Does anesthetic additivity imply a similar molecular mechanism of anesthetic action at N-Methyl-D-aspartate receptors?

Robert J Brosnan, Trung L. Pham

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Background: Isoflurane and carbon dioxide (CO2) negatively modulate N-methyl-D-aspartate (NMDA) receptors, but via different mechanisms. Isoflurane is a competitive antagonist at the NMDA receptor glycine binding site, whereas CO2 inhibits NMDA receptor current through extracellular acidification. Isoflurane and CO2 exhibit additive minimum alveolar concentration effects in rats, but we hypothesized that they would not additively inhibit NMDA receptor currents in vitro because they act at different molecular sites. Methods: NMDA receptors were expressed in frog oocytes and studied using 2-electrode voltage clamp techniques. A glycine concentration response for NMDA was measured in the presence and absence of CO2. Concentration-response curves for isoflurane, H, CO2, and ketamine as a function of NMDA inhibition were measured, and a Hill equation was used to calculate the EC50 for each compound. Results: Binary drug combinations containing 1/2 EC50 were additive if NMDA current inhibition was not statistically different from 50%. The 1/2 EC 50 binary drug combinations decreased the percentage baseline NMDA receptor current as follows (mean ± SD, n = 5 to 6 oocytes each): CO 2 + H (51% ± 5%), CO2 + isoflurane (54% ± 5%), H+ isoflurane (51% ± 3%), CO2 + ketamine (67% ± 8%), and H+ ketamine (64% ± 2%). Conclusions: In contrast to our hypothesis, NMDA receptor inhibition by CO2 and isoflurane is additive. Possibly, CO2 acidification modulates a pH-sensitive loop on the NMDA receptor that in turn alters glycine binding affinity on the GluN1 subunit. However, ketamine plus either CO2 or H synergistically inhibits NMDA receptor currents. Drugs acting via different mechanisms can thus exhibit additive or synergistic receptor effects. Additivity may not robustly indicate commonality between molecular anesthetic mechanisms.

Original languageEnglish (US)
Pages (from-to)568-573
Number of pages6
JournalAnesthesia and Analgesia
Issue number3
StatePublished - Mar 2011

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine


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