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

Abstract

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.

• Authors: Philip Düwel, Thorsten Haasler, Eberhard Jüngling, Thien An Duong, Martin Westhofen, Andreas Lückhoff
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 371 Issue 6 Pg. 441-8 (Jun 2005) ISSN: 0028-1298 [Print] Germany
• PMID: 16041595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channel Blockers
• Calcium Channels, L-Type
• Potassium Channels, Calcium-Activated
• Charybdotoxin
• Cinnarizine
• Calcium

Topics

• Animals
• Calcium (pharmacology)
• Calcium Channel Blockers (pharmacology)
• Calcium Channels, L-Type (drug effects, physiology)
• Charybdotoxin (pharmacology)
• Cinnarizine (pharmacology)
• Guinea Pigs
• Hair Cells, Vestibular (drug effects, physiology)
• Hydrostatic Pressure
• In Vitro Techniques
• Patch-Clamp Techniques
• Potassium Channels, Calcium-Activated (drug effects, physiology)