Ups and downs of Viagra: revisiting ototoxicity in the mouse model.
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.
Otolaryngology Head and Neck Surgery, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
Adrian
A
Au
John Gerka
JG
Stuyt
Daniel
D
Chen
Kumar
K
Alagramam
D000375:Aging / Q000378:metabolism*; D000818:Animals; D003051:Cochlea / Q000378:metabolism / Q000503:physiopathology; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D007172:Erectile Dysfunction / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects*; D034381:Hearing Loss / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D058986:Phosphodiesterase 5 Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D010879:Piperazines / Q000009:adverse effects* / Q000494:pharmacology; D011687:Purines / Q000009:adverse effects / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000009:adverse effects* / Q000494:pharmacology
D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP