Mechanisms of salicylate ototoxicity.

The ototoxic effects of salicylates, reversible hearing loss and tinnitus, are well documented. However, the pharmacological mechanisms underlying these changes in cochlear function are not well understood. The studies reported here were an investigation of the site and mechanism of salicylate ototoxicity through an examination of its effects on ionic, neural and mechanical aspects of cochlear transduction. Salicylate administration produced an intensity dependent reduction of the AP and SP, with the predominant effects occurring at low stimulus levels. In direct contrast, a significant increase was observed for corresponding CM responses, independent of stimulus intensity. Salicylates also reduced the magnitude of efferent induced shifts in the AP, CM and EP. Cochlear mechanics were altered as evidenced by the reduction in two-tone distortion products, electrically evoked emissions, and electrophonic APs. These changes in cochlear function are attributed to a salicylate mediated increase in the membrane conductance of the outer hair cells. This change in membrane permeability interferes with the reverse transduction process, effectively reducing the gain of the cochlear amplifier. Results of single unit recordings suggest parallels between salicylate intoxication and noise trauma, which are discussed with regard to potential mechanisms of tinnitus generation.