Le. Wagner et al., Ketamine blockade of voltage-gated sodium channels - Evidence for a sharedreceptor site with local anesthetics, ANESTHESIOL, 95(6), 2001, pp. 1406-1413
Citations number
34
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Aneshtesia & Intensive Care","Medical Research Diagnosis & Treatment
Background: The general anesthetic ketamine is known to be an N-methyl-D-as
partate receptor blocker. Although ketamine also blocks voltage-gated sodiu
m 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 sodi
um channels were expressed in Xenopus oocytes. The F1579A amino acid substi
tution site is part of the intrapore local anesthetic receptor. The effect
of ketamine was measured in oocytes expressing wild-type or mutant sodium c
hannels using two-electrode voltage clamp.
Results: Ketamine blocked sodium channels in a local anesthetic-like fashio
n, exhibiting tonic blockade (concentration for half-maximal inhibition [IC
50] = 0.8 mM), phasic blockade (IC50 = 2.3 mm), and leftward shift of the s
teady-state inactivation; the parameters of these actions were strongly mod
ified by alteration of the intrapore local anesthetic binding site (IC50 =
2.1 nim and IC50 = 10.3 mM for tonic and phasic blockade, respectively). Co
mpared with lidocaine, ketamine showed greater tonic inhibition but less ph
asic blockade.
Conclusions: Ketamine interacts with sodium channels in a local anesthetic-
like fashion, including sharing a binding site with commonly used clinical
local anesthetics.