All Title Author
Keywords Abstract

PLOS ONE  2013 

Ups and Downs of Viagra: Revisiting Ototoxicity in the Mouse Model

DOI: 10.1371/journal.pone.0079226

Full-Text   Cite this paper   Add to My Lib


Sildenafil citrate (Viagra), a phosphodiesterase 5 inhibitor (PDE5i), is a commonly prescribed drug for erectile dysfunction. Since the introduction of Viagra in 1997, several case reports have linked Viagra to sudden sensorineural hearing loss. However, these studies are not well controlled for confounding factors, such as age and noise-induced hearing loss and none of these reports are based on prospective double-blind studies. Further, animal studies report contradictory data. For example, one study (2008) reported hearing loss in rats after long-term and high-dose exposure to sildenafil citrate. The other study (2012) showed vardenafil, another formulation of PDE5i, to be protective against noise-induced hearing loss in mice and rats. Whether or not clinically relevant doses of sildenafil citrate cause hearing loss in normal subjects (animals or humans) is controversial. One possibility is that PDE5i exacerbates age-related susceptibility to hearing loss in adults. Therefore, we tested sildenafil citrate in C57BL/6J, a strain of mice that displays increased susceptibility to age-related hearing loss, and compared the results to those obtained from the FVB/N, a strain of mice with no predisposition to hearing loss. Six-week-old mice were injected with the maximum tolerated dose of sildenafil citrate (10 mg/kg/day) or saline for 30 days. Auditory brainstem responses (ABRs) were recorded pre- and post injection time points to assess hearing loss. Entry of sildenafil citrate in the mouse cochlea was confirmed by qRT-PCR analysis of a downstream target of the cGMP-PKG cascade. ABR data indicated no statistically significant difference in hearing between treated and untreated mice in both backgrounds. Results show that the maximum tolerated dose of sildenafil citrate administered daily for 4 weeks does not affect hearing in the mouse. Our study gives no indication that Viagra will negatively impact hearing and it emphasizes the need to revisit the issue of Viagra related ototoxicity in humans.


[1]  Keith A (2000) The Economics of Viagra. Health Affairs 19 (2): 147–157.
[2]  Falco M (2007) Impotence drugs may increase risk for sudden hearing loss. Available: Accessed 3 May 2013.
[3]  Pfizer (2012) 2012 Financial report. Availabe: Accessed 12 May 2013.
[4]  Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, et al. (1999) Use of sildenafil (Viagra) in patients with cardiovascular disease. J. American College of Cardiology 33 (21): 273–282.
[5]  Ghofrani HA, Reichenberger F, Kohstall MG, Mrosek EH, Seeger T, et al. (2004) Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: A randomized, double-blind, placebo-controlled crossover trial. Annals of Internal Medicine 141 (3): 169–177.
[6]  Richalet J-P, Gratadour P, Robach P, Pham I, Déchaux M, et al. (2005) Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine 171 (3): 275–281.
[7]  NIDCD (2003) NIH Pub No 00–4757 Sudden Deafness. Available: Accessed 3 May 3 2013.
[8]  Mukherjee B, Shivakumar T (2007) A case of sensorineural deafness following ingestion of sildenafil. J Laryngol Otol 121: 395–397.
[9]  FDA (2011) Information for Healthcare Professionals: Sildenafil (marketed as Viagra and Revatio), Vardenafil (marketed as Levitra), Tadalfil (marketed as Cialis). Available: Accessed 3 May 3 2013.
[10]  FDA (2007) FDA Announces Revisions to Labels for Cialis, Levitra and Viagra; Potential risk for sudden hearing loss with ED drugs to be displayed more prominently. Available: Accessed 3 May 2013.
[11]  Maddox PT, Saunders J, Chandrasekhar SS (2009) Sudden hearing loss from PDE- 5 inhibitors: A possible cellular stress etiology. Laryngoscope 119: 1586–1589.
[12]  McGwin G Jr (2010) Phosphodiesterase type 5 inhibitor use and hearing impairment. Arch. Otolaryngol. Head Neck Surg. 136: 488–492.
[13]  Khan AS, Sheikh Z, Khan S, Dwivedi R, Benjamin E (2011) Viagra Deafness–Sensorineural Hearing Loss and Phosphodiesterase-5 Inhibitors. Laryngoscope 121: 1049–1054.
[14]  Okuyucu S, Guven OE, Akoglu E, Ucar E, Dagli S (2009) Effect of phosphodiesterase-5 inhibitor on hearing. J Laryngol Otol 123(7): 718–22.
[15]  Jaumann M, Dettling J, Gubelt M, Zimmermann U, Gerling A, et al. (2012) cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function. Nature Medicine. 18: 252–260.
[16]  Hong BN, Yi TH, Kim SY, Kang TH (2008) High dosage sildenafil induces hearing impairment in mice. Biol. Pharm. Bull. 31: 1981–1984.
[17]  Bakir S, Firat U, Gun R, Bozkurt Y, Yorgancilar E, et al.. (2012) Histpathologic results of long-term sildenafil administration on rat inner ear. American Journal of Otolaryngology – Head and Neck Medicine and Surgery.
[18]  Pfizer (2010) Viagra. Available at: Accessed 3 May 2013.
[19]  Geng R, Melki S, Chen DH, Tian G, Furness DN, et al. (2012) The Mechanosensory Structure of the Hair Cell Requires Clarin-1, a Protein Encoded by Usher Syndrome III Causative Gene. J Neurosci 32(28): 9485–9498.
[20]  Chance MR, Chang J, Liu S, Gokulrangan G, Chen D H-C, et al. (2010) Proteomics, bioinformatics and targeted gene expression analysis reveals up-regulation of cochlin and identifies other potential biomarkers in the mouse model for deafness in usher syndrome type 1F. Human Molecular Genetics 19(8): 1515–1527.
[21]  Hampton LL, Wright CG, Alagramam KN, Battey JF, Noben-Trauth K (2003) A new spontaneous mutation in the mouse Ames waltzer gene, Pcdh15. Hear Res 180: 67–75.
[22]  Geng R, Geller SF, Hayashi T, Ray CA, Reh TA, et al. (2009) Usher syndrome IIIA gene clarin-1 is essential for hair cell function and associated neural activation. Hum Mol Genet 18: 2748–2760.
[23]  Zheng QY, Scarborough JD, Zheng Y, Yu H, Choi D, et al. (2012) Digenic inheritance of deafness caused by 8J allele of myosin-VIIA and mutations in other Usher I genes. Hum Mol Genet 21: 2588–2598.
[24]  Johnson KR, Yu H, Ding D, Jiang H, Gagnon LH, et al. (2010) Separate and combined effects of Sod1 and Cdh23 mutations on age-related hearing loss and cochlear pathology in C57BL/6J mice. Hear Res 268: 85–92.
[25]  Schweitzer VG (1993) Cisplatin-induced ototoxicity: the effect of pigmentation and inhibitory agents. Laryngoscope 103: 1–52.
[26]  Yoo J, Hamilton SJ, Angel D, Fung K, Franklin J, et al.. (2013) Cisplatin otoprotection using transtympanic L-N-acetylcysteine: A pilot randomized study in head and neck cancer patients. Laryngoscope.
[27]  Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, et al. (1998) Oral Sildenafil in the Treatment of Erectile Dysfunction. NEJM 338: 1397–1404.
[28]  Lincoln TM, Dey N, Sellak H (2001) Invited Review: cGMP-dependent protein kinase signaling mechanisms in smooth muscle: from the regulation of tone to gene expression. J of Applied Physiology 91(3): 1421–1430.
[29]  Johnson KM, Erway LC, Cook SA, Willott JF, Zheng QY (1997) A major gene affecting age-related hearing loss in C57BL/6J mice. Hearing Research 114(1–2): 83–92.
[30]  Uptodate (2013) Sildenafil: Drug Information. Availabe: Accessed 3 May 2013.


comments powered by Disqus