Inhibition of voltage-gated calcium currents in type II vestibular hair cells by cinnarizine

Abstract

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.

Potassium currents induced by hydrostatic pressure modulate membrane potential and transmitter release in vestibular type II hair cells

“…1). Such currents have been previously characterised as slowly inactivating Ca 2+ currents sensitive to dihydropyridine [3]. The current densities amounted to 4.73± 3.22 pA/pF in the present experiments (n=15).…”

“…A difference of about 10 mV was observed for the early peak depolarisation as well as for the more plateau-like subsequent voltage response. The previ-ously established voltage-current relation of Ca 2+ currents [3] predicts that the current amplitudes are smaller in the high than the low bath and therefore might affect transmitter release differently. Transmitter release from hair cells, as assessed by increments in the capacitance in voltage-clamp experiments, proved to be a strictly Ca 2+dependent process and was only evoked in conditions where voltage-dependent Ca 2+ currents are expected to increase the cytosolic Ca 2+ concentration considerably.…”

Cinnarizine for the prophylaxis of migraine associated vertigo: a retrospective study

“…Cinnarizine (CIN) is a well-tolerated L-type calcium channel blocker which has early onset effects on migraine prophylaxis (Togha et al 2006; Mansoureh et al 2008). While, CIN directly inhibits vestibular hair cells stimulation (Arab et al 2004) and also has antihistaminic actions (Pianese et al 2002), it seems to be a good choice in treatment of migraine with vertigo. However, to the best of our knowledge, no investigation has yet been made to assess the efficacy and safety of CIN in the treatment of migraine and vertigo comorbidities.…”

Cinnarizine in refractory migraine prophylaxis: efficacy and tolerability. A comparison with sodium valproate

“…Cinnarizine (CIN) is an L-type calcium channel blocker, which inhibits contractions of vascular smooth muscle cells [7], directly inhibits vestibular hair cells stimulation [8], and has antihistaminic actions [9]; all these mechanisms can potentially contribute to its preventive effects on migraine.…”