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Effects of cinnarizine on calcium and pressure-dependent potassium currents in guinea pig vestibular hair cells.

Düwel P, Haasler T, Jüngling E, Duong TA, Westhofen M, Lückhoff A

Institute of Physiology, Medical Faculty, RWTH Aachen, 52057 Aachen, Germany.

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.

Published 31 August 2005 in Naunyn Schmiedebergs Arch Pharmacol, 371(6): 441-8.
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