis AG. Erectile dysfunction. Annu Rev Med. 2003;54:153–68.

    Article  CAS  Google Scholar 

  4. 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.

    Article  Google Scholar 

  5. 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.

    Article  Google Scholar 

  6. Burnett AL, Musicki B. The nitric oxide signaling pathway in the penis. Curr Pharm Des. 2005;11:3987–94.

    Article  CAS  Google Scholar 

  7. Sezen SF, Lagoda G, Burnett AL. Neuronal nitric oxide signaling regulates erection recovery after cavernous nerve injury. J Urol. 2012;187:757–63.

    Article  CAS  Google Scholar 

  8. Ghalayini IF. Nitric oxide-cyclic GMP pathway with some emphasis on cavernosal contractility. Int J Impot Res. 2004;16:459–69.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. Huang SA, Lie JD. Phosphodiesterase-5 (PDE5) inhibitors in the management of erectile dysfunction. P T. 2013;38:407–19.

    PubMed  PubMed Central  Google Scholar 

  11. Andersson KE. PDE5 inhibitors—pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharm. 2018;175:2554–65.

    Article  CAS  Google Scholar 

  12. Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for erectile dysfunction in the US. Am J Med. 2007;120:151–7.

    Article  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. 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.

    Article  Google Scholar 

  17. 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.

    Article  Google Scholar 

  18. 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.

    Article  Google Scholar 

  19. 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.

    Article  CAS  Google Scholar 

  20. 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.

    Article  Google Scholar 

  21. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 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.

    Article  CAS  Google Scholar 

  23. 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.

    Article  CAS  Google Scholar 

  24. 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.

    Article  CAS  Google Scholar 

  25. 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.

    Article  CAS  Google Scholar 

  26. 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.

    Article  Google Scholar 

Download references


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)].

Author information

Authors and Affiliations


Corresponding author

Correspondence to Kelvin P. Davies.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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 34, 573–580 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links