Dual action of ototoxic antibiotics on sensory hair cells

Abstract

All aminoglycoside antibiotics in clinical use are ototoxic in that they can cause permanent malfunctioning of the cochlea and vestibule^1–3. It is generally assumed that these ototoxic antibiotics primarily affect the sensory hair cells in the inner ear and that degeneration of secretory and neural elements comes later^2–5. Most experimental work on aminoglycoside antibiotic ototoxicity has concentrated on the irreversible effects on inner ear functioning and hair cell morphology^2,3. Little is known about their mode of action on the hair cells. Interference with hair cell protein synthesis, in analogy with the antimicrobial mechanism, has been ruled out as the primary cause of the high selective⁶ toxicity of the aminoglycosides^3,5. Recent evidence indicates that these antibiotics may interfere with membrane phos-pholipid metabolism⁷. Morphological studies have demonstrated that early on in the ototoxic process the membrane of the sensory hairs is already damaged⁴. The aminoglycoside antibiotics are reported to have a direct and reversible^8,9 effect on hair cell functioning in organs of the acoustico-lateralis system of lower vertebrates^8–11. Hence, the primary site of action is probably the hair cell membrane. We have now therefore examined reversible effects of ototoxic antibiotics on single fibre afferent nerve activity and extracellular receptor potentials in the lateral-line organ of Xenopus laevis. Our results show that the antibiotics, in concentrations similar to those measured in the cochlear fluids³, have a dual action on the hair cells. They not only increase the spontaneous afferent nerve activity, probably by an effect on the hair cell membrane, but also severely impair the mechano-electric transduction process, resulting in a large phase lag of the receptor potentials. The latter effect, which is antagonised by Ca²⁺ may be due to interference of the antibiotics with the mechanical properties of the sensory hairs.