Glycine receptor antagonism. Effects of ACEA-1021 on the minimum alveolar concentration for halothane in the rat.
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.
McFarlane, C; Warner, DS; Nader, A; Dexter, F
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