Inhibition of voltage-gated calcium currents in type II vestibular hair cells by cinnarizine.
Cinnarizine is pharmaceutically used in conditions with vestibular vertigo such as Meniere's disease. It is thought to act on extra-vestibular targets. We hypothesized that cinnarizine, as a blocker of L-type Ca2+ channels, may directly target vestibular hair cells where Ca2+ currents are important for the mechano-electrical transduction and transmitter release. Our aim was to clarify whether cinnarizine affected voltage-dependent Ca2+ currents in vestibular type II hair cells. Such cells were isolated from inner ears of guinea pigs by enzymatic and mechanical dissection from the gelatinous otolithic membrane and studied with the patch-clamp technique in conventional whole-cell mode. Ca2+ currents were elicited by depolarizing pulses in a solution containing 1.8 mM Ca2+ and 40 mM Ba2+. These currents resembled L-type currents (I(Ca,L)) with respect to their voltage-dependence and their inhibition by nifedipine and Cd2+ but did not show time-dependent inactivation. The currents were inhibited by cinnarizine in a concentration-dependent and reversible manner. The IC50 was 1.5 microM. A block exceeding 80% was achieved with 10 microM. The onset of current block was faster with higher concentrations but the reversibility after wash-out was less, suggesting accumulation in the membrane. We conclude that these direct actions of cinnarizine on hair cells should be considered as molecular mechanisms contributing to therapeutic effects of cinnarizine in vertigo.
Arab
Sonja F
SF
Department of Oto-Laryngology and Plastic Head and Neck Surgery, University Hospital Aachen, 52057 Aachen, Germany.
Düwel
Philip
P
Jüngling
Eberhard
E
Westhofen
Martin
M
Lückhoff
Andreas
A
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002936:Cinnarizine / Q000494:pharmacology*; D006168:Guinea Pigs; D018069:Hair Cells, Vestibular / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002936:Cinnarizine