Cisplatin modulates voltage gated channel currents of dorsal root ganglion neurons of rats.
The anticancer drug cis-diammindichloroplatin (CDDP, cisplatin) causes severe side effects like peripheral sensitive neuropathy. The toxicity of CDDP has been linked to changes in intracellular calcium homeostasis ([Ca2+]i). Voltage activated calcium channel currents (ICa(V)) are important for the regulation of [Ca2+]i; therefore, this study was designed to examine the effect of CDDP on ICa(V) in comparison to voltage activated potassium (IK(V)) and sodium (INa(V)) channel currents using the whole cell patch clamp method on dorsal root ganglion neurons of rats. In small neurons (<or=Ø20 microm) CDDP reduced peak and sustained ICa(V) concentration dependently (1-100 microM). The IC50 was 23.9+/-4.5 microM (+/-S.D.) for the peak current with a Hill-coefficient of 0.6+/-0.1 and 38.8+/-6.1 microM for the sustained current (Hill-coefficient: 0.7+/-0.1). IK(V) were reduced by 20.9+/-4.8% (10 microM) and INa(V) were only reduced by 9.2%+/-7.2% (10 microM). ICa(V) of large neurons (>or=Ø25 microm) were less sensitive to CDDP. The peak ICa(V) was reduced by 14.1+/-2.3% and IK(V) by 12.8+/-3.4% (100 microM). The sensitivity of INa(V) in large neurons to CDDP was not different compared to small neurons. We conclude that the reduction of ICa(V) in small cells may be responsible for the neurotoxic side effects CDDP causes in sensory neurons.
Tomaszewski
Anke
A
Universität Duisburg-Essen, Universitätsklinik, Institut für Physiologie, Hufelandstrasse 55, 45122 Essen, Germany.
Büsselberg
Dietrich
D
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001464:Barium / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects
D000970:Antineoplastic Agents; D015220:Calcium Channels; D024642:Potassium Channels, Voltage-Gated; D015222:Sodium Channels; D001464:Barium; D002945:Cisplatin