Lidocaine and octanol have different modes of action at tetrodotoxin-resistant Na(+) channels of peripheral nerves.
Local anesthetics and alcohols block impulse conduction in peripheral nerves by inhibiting Na(+) currents. In small peripheral nerve fibers, tetrodotoxin-resistant (TTX-r) Na(+) channels play an important role in impulse generation. We investigated the effects of lidocaine and the alcohol octanol on TTX-r Na(+) channels. Currents were recorded with the whole-cell patch-clamp method from enzymatically isolated rat dorsal root ganglion cells (data evaluation: nonlinear least-squares fitting). Lidocaine and octanol blocked the TTX-r Na(+) current in a reversible and concentration-dependent manner (50% inhibitory concentration values: 177 +/- 25 and 455 +/- 25 microM, respectively). Lidocaine additionally produced a strong use-dependent block. Both drugs showed a strong dynamic block (i.e., block developed during the time course of current activation and inactivation). Double-pulse protocols showed a slow dissociation of lidocaine from the channel during repolarization (time constant: 1763 +/- 63 ms; 300 microM). The dissociation of octanol was too quick to be distinguished from normal current repriming kinetics of 2.2 ms. Lidocaine and octanol acted noncompetitively in the Na(+) channel. Lidocaine and octanol have different blocking properties on the TTX-r Na(+) current and bind to different channel sites.


CONCLUSIONS
Lidocaine and octanol have different inhibitory effects on the function of tetrodotoxin-resistant Na(+) channels in rat dorsal root ganglion cells, as well as noncompetitive modes of action, as investigated by the whole-cell patch-clamp method, and therefore are likely to have different binding sites on the channel.
*Department of Anesthesiology and Intensive Care Medicine, University Hospital Charité Campus Mitte, Humboldt University, Berlin, Germany; †Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital, Justus-Liebig-University, Giessen, Germany; and ‡Department of Physiology, Justus-Liebig-University, Giessen, Germany.
Deniz
D
Poyraz
Michael E
ME
Bräu
Friederike
F
Wotka
Birgit
B
Puhlmann
Andreas M
AM
Scholz
Gunter
G
Hempelmann
Wolfgang J
WJ
Kox
Claudia D
CD
Spies
D020003:1-Octanol / Q000494:pharmacology*; D000465:Algorithms; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D004594:Electrophysiology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D007700:Kinetics; D008012:Lidocaine / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010525:Peripheral Nerves / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology*
D000779:Anesthetics, Local; D015222:Sodium Channels; D013779:Tetrodotoxin; D008012:Lidocaine; D020003:1-Octanol