Skip to main content

Thank you for visiting nature.com. 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.

The effect of an antifibrotic agent, pirfenidone, on penile erectile function in an experimental rat model of ischemic priapism

Abstract

To date, no effective medical approach for the treatment of erectile dysfunction (ED) secondary to ischemic priapism (IP) has been described. The aim of this study was to evaluate the anti-inflammatory, antifibrotic, and antioxidant effects of pirfenidone (PFD) on cavernosal tissue in a rat model of IP. Forty-eight male albino rats aged 8–10 months, with mean weights of 410 ± 18.6 g were randomized into four groups (n = 12 in each group): no IP (group 1); IP for 1 h, followed by intracavernosal pressure (ICP) measurements using electrical cavernous nerve stimulation (CNS) (group 2); IP for 1 h, followed by ICP measurements using electrical CNS 6 weeks later (group 3); and IP for 1 h, oral PFD (30 mg/kg once daily) treatment by oral gavage, followed by ICP measurements using electrical CNS 6 weeks later (group 4). Malondialdehyde (MDA) and reduced glutathione levels were measured spectrophotometrically. In a histological evaluation, cavernosal collagen/smooth muscle ratios were calculated. The intracavernosal pressure values of group 1 were higher than those of groups 2 and 3 (p < 0.05) but similar to those of group 4 (p > 0.05). The mean MDA level was significantly higher in group 3, as compared with that in group 4 (p = 0.004). The mean collagen/smooth muscle ratio in groups 1–4 was 24%, 42%, 65%, and 48%, respectively. Physiological, biochemical, and histopathological evaluations of the PFD effect on cavernosal tissue in a rat model of IP were the strengths and the lack of molecular and immunohistochemical analysis were the limitations of this study. In this study, we examined the effects of PFD on cavernosal tissue in a rat model of IP. We found that PFD reduced cavernosal fibrotic activity and improved erectile function. We conclude that PFD may represent a new treatment option in IP treatment.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3

References

  1. Salonia A, Eardley I, Giuliano F, Hatzichristou D, Moncada I, Vardi Y, et al. European Association of Urology guidelines on priapism. Eur Urol. 2014;65:480–9.

    Article  Google Scholar 

  2. Cherian J, Rao AR, Thwaini A, Kapasi F, Shergill IS, Samman R. Medical and surgical management of priapism. Post Med J. 2006;82:89–94.

    CAS  Article  Google Scholar 

  3. Broderick GA, Kadioglu A, Bivalacqua TJ, Ghanem H, Nehra A, Shamloul R. Priapism: pathogenesis, epidemiology, and management. J Sex Med. 2010;7:476–500.

    Article  Google Scholar 

  4. Zacharakis E, Garaffa G, Raheem AA, Christopher AN, Muneer A, Ralph DJ. Penile prosthesis insertion in patients with refractory ischaemic priapism: early vs delayed implantation. BJU Int. 2014;114:576–81.

    Article  Google Scholar 

  5. Yuan J, Desouza R, Westney OL, Wang R. Insights of priapism mechanism and rationale treatment for recurrent priapism. Asian J Androl. 2008;10:88–101.

    CAS  Article  Google Scholar 

  6. Pautler SE, Brock GB. Priapism. From priapus to the present time. Urol Clin North Am. 2001;28:391–403.

    CAS  Article  Google Scholar 

  7. Kinashi H, Ito Y, Sun T, Katsuno T, Takei Y. Roles of the TGF-β VEGF-C pathway in fibrosis-related lymphangiogenesis. Int J Mol Sci. 2018;19:2487.

    Article  Google Scholar 

  8. Sanli O, Armagan A, Kandirali E, Ozerman B, Ahmedov I, Solakoglu S, et al. TGF-beta1 neutralizing antibodies decrease the fibrotic effects of ischemic priapism. Int J Impot Res. 2004;16:492–7.

    CAS  Article  Google Scholar 

  9. Zanotti S, Bragato C, Zucchella A, Maggi L, Mantegazza R, Morandi L, et al. Anti-fibrotic effect of pirfenidone in muscle derived-fibroblasts from Duchenne muscular dystrophy patients. Life Sci. 2016;15:127–36.

    Article  Google Scholar 

  10. Stahnke T, Kowtharapu BS, Stachs O, Schmitz KP, Wurm J, Wree A, et al. Suppression of TGF-β pathway by pirfenidone decreases extracellular matrix deposition in ocular fibroblasts in vitro. PLoS ONE. 2017;23(12):e0172592. eCollection 2017.

    Article  Google Scholar 

  11. Yu W, Guo F, Song X. Effects and mechanisms of pirfenidone, prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models. Pharm Biol. 2017;55:450–5.

    CAS  Article  Google Scholar 

  12. Zhao XY, Zeng X, Li XM, Wang TL, Wang BE. Pirfenidone inhibits carbon tetrachloride and albumin complex induced liver fibrosis in rodents by preventing activation of hepatic stellate cells. Clin Exp Pharm Physiol. 2009;36:963–8.

    CAS  Article  Google Scholar 

  13. Iyer SN, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on transforming growth factor beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharm Exp Ther. 1999;291:367–73.

    CAS  Google Scholar 

  14. Oku H, Shimizu T, Kawabata T, Nagira M, Hikita I, Ueyama A, et al. Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharm. 2008;590:400–8.

    CAS  Article  Google Scholar 

  15. Chen JF, Ni HF, Pan MM, Liu H, Xu M, Zhang MH, et al. Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats. Am J Physiol Ren Physiol. 2013;304:F67–85. Epub 2012 Nov 14.

    Google Scholar 

  16. Armaendariz Borunda J, Lyra Gonzalez I, Medina Preciado D, Gonzalez-García I, Martinez-Fong D, Miranda RA, et al. A controlled clinical trial with pirfenidone in the treatment of pathological skin scarring caused by burns in pediatric patients. Ann Plast Surg. 2012;68:22–8.

    Article  Google Scholar 

  17. Duan LJ, Qi J, Huang T, Gu X, Xu D, Kong XJ, et al. Pirfenidone attenuates bladder fibrosis and mitigates deterioration of bladder function in a rat model of partial bladder outlet obstruction. Mol Med Rep. 2015;12:3639–47.

    CAS  Article  Google Scholar 

  18. Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, et al. Double-blind, placebo controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2005;171:1040–7.

    Article  Google Scholar 

  19. Poble PB, Phan C, Quatremare T, Bordenave J, Thuillet R, Cumont A, et al. Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension. FASEB J. 2019;33:3670–9.

    CAS  Article  Google Scholar 

  20. Jin YC, Gam SC, Jung JH, Hyun JS, Chang KC, Hyun JS. Expression and activity of heme oxygenase-1 in artificially induced low-flow priapism in rat penile tissues. J Sex Med. 2008;5:1876–82.

    CAS  Article  Google Scholar 

  21. Uluocak N, Atilgan D, Erdemir F, Parlaktas BS, Yasar A, Erkorkmaz U, et al. An animal model of ischemic priapism and the effects of melatonin on antioxidant enzymes and oxidative injury parameters in rat penis. Int Urol Nephrol. 2010;42:889–95. Epub 2010 Jan 30.

    Article  Google Scholar 

  22. Zhao S, Kang R, Deng T, Luo L, Wang J, Li E, et al. Comparison of two cannulation methods for assessment of intracavernosal pressure in a rat model. PLoS ONE. 2018;13:e0193543. https://doi.org/10.1371/journal.pone.0193543. eCollection 2018.

    Article  PubMed  PubMed Central  Google Scholar 

  23. La Favor JD, Fu Z, Venkatraman V, Bivalacqua TJ, Van Eyk JE, Burnett AL. Molecular profile of priapism associated with low nitric oxide bioavailability. J Proteome Res. 2018;17:1031–40.

    Article  Google Scholar 

  24. Casini A, Ferrali M, Pampella A, Maellaro E, Comporti M. Lipid peroxidation and cellular damage in extrahepatic tissues of bromobenzene-intoxicated mice. Am J Pathol. 1986;123:520–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Aykaç G, Uysal M, Yalçin AS, Koçak-Toker N, Sivas A, Oz H. The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats. Toxicology. 1985;36:71–6.

    Article  Google Scholar 

  26. Kehrer JP, Margolin SB. Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice. Toxicol Lett. 19977;90:125–32.

  27. Cevik O, Cadirci S, Sener TE, Tinay I, Akbal C, Tavukçu HH, et al. Quercetin treatment against ischemia/reperfusion injury in rat corpus cavernosum tissue: a role on apoptosis and oxidative stress. Free Radic Res. 2013;47:683–91.

    CAS  Article  Google Scholar 

  28. Kucukdurmaz F, Kucukgergin C, Akman T, Salabas E, Armagan A, Seckin S, et al. Duration of priapism is associated with increased corporal oxidative stress and antioxidant enzymes in a rat model. Andrologia. 2016;48:374–9.

    CAS  Article  Google Scholar 

  29. Karaguzel E, Bayraktar C, Kutlu O, Yulug E, Mentese A, Okatan AE, et al. The possible protective effects of dipyridamole on ischemic reperfusion injury of priapism. Int Braz J Urol. 2016;42:146–53.

    Article  Google Scholar 

  30. Evliyaoglu Y, Kayrin L, Kaya B. Effect of allopurinol on lipid peroxidation induced in corporeal tissue by veno-occlusive priapism in a rat model. Br J Urol. 1997;80:476–9.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We would like to thank Meryem Akpolat Ferah, due to her contribution to staining of slides with Masson’s trichrome stain.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Onder Cinar.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Verify currency and authenticity via CrossMark

Cite this article

Cinar, O., Bolat, M.S., Erdem, S. et al. The effect of an antifibrotic agent, pirfenidone, on penile erectile function in an experimental rat model of ischemic priapism. Int J Impot Res 32, 232–238 (2020). https://doi.org/10.1038/s41443-019-0152-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41443-019-0152-9

Search

Quick links