Effects of Isoflurane and propofol on glutamate and GABA transporters in isolated cortical nerve terminals

• Published in: Anesthesiology (Philadelphia) 2003-02, Vol.98 (2), p.364-372
• Main Authors: WESTPHALEN, Robert I, HEMMINGS, Hugh C
• Format: Article
• Language: English
• Subjects: Algorithms; Amino Acid Transport System X-AG - metabolism; Anesthetics, Inhalation - pharmacology; Anesthetics, Intravenous - pharmacology; Anesthetics. Neuromuscular blocking agents; Animals; Biological and medical sciences; Carrier Proteins - metabolism; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; GABA Plasma Membrane Transport Proteins; In Vitro Techniques; Isoflurane - pharmacology; Kinetics; Male; Medical sciences; Membrane Proteins - metabolism; Membrane Transport Proteins; Nerve Endings - drug effects; Nerve Endings - metabolism; Neuropharmacology; Organic Anion Transporters; Pharmacology. Drug treatments; Propofol - pharmacology; Rats; Rats, Sprague-Dawley; Synaptic Membranes - drug effects; Synaptic Membranes - metabolism; Synaptosomes - drug effects; Synaptosomes - metabolism
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/00000542-200302000-00016

Depression of glutamate-mediated excitatory transmission and potentiation of gamma-aminobutyric acid (GABA)-mediated inhibitory transmission appear to be primary mechanisms by which general anesthetics produce anesthesia. Since effects on transmitter transport have been implicated in anesthetic actions, the authors examined the sensitivity of presynaptic glutamate and GABA transporters to the effects of a representative volatile (isoflurane) and a representative intravenous (propofol) anesthetic. A dual-isotope (l-[3H]glutamate and [14C]GABA) approach allowed simultaneous comparisons of anesthetic effects on three independent assays of glutamate and GABA transporters in adult rat cerebral cortex: transmitter uptake into isolated nerve terminals (synaptosomes), transmitter binding to lysed and washed synaptosomes (synaptic membranes), and carrier-mediated release (reverse transport) of transmitter from preloaded synaptosomes using a modified superfusion system. Isoflurane produced small but statistically significant inhibition of l-[3H]glutamate and [14C]GABA uptake, while propofol had no effect. Inhibition of uptake by isoflurane was noncompetitive, an outcome that was mimicked by indirectly affecting transporter function through synaptosomal depolarization. Neither isoflurane nor propofol affected l-[3H]glutamate or [14C]GABA binding to synaptic membranes or Ca(2+)-independent carrier-mediated l-[3H]glutamate or [14C]GABA release (reverse transport). These findings suggest that isoflurane and propofol at clinical concentrations do not affect excitatory glutamatergic transmission or inhibitory GABAergic transmission directly effects on their presynaptic neuronal transporters.