INHIBITION OF THE CARBACHOL-EVOKED SYNTHESIS OF INOSITOL PHOSPHATES BY OTOTOXIC DRUGS IN THE RAT COCHLEA

The ability of amikacin, neomycin, ethacrynate, mercuric chloride and cisplatin to alter the inositol phosphate (IP) signalling pathway was assessed in the 12-day-old rat cochlea, where the turnover of IPs is c oupled to muscarinic receptors. This study was motivated by: (1) the d emonstration of neomycin binding to phosphatidylinositol 4,5-biphospha te, the precursor of IPs, and (2) the fact that ototoxic drugs induce some common symptoms in outer hair cells. At concentrations below 1 mM , none of the compounds changed the control H-3-IP formation. Mercuric chloride, cisplatin and ethacrynate inhibited the carbachol-induced f ormation of IPs in a dose-dependent manner with IC50 values of 74, 340 and 430 muM, respectively. The aminoglycosides were less efficient in reducing the carbachol-stimulated accumulation of IPs, since neither amikacin nor neomycin, both at 1 mM, had any significant effect. Howev er, neomycin applied at 15 and 30 muM induced 29% and 43% of inhibitio n of the stimulated IP response. Finally, additive effects are obtaine d between some of the toxic drugs. The results suggest that a block of the IP transduction system, associated with the cholinergic efferent innervation of the organ of Corti, is a feature that may be involved i n some types of ototoxicity. The inefficiency of aminoglycosides and t he putative targets of the ototoxic agents are discussed.