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 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.
Bartolami
S
S
INSERM U 254, Université de Montpellier II, France.
Planche
M
M
Pujol
R
R
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
D007295:Inositol Phosphates; D008627:Mercuric Chloride; D000583:Amikacin; D002217:Carbachol; D009355:Neomycin; D004976:Ethacrynic Acid; D002945:Cisplatin