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Both dizocilpine (MK-801) and isoflurane antagonize glutamatergic neurotransmission. In this study, we examined the relative neuroprotective effects of these drugs administered in equianesthetic doses before the onset of focal cerebral ischemia. Rats were anesthetized with 1.0%-1.5% isoflurane and surgically prepared for filament occlusion of the middle cerebral artery (MCAO). After preparation, one group (n = 22) remained anesthetized with 0.7% isoflurane. Another group (n = 18) was given dizocilpine (1 mg/kg intraperitoneally), and isoflurane was discontinued. The third group (n = 18) was allowed to awaken immediately after the onset of ischemia. MCAO persisted for 75 min. Epidural temperature was controlled at 37.5[degree sign]C during ischemia and the first 22 h of recovery. A 7-day recovery interval was allowed. Total infarction volumes (mean +/- SD) were less for the dizocilpine group (100 +/- 65 mm3) versus the awake group (182 +/- 36 mm3; P = 0.001). Infarction volumes did not differ significantly between the isoflurane group (142 +/- 81 mm3) and either the dizocilpine (P = 0.11) or the awake group (P = 0.15). Isoflurane was examined at doses used clinically but smaller than those found to reduce N-methyl-D-aspartate (NMDA)-mediated injury in vitro. This study supports the hypothesis that NMDA receptor activation is injurious during focal ischemia and that amelioration of focal ischemic brain damage by NMDA receptor antagonists persists under normothermic conditions. Implications: Rats underwent focal cerebral ischemia with rigid maintenance of brain normothermia. The glutamate receptor antagonist dizocilpine was effective in reducing cerebral infarction size during persistent conditions of brain normothermia. In contrast, isoflurane administered at equianesthetic doses did not reduce infarction size. This study supports the hypothesis that N-methyl-D-aspartate receptor activation is injurious during focal ischemia and that amelioration of focal ischemic brain damage by N-methyl-D-aspartate receptor antagonists persists under normothermic conditions. (Anesth Analg 1998;87:72-8)

There is increasing evidence that pharmacologic antagonism of glutamatergic neurotransmission can potentiate the anesthetic effects of drugs such as halothane. The purpose of this study was to examine the anesthetic interaction between glutamate receptor antagonists. A competitive NMDA receptor antagonist (CGS 19755) and an AMPA receptor antagonist (NBQX) were administered either alone or in combination prior to determination of the minimum alveolar concentration (MAC) for halothane in the rat. CGS 19755 caused a dose-dependent maximum reduction in halothane MAC of approximately 80%. Doses of NBQX, which were low enough to cause no change in MAC when administered alone, substantially reduced MAC when administered with subanesthetic doses of CGS 19755. This effect decreased as the dose of CGS 19755 was increased. Finally, halothane MAC was reduced to zero when NBQX, in a dose sufficient to reduce halothane MAC by approximately 35% if given alone, was added to a pharmacodynamically similar dose of CGS 19755. Although MAC is believed to predominantly reflect nocioception at the spinal cord level, the results suggests that pharmacologic blockade of glutamatergic neurotransmission is sufficient to result in deep levels of anesthesia. Further, the effect of combinations of NMDA and AMPA receptor antagonists on halothane MAC is consistent with an in vivo physiologic interaction between the NMDA and AMPA receptors.

Background Glycine and glutamate binding sites are allosterically coupled at the N-methyl-D-aspartate (NMDA) receptor complex. Previous studies have shown that antagonism of glutamate at the NMDA receptor reduces the minimum alveolar concentration (MAC) for volatile anesthetics. 5-Nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA-1021) is a competitive antagonist at the glycine recognition site of the NMDA receptor. The purpose of this study was to determine whether glycine receptor antagonism also reduces volatile anesthetic requirements in the rat. Methods In experiment 1, Sprague-Dawley rats were anesthetized with halothane in 50% O2-balance N2 and their lungs mechanically ventilated. They were randomly assigned to one of three groups according to the dose of ACEA-1021 administered (0, 20, or 40 mg/kg intravenously; n = 6). The bolus dose of ACEA-1021 was followed by a continuous intravenous infusion of vehicle or ACEA-1021 at 14 mg.kg-1.h-1. Halothane MAC was then determined by the tail-clamp method. In experiment 2, awake rats were randomly assigned to groups according to the same dosages of ACEA-1021 as in experiment 1. Arterial CO2 tension and mean arterial pressure were recorded before and 5 and 30 min after the start of the infusion. The infusion was then stopped, and the time to recovery of the righting reflex was recorded. Results In experiment 1, ACEA-1021 decreased halothane MAC (mean +/- SD) in a dose-dependent manner (control, 0.95 +/- 0.15 vol%; ACEA-1021 20 mg/kg, 0.50 +/- 0.14 vol%; ACEA-1021 40 mg/kg, 0.14 +/- 0.16 vol%; P < 0.01). In experiment 2, arterial CO2 tension was increased by ACEA-1021 (control, 38 +/- 3 mmHg; ACEA-1021 20 mg/kg, 43 +/- 3 mmHg; ACEA-1021 40 mg/kg, 48 +/- 2 mmHg; P < 0.01). Mean arterial pressure was not affected by any dose of ACEA-1021. The righting reflex was abolished in rats receiving ACEA-1021 40 mg/kg only and recovered 30 +/- 7 min after discontinuation of the infusion. Conclusions Halothane MAC reduction by glycine receptor antagonism was greater than that previously observed for antagonism of glutamate at the NMDA or AMPA receptor. In rats receiving ACEA-1021 only, minimal hemodynamic depression and moderate hypoventilation were observed. Antagonism of glycine at the NMDA receptor recognition site offers a potential mechanism of action of anesthesia.

We tested the hypothesis that glutamate receptor antagonists increase the dose of lidocaine required to induce seizure activity. Sprague-Dawley rats were anesthetized with halothane in 40% O2/balance N2 and mechanically ventilated. After surgical preparation, halothane was discontinued. Normocapnia, normoxia, and normothermia were maintained. The electroencephalogram (EEG) and arterial blood pressure were monitored continuously. Rats were then randomized to one of six groups (control, one of three intravenous [i.v.] bolus doses of the competitive glutamate N-methyl-D-aspartate [NMDA] receptor antagonist CGS 19755, or one of two i.v. bolus and continuous infusion regimens of the competitive glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)quinoxalline [NBQX]). Thirty minutes after onset of CGS 19755 or NBQX administration (end-tidal halothane0.2%), rats received a continuous i.v. infusion of 1.5% lidocaine until EEG seizures occurred. The duration of the infusion (min) and total lidocaine dose (mg/kg) administered were recorded. CGS 19755 increased the lidocaine seizure threshold in a log-linear dose-dependent fashion (P10(-6)). The largest dose of CGS 19755 (112.5 mg/kg) increased the time to initial EEG seizure activity more than twofold (e.g., control = 12.6 +/- 2.6 min; CGS 19755 = 28.6 +/- 6.9 min). The effect of AMPA receptor antagonism was less obvious because treatment resulted in an EEG morphology dissimilar to that observed in the CGS 19755 or control groups. Our findings indicate that competitive NMDA receptor antagonists (e.g., CGS 19755) increase the dose of lidocaine required for seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Various subtypes of receptors have been identified for glutamate, an excitatory neurotransmitter. Previous studies have shown that antagonism of glutamate at the NMDA receptors reduces minimum alveolar concentration (MAC) for volatile anesthetics. NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline) is a selective antagonist at the glutamatergic AMPA receptor. The purpose of this experiment was to determine whether AMPA receptor antagonism influences halothane MAC in the rat. Sprague-Dawley rats were anesthetized with halothane in 50% O2/balance N2, tracheally intubated and the lungs were mechanically ventilated. Increasing doses of NBQX were intravenously infused in three groups while the control group was infused with vehicle (D5W). Halothane MAC was then determined by the tail-clamp method. Halothane MAC was log-linearly related to plasma NBQX concentrations (MAC = 0.125 (In plasma concentration NBQX) + 1.035, r2 = 0.77). A maximal 58% reduction of halothane MAC was achieved with an NBQX loading dose of 42 mg/kg followed by a continuous infusion rate of 36 mg x kg-1 x h-1 (control = 1.02 +/- 0.07%; NBQX = 0.43 +/- 0.12%; P.01). Larger doses of NBQX were not possible because of the poor aqueous solubility of this compound. In a separate experiment, awake rats were randomly assigned to groups based on the dose of NBQX infused. Pa(CO2) and mean arterial pressure were measured at time 0 and at 5 and 30 min after start of NBQX infusion. The infusion was then stopped. Time until recovery of the righting reflex was recorded.(ABSTRACT TRUNCATED AT 250 WORDS)