Pharmacological modulation of transmitter release by inhibition of pressure-dependent potassium currents in vestibular hair cells.
Vestibular vertigo may be induced by increases in the endolymphatic pressure that activate pressure-dependent K(+) currents (I(K,p)) in vestibular hair cells. I(K,p) have been demonstrated to modulate transmitter release and are inhibited by low concentrations of cinnarizine. Beneficial effects against vestibular vertigo of cinnarizine have been attributed to its inhibition of calcium currents. Our aim was to determine the extent by which the inhibition of I(K,p) by cinnarizine may alter the voltage response to stimulating currents and to analyze whether such alterations may be sufficient to modulate the activation of Ca(2+) currents and transmitter release. Vestibular type II hair cells from guinea pigs were studied using the whole-cell patch-clamp technique. In current clamp, voltage responses to trains of stimulating currents were recorded. In voltage clamp, transmitter release was assessed from changes in the cell capacitance, as calculated from the phase shift during application of sine waves. Cinnarizine (0.05-3 microM) concentration dependently reversed the depressing effects of increases in the hydrostatic pressure (from 0.2 to 0.5 cm H(2)O) on the voltage responses to stimulating currents. Voltage protocols that simulated these responses were applied in voltage clamp and revealed a significantly enhanced transmitter release in conditions mimicking an inhibition of I(K,p). Cinnarizine (< or =0.5 microM) did not inhibit calcium currents. We conclude that cinnarizine, in pharmacologically relevant concentrations, enhances transmitter release in the presence of elevated hydrostatic pressure by an indirect mechanism, involving inhibition of I(K,p), enhancing depolarization, and increasing the voltage-dependent activation of Ca(2+) currents, without directly affecting Ca(2+) current.
Haasler
Thorsten
T
Institute of Physiology, Medical Faculty, RWTH Aachen, Aachen, Germany.
Homann
Georg
G
Duong Dinh
Thien An
TA
Jüngling
Eberhard
E
Westhofen
Martin
M
Lückhoff
Andreas
A
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D002936:Cinnarizine / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D018069:Hair Cells, Vestibular / Q000187:drug effects*; D006874:Hydrostatic Pressure; D008575:Meniere Disease / Q000188:drug therapy / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*
D002121:Calcium Channel Blockers; D015221:Potassium Channels; D002936:Cinnarizine; D002118:Calcium