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An energy-dependent step in aminoglycoside ototoxicity: prevention of gentamicin ototoxicity during reduced
Abstract:
Guinea pigs received a bolus of gentamicin (10 mM for 5 min) by perilymphatic perfusion which normally led to an irreversible loss of the cochlear microphonic potential (CM). Various experimental conditions that reduced the endolymphatic potential (EP) were then superimposed on the gentamicin application. Reversible reductions in EP (and, concomitantly, in CM) were induced by asphyxia (3 min), intravenous furosemide (50 mg/kg), and perilymphatic perfusion of aminooxyacetic acid (10 mM). When the administration of gentamicin was initiated at the time of maximal EP reduction the usual irreversible gentamicin-induced decline of CM was prevented. The results indicate that a metabolic process is essential in the expression of gentamicin toxicity. The data are consistent with the inhibition of an energy-dependent transport of the aminoglycoside. Alternatively, the data are also compatible with the hypothesis that entry of gentamicin into hair cells is prevented by a reduction in their transmembrane electrical potential.
Insights
Gentamicin-induced hearing loss in guinea pigs was prevented by reducing the endolymphatic potential (EP). This suggests a metabolic process, possibly energy-dependent transport, is crucial for gentamicin
Area of Science:
- Ototoxicity and Auditory Neuroscience
- Pharmacology of Aminoglycosides
Background:
- Gentamicin is a common antibiotic with known ototoxic side effects.
- Ototoxicity, particularly damage to the cochlea, can lead to irreversible hearing loss.
- The cochlear microphonic potential (CM) is a measure of outer hair cell function.
Purpose of the Study:
- To investigate the role of the endolymphatic potential (EP) in gentamicin-induced ototoxicity.
- To determine if reducing EP can prevent gentamicin-induced damage to cochlear function.
Main Methods:
- Guinea pigs were subjected to perilymphatic perfusion of gentamicin.
- Experimental conditions were used to reversibly reduce the endolymphatic potential (EP), including asphyxia, furosemide administration, and aminooxyacetic acid perfusion.
- The effect of gentamicin on the cochlear microphonic potential (CM) was measured under normal and reduced EP conditions.
Main Results:
- Gentamicin administration typically caused irreversible loss of CM.
- Reversible reductions in EP were achieved through asphyxia, furosemide, and aminooxyacetic acid.
- When gentamicin was applied during maximal EP reduction, the usual irreversible CM decline was prevented.
Conclusions:
- A metabolic process is essential for gentamicin's ototoxic effects.
- The findings support the hypothesis of an energy-dependent transport mechanism for gentamicin entry into cochlear cells.
- Alternatively, reduced transmembrane electrical potential in hair cells may prevent gentamicin entry.