Neuroprotective doses of N-methyl-D-aspartate receptor antagonists profoundly reduce the minimum alveolar anesthetic concentration (MAC) for isoflurane in rats

N-methyl-D-aspartate (NMDA) receptor antagonists, which block one of the glutamate receptors, have provided evidence of cerebral protection in animal models of focal cerebral ischemia. We examined the effect of neuroprotective doses of one noncompetitive (dizocilpine) and two competitive (D-CPP-ene, CGS 19755) NMDA antagonists on the minimum alveolar anesthetic concentration (MAC) of isoflurane in rats. A single bolus injection of any of the three NMDA antagonists produced a significant (P < 0.01) and sustained (>3 h) decrease in the MAC of isoflurane. Dizocilpine decreased MAC by 33%-38% at a dose of 0.15 mg/kg and 48%-54% at a dose of 0.5 mg/kg. D-CPP-ene decreased MAC by 32%-37% at a dose of 1.5 mg/kg and 39%-45% at a dose of 4.5 mg/kg. CGS 19755 decreased MAC by 19%-24% at a dose of 3 mg/kg and 49%-58% at a dose of 10 mg/kg. Dizocilpine, but not the competitive antagonists, produced a small transient decrease in mean arterial blood pressure. The sustained anesthetic potency of neuroprotective doses of NMDA antagonists supports the idea that glutaminergic receptor activity is involved in determining the anesthetic state.