Pharmacological antagonism of the slow-activating delayed rectifying potassium channel (IKs) has no effect on cochlear structure and function in vivo

Abstract

The experimental class III antiarrhythmic drug, L-768673, prolongs the refractory period of cardiac myocytes by selectively blocking the slow-activating delayed rectifying potassium (IKs) channel. The IKs channel has also been identified in vestibular dark cells and in the marginal cells of the stria vascularis. In the stria vascularis, the IKs channel plays an important role in cochlear homeostasis. Genetic null deletion of the IKs channel in mice and man results in profound hearing loss and cochlear pathology. Therefore, the purpose of the present study was to investigate the effect of L-768673 on the auditory function and cochlear morphology in rats using auditory brainstem-evoked response and light microscopy. Auditory testing was performed one week prior to dosing, following 14 days of administration and 28 days after the completion of dosing. L-768673 (50 or 250 mg/kg/day for 14 days), had no significant effects on auditory function or cochlear morphology. The results of this study suggest that high doses of L-768673 are not toxic to the inner ear of adult rats treated for 14 consecutive days, and that the ototoxic potential of orally administered L-768673 and similar IKs-selective compounds is unlikely at doses within the therapeutic range.