Zur Drucksensitivität der Kanalfunktion vestibulärer Haarzellen Typ II

Acute vertigo attack, hearing loss and tinnitus in patients with Menières disease can be related to an increase in hydrostatic pressure within the endolymphatic space. However, there is no convincing pathophysiological model that might explain, on a cellular and molecular level, how a pressure increases may cause disturbed functions of vestibular hair cells and vertigo attacks. It is not well understood how hydrostatic pressure causes a dysfunction of vestibular hair cells in Menières disease. Different theories describe osmotic mechanisms leading to electrolyte imbalance in endolymphatic space or change in longitudinal flow in the endolymphatic space. On the other hand in animal models of vertigo a pressure change of 0.3 cm H2O can be observed when an endolymphatic hydrops is induced by a ligature of the endolymphatic duct. This range of pressure changes fits well to activate a pressure-sensitive K+ current. These currents are inhibited by charybdotoxin, an inhibitor of Ca2+ dependent K+ channels. Furthermore cinnarizine is an inhibitor of voltage-gated Ca2+ currents in hair cells and is used as a drug in condition with vestibular vertigo. An aim of the presented experiments was to test, whether cinnarizine inhibits pressure- and Ca2+-sensitive K+ currents by reducing Ca2+ influx. Therefore vestibular type-II hair cells of guinea pigs were investigated in patch-clamp experiments (conventional whole-cell mode). The results demonstrate, that a quantitatively similar inhibition of K+ currents is produced by Cinnarizine [0.5 µM], the L-type Ca2+ channel blocker nifedipine [3 µM] and by extracellular Ca2+ removal. Further experiments turn out that Cinnarizine erase increases of K+ currents induced by increases in the hydrostatic pressure (from 0.2 to 0.5 cm H2O). Moreover Cinnarizine at a higher concentration (1 µM) extinguish K+ currents larger than those extinguished by Ca2+ removal. Additionally, the results show a reduction of K+ currents in the presence of Cinnarizine without Ca2+. These results could not be seen for nifedipine. To test the hypothesis, whether cinnarizine immediately inhibits Ca2+ sensitive K+ currents control tests with charybdotoxin were done. The reduction of Ca2+ sensitive K+ currents by cinnarizine is comparable to charybdotoxin. In conclusion cinnarizine inhibits by two mechanisms pressure-induced currents. It minimizes Ca2+ sensitive K+ currents by reducing Ca2+ influx and performs a Ca2+ independent inhibition. Furthermore the required IC50 for Ca2+ channel blockade is higher than that for pressure sensitive K+ currents. In connection with these results therapeutic benefit of Cinnarizine in acute vertigo can be explained. In addition it can be discussed, whether pressure-sensitive K+ currents alter the frequency behaviour of vestibular hair cells in an endolymphatic hydrops.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2007

Author dc:creator

• Haasler, Thorsten

Contributors dc:contributor

• Westhofen, Martin

• info:eu-repo/classification/ddc/610
• Gleichgewichtssinn
• Patch-Clamp-Methode
• Calciumantagonist
• Nifedipin
• Vestibulärer Schwindel
• Hörzelle
• Ionentransport
• Medizin
• vestibular
• hair cell
• Nifedipine
• Charybdotoxin
• Patch clamp
• Hydrostatic pressure
• Calcium currents

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-123930%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:62359