Annals of Otology, Rhinology & Laryngology 119(5):342-349, © 2010 Annals Publishing Company. All rights reserved. Furosemide Administered Before Noise Exposure Can Protect the Ear Cahtia Adelman, PhD; Ronen Perez, MD; Yoram Nazarian, MD; Sharon Freeman, PhD; Jeffrey Weinberger, MD; Haim Sohmer, PhD Objectives: We assessed the effect of furosemide administration on noise-induced hearing loss. This drug reversibly ele- vates the auditory threshold by inducing a temporary reduction of the endocochlear potential and thereby suppresses the cochlear amplifier and active cochlear mechanics. Methods: Mice were given a single injection of furosemide 30 minutes before exposure to 113 dB sound pressure level broadband noise. Control animals received saline solution. Furosemide was administered in other mice after the noise exposure. Auditory threshold shifts were assessed by recording auditory nerve brain stem evoked response (ABR) thresh- olds to broadband clicks. Results: The mean ABR threshold in the group injected with furosemide and exposed to temporary threshold shift (TIS)-producing noise was elevated by 20.4 ± 12.3 dB, and that in the saline control group was elevated by 35.4 ± 18.3 dB (p < 0.02). The mean threshold elevations in the group injected with furosemide and exposed to permanent threshold shift (PTS)-producing noise and in the PTS saline control group were 15.0 ± 10.3 dB and 27.0 ± 12.7 dB, respectively (p < 0.01). Similar results were obtained when the PTS was assessed with an 8-kHz tone burst ABR. There was no signifi- cant difference in the PTS between mice given a single injection of furosemide and those given saline solution after the noise; this finding shows that furosemide is not acting as an antioxidant. Conclusions: It appears that reversible hearing threshold elevation as a result of furosemide administration before noise exposure can reduce the TIS and PTS. This finding provides insight into the mechanism of noise-induced hearing loss. Key Words: cochlear amplifier, free radical, furosemide, hearing loss, noise, protection. INTRODUCTION The sensorineural hearing loss following expo- sure to noise (noise-induced hearing loss; NIHL) is probably related in one way or another to exces- sive vibrations of inner ear structures induced by the noise during both temporary and permanent auditory threshold shifts (TIS and PTS). The major compo- nents of the sound-induced vibrations are active dis- placements, requiring metabolic energy to maintain the electrochemical gradients involved in mechano- electrical and electro-mechanical transduction, the latter involving outer hair cell (OHC) motility pro- duced by the motor protein prestin. There is experimental evidence that active dis- placements are also present during high-level stimu- lation, eg, the presence, in prestin-null mice, of dis- tortion product otoacoustic emissions in response to high-intensity stimulation, which disappear rapidly after death. I The excessive vibrations can directly cause structural damage to delicate inner ear struc- tures such as the stereocilia of the OHCs and the OHCs themselves.s-' Excessive vibrations may also induce increased metabolic activity (to maintain the electrochemical gradients), leading to the formation of free radicals (reactive oxygen species [ROS]) that can indirectly cause metabolically induced structur- al damage to the organ of Corti.t-' Therefore, it is possible that reduction of these excessive vibrations during the period of noise exposure could serve to minimize damage to the ear. The dominant driving force for the hair cell elec- trical changes (and hence for prestin-dependent mo- tility of OHCs, active cochlear mechanics, and the cochlear amplifier) is the large extracellular positive potential in the scala media of the cochlea called the endocochlear potential.s Depression of this poten- tial is accompanied by large reductions in basilar membrane displacement? as a result of the reduced OHC motility. This potential can be reduced by in- jection of the loop diuretic furosemide, which re- From the Speech and Hearing Center (Adelman) and the Department of Otolaryngology-Head and Neck Surgery (Weinberger). Hadas- sah University Hospital. the Department of Physiology. Hebrew University-Hadassah Medical School (Adelman, Freeman, Sohmer), and the Department of Otolaryngology-Head and Neck Surgery. Shaare Zedek Medical Center (Perez, Nazarian), Jerusalem, Israel. Correspondence: Haim Sohmer, PhD, Dept of Physiology, Hebrew University-Hadassah Medical School, POB 12272. Jerusalem 91120, Israel. 342