Longitudinal Distribution of Drugs in Perilymph Assessed by Cochlear Action Potentials.

Alec N. Salt, Shane A. Hale

Abstract

Although chemical marker studies indicate that the spread of substances in the fluids of the ear is dominated by passive diffusion, it has not been established whether this principle is generally applicable to all substances. In the present study, we have used the spread of suppression of cochlear responses to quantify the spread of drugs applied to perilymph. We injected one of three drugs: tetrodotoxin, kainic acid or furosemide at 50 or 100 nl/min into scala tympani perilymph of the basal or third turn. Injection pipettes were sealed into the bony otic capsule to prevent artifacts from perilymph leakage. Cochlear action potential (AP) thresholds were monitored as a function of time for frequencies from 1 kHz to 23 kHz in half or quarter octave steps. Thresholds were established in an automated procedure using a 10 µV response criterion. Sensitivity was determined for up to 10 test frequencies at 2 min intervals during the 90 min period following drug injection. For tetrodotoxin and kainate, the spread of response suppression as a function of frequency and time was in close agreement with simulations of the spread of drug along the scala. In contrast, for furosemide, the initial threshold changes close to the injection site were consistent with the drug's effects, but furosemide also induced threshold elevations at distant sites in a manner inconsistent with longitudinal diffusion of drug along the scala. The findings suggest that furosemide may be spreading by other mechanisms, such as via the vasculature, or that local effects of furosemide on one part of the endolymphatic system are influencing endolymph status, and function, at distant sites. The results with TTX and kainate validate the use of AP thresholds as a method to quantify the dispersal characteristics of an applied drug, but the anomalous findings with furosemide show that for some drugs, alternative mechanisms may need to be considered.
 

This study was supported by the National Institutes of Health through the National Institute on Deafness and other Communication Disorders, Grant number DC01368

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