title: Inhibition of the carbachol-evoked synthesis of inositol phosphates by ototoxic drugs in the rat cochlea.
abstract: 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 coupled to muscarinic receptors. This study was motivated by: (1) the demonstration of neomycin binding to phosphatidylinositol 4,5-biphosphate, 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 3H-IP formation. Mercuric chloride, cisplatin and ethacrynate inhibited the carbachol-induced formation of IPs in a dose-dependent manner with IC50 values of 74,340 and 430 microM, 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. However, neomycin applied at 15 and 30 microM induced 29% and 43% of inhibition of the stimulated IP response. Finally, additive effects are obtained 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 in some types of ototoxicity. The inefficiency of aminoglycosides and the putative targets of the ototoxic agents are discussed.
authors.affiliation: INSERM U 254, Université de Montpellier II, France.
authors.forename: S
authors.initials: S
authors.lastname: Bartolami
authors.forename: M
authors.initials: M
authors.lastname: Planche
authors.forename: R
authors.initials: R
authors.lastname: Pujol
mesh_terms: D000583:Amikacin / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000037:antagonists & inhibitors*; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003051:Cochlea / Q000187:drug effects* / Q000378:metabolism; D004976:Ethacrynic Acid / Q000494:pharmacology; D006311:Hearing Disorders / Q000139:chemically induced*; D007295:Inositol Phosphates / Q000096:biosynthesis*; D008627:Mercuric Chloride / Q000494:pharmacology; D009355:Neomycin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D007295:Inositol Phosphates; D008627:Mercuric Chloride; D000583:Amikacin; D002217:Carbachol; D009355:Neomycin; D004976:Ethacrynic Acid; D002945:Cisplatin