Effect of round window membrane application of salicylate and indomethacin on hearing and levels of arachidonic acid metabolites in perilymph.
Our previous studies revealed that systemic salicylate-induced ototoxicity is associated with altered levels of arachidonic acid metabolites (AAMs) in the perilymph. In order to eliminate the possibility of systemic toxic effects of salicylate when it is given parenterally, an animal model of salicylate-induced ototoxicity was developed by applying it on the round window membrane (RWM). Using chinchillas as experimental animals, sodium salicylate (150 micrograms) or another nonsteroidal anti-inflammatory drug (NSAID), indomethacin (20 micrograms) was applied on the RWM, cochlear function was determined by auditory brainstem response (ABR) and perilymph assayed for AAMs both prostaglandins (PGs) and leukotrienes (LTs) by high performance liquid chromatography (HPLC) and radioimmunoassay (RIA) at different time intervals. When salicylate or indomethacin was applied on the RWM, dose-dependent ABR threshold losses of 20 to 50 dB was observed in 1 to 2 hours associated with decreased concentrations of 6-keto-PGF1 alpha and elevated levels of LTs. The hearing loss recovered to normal threshold over a period of 8 hours. The control group showed no hearing loss or any change in PG or LT-levels in the prilymph. The results of this study suggest that the method of inducing ototoxicity by applying salicylate or indomethacin on the RWM seems to be a reliable method for avoiding systemic toxicity of the parenteral treatment method and that ototoxicity induced by salicylate or indomethacin may be mediated by decreased PGs and elevated LTs.
Jung
T T
TT
Department of Surgery, Loma Linda University School of Medicine, CA 92354.
Miller
S K
SK
Rozehnal
S
S
Woo
H Y
HY
Park
Y M
YM
Baer
W
W
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism* / Q000493:pharmacokinetics; D002682:Chinchilla; D002853:Chromatography, Liquid; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism; D015777:Eicosanoids / Q000032:analysis*; D005260:Female; D006309:Hearing / Q000187:drug effects*; D006311:Hearing Disorders / Q000209:etiology / Q000378:metabolism; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D010498:Perilymph / Q000378:metabolism*; D011457:Prostaglandins D; D012405:Round Window, Ear / Q000187:drug effects*; D012459:Salicylates / Q000494:pharmacology* / Q000633:toxicity
D015777:Eicosanoids; D011457:Prostaglandins D; D012459:Salicylates; D016718:Arachidonic Acid; D007213:Indomethacin