Thapsigargin suppresses cochlear potentials and DPOAEs and is toxic to hair cells

Thapsigargin, a drug that inhibits sarco-endoplasmic reticulum Ca2+ ATPases (SERCAs), was infused into the perilymph compartment of the guinea pig cochlea in increasing concentrations (0.1–10 μM) while sound evoked cochlear potentials were monitored. Thapsigargin significantly suppressed the compound action potential of the auditory nerve, cochlear microphonics, and increased N1 latency at low (56 dB SPL) and high intensity (92 dB SPL) levels of sound, suppressed low intensity sound evoked summating potential (SP) and greatly increased the magnitude of the high intensity sound evoked SP. At 10 μM, the drug suppressed the cubic distortion product otoacoustic emissions (2f1−f2=8 kHz, f2=12 kHz) evoked by both high and low intensity primaries (45, 60, 70 dB SPL). Thapsigargin (10 μM; 30 min) increased the endocochlear potential slightly (5 mV). In chronic animals, thapsigargin (10 μM; 60 min) destroyed many outer hair cells and some inner hair cells, especially in the basal turns. These effects are consistent with the hypothesis that the inhibition of the SERCAs affects the function of the cochlear amplifier and outer hair cells to a greater degree than it affects other functions of the cochlea.