Volatile anesthetics inhibit NMDA-stimulated 45Ca uptake by rat brain microvesicles.

We have previously shown that volatile anesthetics inhibit glutamate-stimulated [3H]MK-801 binding to the ionophore of NMDA receptor complexes in rat brain. In the present study, we examined the influence of enflurane and halothane on NMDA-stimulated 45Ca uptake by a microvesicle fraction isolated from rat brain. NMDA stimulated 45Ca uptake (30 sec) by rat brain microvesicles by up to 70% with an EC50 of 1.4 +/- 0.5 microM. The NMDA-stimulated 45Ca uptake was inhibited by MK-801 and D-AP-5 with IC50's of approximately 10 microM. Enflurane and halothane inhibited 45Ca uptake stimulated by 100 microM NMDA by as much as 60-80% with IC50's of 0.2-0.3 mM, concentrations achieved during routine clinical use. Basal 45Ca uptake measured in the absence of agonist was not affected by the anesthetics. Glycine did not affect the level of NMDA-stimulated 45Ca uptake, but markedly reduced the inhibition of uptake caused by enflurane and halothane. Preincubation of microvesicles with NMDA resulted in a desensitization of NMDA-stimulated 45Ca uptake, with a t1/2 of approximately 20 sec. Enflurane and halothane diminished both the extent and rate of development of this desensitization, as did glycine. These findings support the idea that volatile anesthetic interference with neurotransmission at NMDA receptor complexes contributes to the development of the anesthetic state.