Effect of exogenous arachidonic acid metabolites applied on round window membrane on hearing and their levels in the perilymph.
Our previous studies revealed that treatment with sodium salicylate or indomethacin caused hearing loss, a decrease in prostaglandin (PG) levels, and an increase in leukotriene (LT) levels of the arachidonic acid (AA) cascade in the perilymph. We suspected that decreased PG-levels and/or elevated LT-levels in the inner ear may be responsible for the salicylate ototoxicity. In order to test this hypothesis, effects of exogenous treatments with PGs, PG-analog, LTs, and other lipoxygenase products on hearing and levels of AA metabolites in the perilymph were studied in chinchillas. Cyclooxygenase products, PGI2, 6-keto-PGF1 alpha, Iloprost (PGI2 analog), PGE2, and LTB4, LTC4, and 15-hydroxyeicosatetraenoic acid (15-HETE) in the lipoxygenase products in the dose of 150 ng were applied on the round window membrane (RWM); cochlear function tested by auditory brainstem response (ABR) and samples of perilymph were collected at 0.5, 1, 2, and 4 hours after the application. Samples of perilymph were assayed for all spectra of AA metabolites by high performance liquid chromatography (HPLC) and radioimmunoassay (RIA). PG-treated animals developed minimal or no hearing loss. LT-treated animals exhibited hearing loss of 20 to 40 dB, peaking at one hour after the treatment. Elevated levels of arachidonic acid metabolites were measured in the perilymph of the ears treated with respective AA metabolites, with peak levels at one hour from the application. The findings of this study indicate that hearing loss can be induced by altered levels of PGs or LTs in the perilymph. This is another strong evidence that salicylate induced ototoxicity can be mediated by abnormal arachidonic acid metabolism in the inner ear.
Jung
T T
TT
Department of Surgery, Loma Linda University School of Medicine, CA.
Park
Y M
YM
Miller
S K
SK
Rozehnal
S
S
Woo
H Y
HY
Baer
W
W
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism* / Q000494:pharmacology; D002682:Chinchilla / Q000378:metabolism / Q000502:physiology; D002853:Chromatography, Liquid; D003051:Cochlea / Q000378:metabolism / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D006311:Hearing Disorders / Q000139:chemically induced / Q000209:etiology; D015289:Leukotrienes / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D010498:Perilymph / Q000737:chemistry / Q000378:metabolism*; D010539:Permeability; D011863:Radioimmunoassay; D012405:Round Window, Ear / Q000378:metabolism*
D016861:Cyclooxygenase Inhibitors; D015289:Leukotrienes; D016718:Arachidonic Acid