Blocking mechanisms of ketamine and its enantiomers in enzymatically demyelinated peripheral nerve as revealed by single-channel experiments

• Published in: Anesthesiology (Philadelphia) Vol. 86; no. 2; pp. 394 - 404
• Main Authors: BRÄU, M. E, SANDER, F, VOGEL, W, HEMPELMANN, G
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott 01.02.1997
• Subjects: Anesthetics, Dissociative - pharmacology; Anesthetics. Neuromuscular blocking agents; Animals; Biological and medical sciences; Ketamine - pharmacology; Medical sciences; Membrane Potentials - drug effects; Neuropharmacology; Peripheral Nerves - drug effects; Peripheral Nerves - physiology; Pharmacology. Drug treatments; Potassium Channel Blockers; Sodium Channel Blockers; Stereoisomerism; Xenopus laevis; Local anesthetic; Stereoselectivity; Peripheral nerve; Ketamine; Potassium ion; Enantiomer; Sodium ion; Ionic channel; Ionic current; Mechanism of action; In vitro; Sciatic nerve
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/00000542-199702000-00014

Ketamine shows, besides its general anesthetic effect, a local anesthetic-like action that is due to blocking of peripheral nerve sodium currents. In this study, the stereoselectivity of the blocking effects of the ketamine enantiomers S(+) and R(-) was investigated in sodium and potassium channels in peripheral nerve membranes. Ion channel blockade of ketamine was investigated in enzymatically dissociated Xenopus sciatic nerves in multiple-channel and in single-channel outside-out patches. Concentration-effect curves for the Na+ peak current revealed half-maximal inhibiting concentrations (IC50) of 347 microM and 291 microM for S(+) and R(-) ketamine, respectively. The potential-dependent K+ current was less sensitive than the Na+ current with IC50 values of 982 microM and 942 microM. The most sensitive ion channel was the flickering background K+ channel, with IC50 values of 168 microM and 146 microM for S(+) and R(-) ketamine. Competition experiments suggest one binding site at the flicker K+ channel, with specific binding affinities for each of the enantiomers. For the Na+ channel, the block was weaker in acidic (pH = 6.6) than in neutral (pH = 7.4) and basic (pH = 8.2) solutions; for the flicker K+ channel, the block was weaker in acidic and stronger in basic solutions. Ketamine blockade of sodium and potassium channels in peripheral nerve membranes shows no stereoselectivity except for the flicker K+ channel, which showed a very weak stereoselectivity in favor of the R(-) form. This potential-insensitive flicker K+ channel may contribute to the resting potential. Block of this channel and subsequent depolarization of the resting membrane potential leads, besides to direct Na+ channel block, to inexcitability via Na+ channel inactivation.