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

Abstract

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.

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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.

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Acknowledgements

The authors would like to thank Scott Pancoast and Lisa Lallos for suggestions to improve the manuscript.

Funding

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)].

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Correspondence to Kelvin P. Davies.

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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

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