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. Access through your

institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print

issues and online access $259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to

local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT

BEING VIEWED BY OTHERS LACOSAMIDE ALLEVIATES BILATERAL CAVERNOUS NERVE INJURY-INDUCED ERECTILE DYSFUNCTION IN THE RAT MODEL BY AMELIORATING PATHOLOGICAL CHANGES IN THE CORPUS CAVERNOSUM

Article 15 March 2023 GALECTIN-3 IS INVOLVED IN INFLAMMATION AND FIBROSIS IN ARTERIOGENIC ERECTILE DYSFUNCTION VIA THE TLR4/MYD88/NF-ΚB PATHWAY Article Open access 20 February 2024 VITAMIN

D3 IMPROVED ERECTILE FUNCTION RECOVERY BY REGULATING AUTOPHAGY AND APOPTOSIS IN A RAT MODEL OF CAVERNOUS NERVE INJURY Article 22 February 2023 REFERENCES * 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  * 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. Article  CAS  Google Scholar  * 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  * 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  * 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. Article  CAS  Google Scholar  * Pautler SE, Brock GB. Priapism.

From priapus to the present time. Urol Clin North Am. 2001;28:391–403. Article  CAS  Google Scholar  * 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  * 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. Article  CAS  Google Scholar  * 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  * 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  * 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. Article  CAS  Google Scholar  * 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. Article  CAS  Google Scholar  * 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  * 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. Article  CAS  Google Scholar  * 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  * 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  * 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. Article  CAS  Google Scholar  * 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  * 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. Article  CAS  Google Scholar  * 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. Article  CAS  Google Scholar  * 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  * 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  * 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  * 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  *

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

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. Article  CAS  Google Scholar  * 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. Article  CAS  Google Scholar  * 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  * 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. Article  CAS  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 * Department of Urology, Zonguldak Bulent Ecevit University, Health Application and Research Center, Zonguldak, Turkey Onder Cinar, Engin D. Demirkiran, Reha Girgin, Ersan

Bulut, Bulent Akduman & Necmettin A. Mungan * Department of Urology, Samsun Gazi State Hospital, Samsun, Turkey Mustafa S. Bolat * Department of Physiology, Zonguldak Bulent Ecevit

University, Health Application and Research Center, Zonguldak, Turkey Salih Erdem * Department of Pathology, Zonguldak Bulent Ecevit University, Health Application and Research Center,

Zonguldak, Turkey Esin Kaymaz Authors * Onder Cinar View author publications You can also search for this author inPubMed Google Scholar * Mustafa S. Bolat View author publications You can

also search for this author inPubMed Google Scholar * Salih Erdem View author publications You can also search for this author inPubMed Google Scholar * Esin Kaymaz View author publications

You can also search for this author inPubMed Google Scholar * Engin D. Demirkiran View author publications You can also search for this author inPubMed Google Scholar * Reha Girgin View

author publications You can also search for this author inPubMed Google Scholar * Ersan Bulut View author publications You can also search for this author inPubMed Google Scholar * Bulent

Akduman View author publications You can also search for this author inPubMed Google Scholar * Necmettin A. Mungan View author publications You can also search for this author inPubMed 

Google Scholar 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 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: 24 January 2019 * Revised: 04 April 2019 * Accepted: 23 April

2019 * Published: 11 June 2019 * Issue Date: March 2020 * DOI: https://doi.org/10.1038/s41443-019-0152-9 SHARE THIS ARTICLE Anyone you share the following link with will be able to read

this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative