Ketamine blockade of voltage-gated sodium channels: evidence for a shared receptor site with local anesthetics.
BACKGROUND
The general anesthetic ketamine is known to be an N-methyl-D-aspartate receptor blocker. Although ketamine also blocks voltage-gated sodium channels in a local anesthetic-like fashion, little information exists on the molecular pharmacology of this interaction. We measured the effects of ketamine on sodium channels.


METHODS
Wild-type and mutant (F1579A) recombinant rat skeletal muscle sodium channels were expressed in Xenopus oocytes. The F1579A amino acid substitution site is part of the intrapore local anesthetic receptor. The effect of ketamine was measured in oocytes expressing wild-type or mutant sodium channels using two-electrode voltage clamp.


RESULTS
Ketamine blocked sodium channels in a local anesthetic-like fashion, exhibiting tonic blockade (concentration for half-maximal inhibition [IC50] = 0.8 mm), phasic blockade (IC50 = 2.3 mm), and leftward shift of the steady-state inactivation; the parameters of these actions were strongly modified by alteration of the intrapore local anesthetic binding site (IC50 = 2.1 mm and IC50 = 10.3 mm for tonic and phasic blockade, respectively). Compared with lidocaine, ketamine showed greater tonic inhibition but less phasic blockade.


CONCLUSIONS
Ketamine interacts with sodium channels in a local anesthetic-like fashion, including sharing a binding site with commonly used clinical local anesthetics.
Wagner
L E
LE
Department of Anesthesiology, University of Rochester Medical Center, New York 14642, USA.
Gingrich
K J
KJ
Kulli
J C
JC
Yang
J
J
D000465:Algorithms; D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D000818:Animals; D015640:Ion Channel Gating / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics; D014981:Xenopus
D000778:Anesthetics, Dissociative; D011994:Recombinant Proteins; D015222:Sodium Channels; D007649:Ketamine