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ANESTHETIC PHARMACOLOGY

Modulation of NMDA Receptor Function by Ketamine and Magnesium. Part II: Interactions with Volatile Anesthetics

Markus W. Hollmann, MD, Hong-Tao Liu, MD, Christian W. Hoenemann, MD, Wei-Hua Liu, MD, and Marcel E. Durieux, MD, PhD^*

*Department of Anesthesiology and Pain Management, University Hospital Maastricht, Maastricht, The Netherlands; Department of Anesthesiology, University of Virginia, Charlottesville, Virginia; Department of Anesthesiology and Intensive Care, University of Muenster, Muenster; and Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany

Address correspondence and reprint requests to Marcel E. Durieux, MD, PhD, Department of Anesthesiology and Pain Management, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Address e-mail to mdu{at}sane.azm.nl

Mg²⁺ and ketamine interact superadditively at N- methyl-D-aspartate (NMDA) receptors, which may explain the clinical efficacy of the combination. Because patients are usually exposed concomitantly to volatile anesthetics, we tested the hypothesis that volatile anesthetics interact with ketamine and/or Mg²⁺ at recombinantly expressed NMDA receptors. NR1/NR2A or NR1/NR2B receptors were expressed in Xenopus oocytes. We determined the effects of isoflurane, sevoflurane, and desflurane on NMDA receptor signaling, alone and in combination with S(+)-ketamine (4.1 µM on NR1/NR2A, 3.0 µM on NR2/NR2B) and/or Mg²⁺ (416 µM on NR1/NR2A, 629 µM on NR1/NR2B). Volatile anesthetics inhibited NR1/NR2A and NR1/NR2B glutamate receptor function in a reversible, concentration-dependent, voltage-insensitive and noncompetitive manner (half-maximal inhibitory concentration at NR1/NR2A receptors: 1.30 ± 0.02 minimum alveolar anesthetic concentration [MAC] for isoflurane, 1.18 ± 0.03 MAC for desflurane, 1.24 ± 0.06 MAC for sevoflurane; at NR1/NR2B receptors: 1.33 ± 0.12 MAC for isoflurane, 1.22 ± 0.08 MAC for desflurane, and 1.28 ± 0.08 MAC for sevoflurane). On both NR1/NR2A and NR1/NR2B receptors, 50% inhibitory concentration for volatile anesthetics was reduced approximately 20% by Mg²⁺, approximately 30% by S(+)-ketamine, and approximately 50% by the compounds in combination. Volatile anesthetic effects on NMDA receptors can be potentiated significantly by Mg²⁺, S(+)-ketamine, or—most profoundly—both. Therefore, the analgesic effects of ketamine and Mg²⁺ are likely to be enhanced in the presence of volatile anesthetics.

Implications: Clinically relevant concentrations of volatile anesthetics inhibit functioning of N-methyl-D-aspartate receptors expressed recombinantly in Xenopus oocytes. This inhibition is reversible, concentration-dependent and voltage-insensitive, and results from noncompetitive antagonism of glutamate/glycine signaling. In addition, these effects can be potentiated significantly by co-application of either Mg²⁺, S(+)-ketamine, or—most profoundly—both.

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