Effects of cinnarizine on calcium and pressure-dependent potassium currents in guinea pig vestibular hair cells.
In vestibular hair cells, K+ currents induced by rises in hydrostatic pressure have recently been demonstrated. These currents are inhibited by charybdotoxin, a blocker of Ca2+-dependent K+ channels. On the other hand, cinnarizine is a blocker of voltage-gated Ca2+ currents in hair cells and is used as a drug in conditions with vestibular vertigo. Our aim was to test in patch-clamp experiments (conventional whole-cell mode) whether cinnarizine, by reducing Ca2+ influx, inhibited Ca2+ and pressure-sensitive K+ currents in vestibular type-II hair cells of guinea pigs. A quantitatively similar inhibition of K+ currents was evoked by extracellular Ca2+ removal, cinnarizine (0.5 microM), and the L-type Ca2+ channel blocker nifedipine (3 microM). Cinnarizine abrogated increases of K+ currents induced by increases in the hydrostatic pressure (from 0.2 to 0.5 cm H2O). At a higher concentration (1 microM), cinnarizine elicited K+ current inhibitions larger than those elicited by Ca2+ removal. Moreover, it reduced K+ currents in the absence of Ca2+, in contrast to nifedipine. However, charybdotoxin abolished these effects of cinnarizine. We thus conclude that cinnarizine inhibits, by two mechanisms, pressure-induced currents that are sensitive to charybdotoxin and Ca2+. It reduces Ca2+ influx and exerts a Ca2+-independent inhibition, with a lower IC50 than that required for Ca2+ channel blockade. These two actions may importantly contribute to its therapeutic effects.
Düwel
Philip
P
Institute of Physiology, Medical Faculty, RWTH Aachen, 52057 Aachen, Germany.
Haasler
Thorsten
T
Jüngling
Eberhard
E
Duong
Thien An
TA
Westhofen
Martin
M
Lückhoff
Andreas
A
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D018999:Charybdotoxin / Q000494:pharmacology; D002936:Cinnarizine / Q000494:pharmacology*; D006168:Guinea Pigs; D018069:Hair Cells, Vestibular / Q000187:drug effects* / Q000502:physiology; D006874:Hydrostatic Pressure; D066298:In Vitro Techniques; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects* / Q000502:physiology
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D024681:Potassium Channels, Calcium-Activated; D018999:Charybdotoxin; D002936:Cinnarizine; D002118:Calcium